Genitourinary Cancer

Intermittent androgen deprivation was not associated with inferior survival for men with a rising prostate-specific antigen level after definitive radiotherapy in a study reported in the Sept. 6 issue of the New England Journal of Medicine.

The findings from the phase III National Cancer Institute of Canada (NCIC) Clinical Trials Group study appear to conflict with those of another international phase III clinical trial reported in June at the annual meeting of the American Society of Clinical Oncology, and as such may fuel rather than extinguish the longstanding debate regarding the proper use and timing of endocrine therapy with androgen antagonists.

In the NCIC trial, 696 of 1,386 men with a PSA level greater than 3 ng/mL more than 1 year after primary or salvage radiotherapy for localized prostate cancer were randomized to continuous androgen suppression therapy consisting of a luteinizing hormone–releasing hormone agonist (LHRHa), combined with a minimum of 4 weeks of a nonsteroidal antiandrogen, or orchiectomy.

Another 690 men were randomized to intermittent androgen deprivation in 8-month cycles, with periods of nontreatment determined by PSA level. Each treatment cycle for the latter group began with the administration of LHRHa injections combined with a nonsteroidal antiandrogen for a minimum of 4 weeks and ended after 8 months if there was no evidence of clinical disease progression and if the patient’s PSA level was less than 4 ng/mL and not more than 1 ng/mL above the previous recorded value.

"During the treatment interval, the PSA level was monitored every 2 months until it reached 10 ng/mL, provided there was no intervening evidence of disease progression," stated lead investigator Dr. Juanita M. Crook of the British Columbia Cancer Agency, Kelowna, and her colleagues. (N. Engl. J. Med. 2012;367:895-903).

Overall survival was the primary end point of the study, and time to castration-resistant disease and quality of life were secondary end points, the authors wrote. Duration of off-treatment intervals, time to testosterone recovery, and time to potency recovery were additional end points for patients randomized to intermittent therapy.

At a median follow-up of 6.9 years, 524 patients had died, including 268 in the intermittent group and 256 in the continuous group, the authors reported. Median overall survival in both arms was statistically similar, at 8.8 years in the intermittent group and 9.1 years in the continuous therapy group.

"The hazard ratio for death with intermittent therapy versus continuous therapy was 1.02," the authors wrote, and the P value for noninferiority, at.009, supported the investigators’ initial hypothesis that intermittent therapy was not inferior to continuous therapy. A nonsignificant increase in deaths from other causes was observed in the continuous therapy group.

Because most of the deaths (59%) were unrelated to prostate cancer, the investigators retrospectively analyzed disease-specific survival "to determine whether a significant difference in treatment effect was obscured by the data on deaths from causes other than prostate cancer," they said. The estimated disease-specific hazard ratio after adjustment for stratification and confounding factors was 1.23, and the estimated 7-year cumulative disease-related death rates were 18% and 15%, respectively, for the intermittent and continuous groups.

With respect to time to castration-resistant disease, based on a Cox regression analysis adjusted for stratification and prognostic factors, the estimated hazard ratio for intermittent versus continuous therapy was 0.81, the authors reported, noting, however, that the study design contributed to a bias "by an unknown magnitude" against continuous androgen-deprivation therapy.

"For patients in the intermittent-therapy group, there was an inherent delay in the identification of castration-resistant disease, because treatment had to be restarted in these patients and they had to have a ‘castrate-range’ testosterone level and an additional three increases in the PSA level before being classified as having castration-resistant disease," the investigators wrote.

In quality of life measures, the intermittent therapy group had nonsignificantly better scores for functional domains (physical, role, and global health) and significantly better scores for symptoms, including hot flashes, desire for sexual activity, and urinary symptoms, the authors reported. Full testosterone recovery in the intermittent group occurred in 35% of the patients, while recovery to the trial entry threshold occurred in 79%, they said.

The authors concluded that their trial "raises provocative questions" and cautioned that their results "cannot be extrapolated to other intermittent-treatment schedules or disease characteristics."

The article did not address the apparent contradiction between the NCIC trial results and the findings of the Southwest Oncology Group (SWOG) 9346 trial reported earlier in the year at the ASCO annual meeting.

The latter trial randomized 3,040 patients with newly diagnosed hormone-sensitive metastatic prostate cancer with a PSA level of at least 5 ng/mL before androgen deprivation and a SWOG performance status of 0-2 to intermittent or continuous therapy. The investigators reported a 9% increase in the relative risk of death associated with intermittent therapy, which did not meet the prespecified criteria for noninferiority.

A secondary analysis of the SWOG 9346 data suggested that intermittent therapy was noninferior to continuous in patients with extensive disease but not minimal disease.

"The two studies targeted different populations," Dr. Crook said in an interview. "There are also some important differences in the way the results were handled in the statistical analysis. The results of the SWOG study are equivocal regarding survival."

"Our study has shown that men with only PSA evidence of recurrent prostate cancer and no evidence of metastatic disease can safely be treated with this intermittent program of androgen suppression to gain quality of life benefits without sacrificing length of life," she added.

"Our study did not address the optimal time to begin androgen ablation, or specifically how long intervention can be safely postponed."

The NCIC trial was supported by grants from the Canadian Cancer Society, the U.S. National Cancer Institute, and Hoeschst Marion Roussel Canada Research. Dr. Crook disclosed no relevant financial conflicts. Study coinvestigators disclosed financial relationships with numerous companies.

*This story was updated 9/6/2012.

Intermittent androgen deprivation was not associated with inferior survival for men with a rising prostate-specific antigen level after definitive radiotherapy in a study reported in the Sept. 6 issue of the New England Journal of Medicine.

The findings from the phase III National Cancer Institute of Canada (NCIC) Clinical Trials Group study appear to conflict with those of another international phase III clinical trial reported in June at the annual meeting of the American Society of Clinical Oncology, and as such may fuel rather than extinguish the longstanding debate regarding the proper use and timing of endocrine therapy with androgen antagonists.

In the NCIC trial, 696 of 1,386 men with a PSA level greater than 3 ng/mL more than 1 year after primary or salvage radiotherapy for localized prostate cancer were randomized to continuous androgen suppression therapy consisting of a luteinizing hormone–releasing hormone agonist (LHRHa), combined with a minimum of 4 weeks of a nonsteroidal antiandrogen, or orchiectomy.

Another 690 men were randomized to intermittent androgen deprivation in 8-month cycles, with periods of nontreatment determined by PSA level. Each treatment cycle for the latter group began with the administration of LHRHa injections combined with a nonsteroidal antiandrogen for a minimum of 4 weeks and ended after 8 months if there was no evidence of clinical disease progression and if the patient’s PSA level was less than 4 ng/mL and not more than 1 ng/mL above the previous recorded value.

"During the treatment interval, the PSA level was monitored every 2 months until it reached 10 ng/mL, provided there was no intervening evidence of disease progression," stated lead investigator Dr. Juanita M. Crook of the British Columbia Cancer Agency, Kelowna, and her colleagues. (N. Engl. J. Med. 2012;367:895-903).

Overall survival was the primary end point of the study, and time to castration-resistant disease and quality of life were secondary end points, the authors wrote. Duration of off-treatment intervals, time to testosterone recovery, and time to potency recovery were additional end points for patients randomized to intermittent therapy.

At a median follow-up of 6.9 years, 524 patients had died, including 268 in the intermittent group and 256 in the continuous group, the authors reported. Median overall survival in both arms was statistically similar, at 8.8 years in the intermittent group and 9.1 years in the continuous therapy group.

"The hazard ratio for death with intermittent therapy versus continuous therapy was 1.02," the authors wrote, and the P value for noninferiority, at.009, supported the investigators’ initial hypothesis that intermittent therapy was not inferior to continuous therapy. A nonsignificant increase in deaths from other causes was observed in the continuous therapy group.

Because most of the deaths (59%) were unrelated to prostate cancer, the investigators retrospectively analyzed disease-specific survival "to determine whether a significant difference in treatment effect was obscured by the data on deaths from causes other than prostate cancer," they said. The estimated disease-specific hazard ratio after adjustment for stratification and confounding factors was 1.23, and the estimated 7-year cumulative disease-related death rates were 18% and 15%, respectively, for the intermittent and continuous groups.

With respect to time to castration-resistant disease, based on a Cox regression analysis adjusted for stratification and prognostic factors, the estimated hazard ratio for intermittent versus continuous therapy was 0.81, the authors reported, noting, however, that the study design contributed to a bias "by an unknown magnitude" against continuous androgen-deprivation therapy.

"For patients in the intermittent-therapy group, there was an inherent delay in the identification of castration-resistant disease, because treatment had to be restarted in these patients and they had to have a ‘castrate-range’ testosterone level and an additional three increases in the PSA level before being classified as having castration-resistant disease," the investigators wrote.

In quality of life measures, the intermittent therapy group had nonsignificantly better scores for functional domains (physical, role, and global health) and significantly better scores for symptoms, including hot flashes, desire for sexual activity, and urinary symptoms, the authors reported. Full testosterone recovery in the intermittent group occurred in 35% of the patients, while recovery to the trial entry threshold occurred in 79%, they said.

The authors concluded that their trial "raises provocative questions" and cautioned that their results "cannot be extrapolated to other intermittent-treatment schedules or disease characteristics."

The article did not address the apparent contradiction between the NCIC trial results and the findings of the Southwest Oncology Group (SWOG) 9346 trial reported earlier in the year at the ASCO annual meeting.

The latter trial randomized 3,040 patients with newly diagnosed hormone-sensitive metastatic prostate cancer with a PSA level of at least 5 ng/mL before androgen deprivation and a SWOG performance status of 0-2 to intermittent or continuous therapy. The investigators reported a 9% increase in the relative risk of death associated with intermittent therapy, which did not meet the prespecified criteria for noninferiority.

A secondary analysis of the SWOG 9346 data suggested that intermittent therapy was noninferior to continuous in patients with extensive disease but not minimal disease.

"The two studies targeted different populations," Dr. Crook said in an interview. "There are also some important differences in the way the results were handled in the statistical analysis. The results of the SWOG study are equivocal regarding survival."

"Our study has shown that men with only PSA evidence of recurrent prostate cancer and no evidence of metastatic disease can safely be treated with this intermittent program of androgen suppression to gain quality of life benefits without sacrificing length of life," she added.

"Our study did not address the optimal time to begin androgen ablation, or specifically how long intervention can be safely postponed."

The NCIC trial was supported by grants from the Canadian Cancer Society, the U.S. National Cancer Institute, and Hoeschst Marion Roussel Canada Research. Dr. Crook disclosed no relevant financial conflicts. Study coinvestigators disclosed financial relationships with numerous companies.

*This story was updated 9/6/2012.

Intermittent androgen deprivation was not associated with inferior survival for men with a rising prostate-specific antigen level after definitive radiotherapy in a study reported in the Sept. 6 issue of the New England Journal of Medicine.

The findings from the phase III National Cancer Institute of Canada (NCIC) Clinical Trials Group study appear to conflict with those of another international phase III clinical trial reported in June at the annual meeting of the American Society of Clinical Oncology, and as such may fuel rather than extinguish the longstanding debate regarding the proper use and timing of endocrine therapy with androgen antagonists.

In the NCIC trial, 696 of 1,386 men with a PSA level greater than 3 ng/mL more than 1 year after primary or salvage radiotherapy for localized prostate cancer were randomized to continuous androgen suppression therapy consisting of a luteinizing hormone–releasing hormone agonist (LHRHa), combined with a minimum of 4 weeks of a nonsteroidal antiandrogen, or orchiectomy.

Another 690 men were randomized to intermittent androgen deprivation in 8-month cycles, with periods of nontreatment determined by PSA level. Each treatment cycle for the latter group began with the administration of LHRHa injections combined with a nonsteroidal antiandrogen for a minimum of 4 weeks and ended after 8 months if there was no evidence of clinical disease progression and if the patient’s PSA level was less than 4 ng/mL and not more than 1 ng/mL above the previous recorded value.

"During the treatment interval, the PSA level was monitored every 2 months until it reached 10 ng/mL, provided there was no intervening evidence of disease progression," stated lead investigator Dr. Juanita M. Crook of the British Columbia Cancer Agency, Kelowna, and her colleagues. (N. Engl. J. Med. 2012;367:895-903).

Overall survival was the primary end point of the study, and time to castration-resistant disease and quality of life were secondary end points, the authors wrote. Duration of off-treatment intervals, time to testosterone recovery, and time to potency recovery were additional end points for patients randomized to intermittent therapy.

At a median follow-up of 6.9 years, 524 patients had died, including 268 in the intermittent group and 256 in the continuous group, the authors reported. Median overall survival in both arms was statistically similar, at 8.8 years in the intermittent group and 9.1 years in the continuous therapy group.

"The hazard ratio for death with intermittent therapy versus continuous therapy was 1.02," the authors wrote, and the P value for noninferiority, at.009, supported the investigators’ initial hypothesis that intermittent therapy was not inferior to continuous therapy. A nonsignificant increase in deaths from other causes was observed in the continuous therapy group.

Because most of the deaths (59%) were unrelated to prostate cancer, the investigators retrospectively analyzed disease-specific survival "to determine whether a significant difference in treatment effect was obscured by the data on deaths from causes other than prostate cancer," they said. The estimated disease-specific hazard ratio after adjustment for stratification and confounding factors was 1.23, and the estimated 7-year cumulative disease-related death rates were 18% and 15%, respectively, for the intermittent and continuous groups.

With respect to time to castration-resistant disease, based on a Cox regression analysis adjusted for stratification and prognostic factors, the estimated hazard ratio for intermittent versus continuous therapy was 0.81, the authors reported, noting, however, that the study design contributed to a bias "by an unknown magnitude" against continuous androgen-deprivation therapy.

"For patients in the intermittent-therapy group, there was an inherent delay in the identification of castration-resistant disease, because treatment had to be restarted in these patients and they had to have a ‘castrate-range’ testosterone level and an additional three increases in the PSA level before being classified as having castration-resistant disease," the investigators wrote.

In quality of life measures, the intermittent therapy group had nonsignificantly better scores for functional domains (physical, role, and global health) and significantly better scores for symptoms, including hot flashes, desire for sexual activity, and urinary symptoms, the authors reported. Full testosterone recovery in the intermittent group occurred in 35% of the patients, while recovery to the trial entry threshold occurred in 79%, they said.

The authors concluded that their trial "raises provocative questions" and cautioned that their results "cannot be extrapolated to other intermittent-treatment schedules or disease characteristics."

The article did not address the apparent contradiction between the NCIC trial results and the findings of the Southwest Oncology Group (SWOG) 9346 trial reported earlier in the year at the ASCO annual meeting.

The latter trial randomized 3,040 patients with newly diagnosed hormone-sensitive metastatic prostate cancer with a PSA level of at least 5 ng/mL before androgen deprivation and a SWOG performance status of 0-2 to intermittent or continuous therapy. The investigators reported a 9% increase in the relative risk of death associated with intermittent therapy, which did not meet the prespecified criteria for noninferiority.

A secondary analysis of the SWOG 9346 data suggested that intermittent therapy was noninferior to continuous in patients with extensive disease but not minimal disease.

"The two studies targeted different populations," Dr. Crook said in an interview. "There are also some important differences in the way the results were handled in the statistical analysis. The results of the SWOG study are equivocal regarding survival."

"Our study has shown that men with only PSA evidence of recurrent prostate cancer and no evidence of metastatic disease can safely be treated with this intermittent program of androgen suppression to gain quality of life benefits without sacrificing length of life," she added.

"Our study did not address the optimal time to begin androgen ablation, or specifically how long intervention can be safely postponed."

The NCIC trial was supported by grants from the Canadian Cancer Society, the U.S. National Cancer Institute, and Hoeschst Marion Roussel Canada Research. Dr. Crook disclosed no relevant financial conflicts. Study coinvestigators disclosed financial relationships with numerous companies.

*This story was updated 9/6/2012.

Editor-in-chief Dr. David H. Henry takes you on an audio tour of the August issue of Community Oncology featuring a Community Translation: Abiraterone boosts survival in metastatic prostate cancer and a review on maintenance therapy in solid tumors.

Editor-in-chief Dr. David H. Henry takes you on an audio tour of the August issue of Community Oncology featuring a Community Translation: Abiraterone boosts survival in metastatic prostate cancer and a review on maintenance therapy in solid tumors.

Editor-in-chief Dr. David H. Henry takes you on an audio tour of the August issue of Community Oncology featuring a Community Translation: Abiraterone boosts survival in metastatic prostate cancer and a review on maintenance therapy in solid tumors.

Enzalutamide – an oral agent formerly known as MDV3100 – has won Food and Drug Administration approval as a second-line treatment for metastatic castration-resistant prostate cancer.

The new agent, to be marketed under the brand name Xtandi, is the latest in a stream of new therapies transforming treatment of prostate cancer. Other approvals within the last 3 years include the cancer vaccine sipuleucel-T (Provenge), abiraterone (Zytiga), cabazitaxel (Jevtana), and denosumab (Prolia, Xgeva) for bone-related indications.

Only the timing of the enzalutamide decision, announced Aug. 31 at the start of the Labor Day weekend, was a surprise. It came 3 months earlier than the Nov. 22 deadline set for FDA action under the agency’s priority review program.

"The need for additional treatment options for advanced prostate cancer continues to be important for patients. Xtandi is the latest treatment for this disease to demonstrate its ability to extend a patient’s life," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, said in the agency’s announcement.

Enzalutamide inhibits signaling by the androgen receptor. Approval is based on results of the randomized, double-blind, placebo-controlled AFFIRM trial, the results of which were published Aug. 15 online (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).

The new agent prolonged overall survival by a median of 4.8 months and reduced the risk of death by 37% in the study, which evaluated 1,199 patients with metastatic castration-resistant prostate cancer who had received prior treatment with docetaxel (Taxotere). Medium overall survival reached 18.4 months with enzalutamide vs. 13.6 months with placebo.

The FDA noted that about 1% of patients receiving enzalutamide had seizures and stopped therapy. The study had excluded patients with "a history of seizure, an underlying brain injury with loss of consciousness, a temporary decrease in blood to the brain within the past 12 months, a stroke, brain metastases, an abnormal connection of the arteries and veins in the brain, or patients taking medications that may lower the seizure threshold."

The announcement advised, "The safety of Xtandi is unknown in patients with these conditions."

Otherwise, the most common side effects listed by the FDA were "weakness or fatigue, back pain, diarrhea, joint pain, hot flush, tissue swelling, musculoskeletal pain, headache, upper respiratory infections, dizziness, spinal cord compression and cauda equina syndrome, muscular weakness, difficulty sleeping, lower respiratory infections, blood in urine, tingling sensation, anxiety, and high blood pressure."

Enzalutamide will be co-marketed by Astellas Pharma U.S., Inc. of Northbrook, Ill., and Medivation Inc. of San Francisco.

Enzalutamide – an oral agent formerly known as MDV3100 – has won Food and Drug Administration approval as a second-line treatment for metastatic castration-resistant prostate cancer.

The new agent, to be marketed under the brand name Xtandi, is the latest in a stream of new therapies transforming treatment of prostate cancer. Other approvals within the last 3 years include the cancer vaccine sipuleucel-T (Provenge), abiraterone (Zytiga), cabazitaxel (Jevtana), and denosumab (Prolia, Xgeva) for bone-related indications.

Only the timing of the enzalutamide decision, announced Aug. 31 at the start of the Labor Day weekend, was a surprise. It came 3 months earlier than the Nov. 22 deadline set for FDA action under the agency’s priority review program.

"The need for additional treatment options for advanced prostate cancer continues to be important for patients. Xtandi is the latest treatment for this disease to demonstrate its ability to extend a patient’s life," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, said in the agency’s announcement.

Enzalutamide inhibits signaling by the androgen receptor. Approval is based on results of the randomized, double-blind, placebo-controlled AFFIRM trial, the results of which were published Aug. 15 online (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).

The new agent prolonged overall survival by a median of 4.8 months and reduced the risk of death by 37% in the study, which evaluated 1,199 patients with metastatic castration-resistant prostate cancer who had received prior treatment with docetaxel (Taxotere). Medium overall survival reached 18.4 months with enzalutamide vs. 13.6 months with placebo.

The FDA noted that about 1% of patients receiving enzalutamide had seizures and stopped therapy. The study had excluded patients with "a history of seizure, an underlying brain injury with loss of consciousness, a temporary decrease in blood to the brain within the past 12 months, a stroke, brain metastases, an abnormal connection of the arteries and veins in the brain, or patients taking medications that may lower the seizure threshold."

The announcement advised, "The safety of Xtandi is unknown in patients with these conditions."

Otherwise, the most common side effects listed by the FDA were "weakness or fatigue, back pain, diarrhea, joint pain, hot flush, tissue swelling, musculoskeletal pain, headache, upper respiratory infections, dizziness, spinal cord compression and cauda equina syndrome, muscular weakness, difficulty sleeping, lower respiratory infections, blood in urine, tingling sensation, anxiety, and high blood pressure."

Enzalutamide will be co-marketed by Astellas Pharma U.S., Inc. of Northbrook, Ill., and Medivation Inc. of San Francisco.

Enzalutamide – an oral agent formerly known as MDV3100 – has won Food and Drug Administration approval as a second-line treatment for metastatic castration-resistant prostate cancer.

The new agent, to be marketed under the brand name Xtandi, is the latest in a stream of new therapies transforming treatment of prostate cancer. Other approvals within the last 3 years include the cancer vaccine sipuleucel-T (Provenge), abiraterone (Zytiga), cabazitaxel (Jevtana), and denosumab (Prolia, Xgeva) for bone-related indications.

Only the timing of the enzalutamide decision, announced Aug. 31 at the start of the Labor Day weekend, was a surprise. It came 3 months earlier than the Nov. 22 deadline set for FDA action under the agency’s priority review program.

"The need for additional treatment options for advanced prostate cancer continues to be important for patients. Xtandi is the latest treatment for this disease to demonstrate its ability to extend a patient’s life," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, said in the agency’s announcement.

Enzalutamide inhibits signaling by the androgen receptor. Approval is based on results of the randomized, double-blind, placebo-controlled AFFIRM trial, the results of which were published Aug. 15 online (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).

The new agent prolonged overall survival by a median of 4.8 months and reduced the risk of death by 37% in the study, which evaluated 1,199 patients with metastatic castration-resistant prostate cancer who had received prior treatment with docetaxel (Taxotere). Medium overall survival reached 18.4 months with enzalutamide vs. 13.6 months with placebo.

The FDA noted that about 1% of patients receiving enzalutamide had seizures and stopped therapy. The study had excluded patients with "a history of seizure, an underlying brain injury with loss of consciousness, a temporary decrease in blood to the brain within the past 12 months, a stroke, brain metastases, an abnormal connection of the arteries and veins in the brain, or patients taking medications that may lower the seizure threshold."

The announcement advised, "The safety of Xtandi is unknown in patients with these conditions."

Otherwise, the most common side effects listed by the FDA were "weakness or fatigue, back pain, diarrhea, joint pain, hot flush, tissue swelling, musculoskeletal pain, headache, upper respiratory infections, dizziness, spinal cord compression and cauda equina syndrome, muscular weakness, difficulty sleeping, lower respiratory infections, blood in urine, tingling sensation, anxiety, and high blood pressure."

Enzalutamide will be co-marketed by Astellas Pharma U.S., Inc. of Northbrook, Ill., and Medivation Inc. of San Francisco.

It only took a day.

On Aug. 16, seven-time Tour de France–winning cyclist Lance Armstrong became just cyclist Lance Armstrong by announcing he was giving up his fight to disprove doping charges leveled in what he contended was an unfair investigation by the U.S. Anti-Doping Agency.

By Aug. 17, on Amazon.com, the most recent reader review for "It’s Not About the Bike: My Journey Back to Life," Lance Armstrong’s inspirational story about recovering from metastatic testicular cancer, read, "It’s not about the bike, it’s about the EPO."

"Naive, but still heartbroken," posted one fan on San Francisco’s Storify social media website.

"Burned by another fraud masquerading as a hero," scoffed Yahoo sports columnist Les Carpenter.

Reader Tom Noll, posting a comment in response to a story in USA Today, wrote, "You are a disgrace to all competitive athletes, and will forever be synonymous with cheating, mr dopestrong."

But these were not cancer survivors, wearers of the yellow bracelet, participants in Armstrong’s fundraising rides, and in some cases, recipients of the largess of Armstrong’s nearly 15-year-old charity, which has grown to a staff of 88 and annual revenues of roughly $50 million.

For the most part, cancer survivors would hear none of it.

In the wake of Armstrong’s announcement, donations soared, according to the Lance Armstrong Foundation at livestrong.org (not to be confused with livestrong.com, the Armstrong-approved fitness and vitamin site that shares the name). In just one day, $174,000 poured in, compared with $3,000 on an average day at the Austin, Tex.–based headquarters.

Money wasn’t the only symbol of impassioned support for Armstrong. Survivors took to the airwaves, to Facebook, and to blogs to defend a hero who inspired them through their struggles with chemotherapy, radiation, despair, and frayed hopes and dreams.

In response to a friend’s Facebook posting, one wrote, "... You should side with Lance. As a person who’s had cancer ... winning any bicycle race, let alone the Tour de France 7, 7, 7 times ... I am so angry and upset by this that I think I need another day to respond. I am so saddened by our country’s need to build someone up and tear them down. This is sick behavior. I probably have the chemo present in MY blood after 7 years."

Came one response, "Even if he IS guilty, it looks like they were ALL doping."

Then, meekly, another, "I want to side with him too, but if someone were making false accusations about me, I would fight to the death."

Social psychologists have an array of explanations (backed up by confirmatory data) for why we, as human beings, hold even more tightly to our beliefs about people, once they are challenged. We also harbor favorable biases about celebrities of all sorts, and unconsciously believe that a person we admire for one trait (good looks, for example, or, ahem, undeniable athletic prowess) must also be smart and honorable.

In the case of cancer patients, who felt befriended by Armstrong and inspired by his amazing story, the loyalty will likely hold strong, which makes the specter of betrayal – if it is so – particularly sad.

Of course, I have no way of knowing that Lance Armstrong doped to win, but I did cringe at the recollection, in a scathing profile in February’s Outside Magazine, of a 2009 Nike ad featuring Armstrong saying, "They say I’m arrogant ... a doper ... washed up ... a fraud." Following images of cancer patients struggling to regain their strength, he adds, referring to his critics: "I’m not back on my bike for them."

The Outside piece’s central theme is that Armstrong’s money-making enterprises are fuzzily distinguished from his nonprofit foundation, which has ceased funding basic cancer research.

Fair enough, but the foundation does do genuine good, from offering financial counseling, clinical trial referrals, fertility preservation awareness, support for young adults and survivors of all ages, YMCA-linked exercise programs, anti-stigma campaigns, and psychosocial support to direct monetary support for patients.

It prides itself on spending 82 cents of every dollar on programs, and the website Charity Navigator gives it a rating of 63 points out of 70, 4 stars. (By way of comparison, the American Cancer Society receives 2.)

I do hope that cancer survivors don’t suffer in the long run, once the fireworks die down and sponsors quietly consider how closely they want to be tied to an athlete celebrity stripped of his ribbons and authenticity. Forbes.com reported that he personally stands to lose at least $7 million in prize money he must return and perhaps $50 million in product endorsements over time.

And that’s just the sports money.

It seems likely that charitable enthusiasm may wane as well, as the reality sets in that Lance Armstrong, the invincible hero, was always just a man, and one who many must conclude compromised his ethics (and ironically, the sanctity of his cancer-free body) to win.

Dr. Freed is a psychologist in Santa Barbara, Calif., and a medical journalist.

It only took a day.

On Aug. 16, seven-time Tour de France–winning cyclist Lance Armstrong became just cyclist Lance Armstrong by announcing he was giving up his fight to disprove doping charges leveled in what he contended was an unfair investigation by the U.S. Anti-Doping Agency.

By Aug. 17, on Amazon.com, the most recent reader review for "It’s Not About the Bike: My Journey Back to Life," Lance Armstrong’s inspirational story about recovering from metastatic testicular cancer, read, "It’s not about the bike, it’s about the EPO."

"Naive, but still heartbroken," posted one fan on San Francisco’s Storify social media website.

"Burned by another fraud masquerading as a hero," scoffed Yahoo sports columnist Les Carpenter.

Reader Tom Noll, posting a comment in response to a story in USA Today, wrote, "You are a disgrace to all competitive athletes, and will forever be synonymous with cheating, mr dopestrong."

But these were not cancer survivors, wearers of the yellow bracelet, participants in Armstrong’s fundraising rides, and in some cases, recipients of the largess of Armstrong’s nearly 15-year-old charity, which has grown to a staff of 88 and annual revenues of roughly $50 million.

For the most part, cancer survivors would hear none of it.

In the wake of Armstrong’s announcement, donations soared, according to the Lance Armstrong Foundation at livestrong.org (not to be confused with livestrong.com, the Armstrong-approved fitness and vitamin site that shares the name). In just one day, $174,000 poured in, compared with $3,000 on an average day at the Austin, Tex.–based headquarters.

Money wasn’t the only symbol of impassioned support for Armstrong. Survivors took to the airwaves, to Facebook, and to blogs to defend a hero who inspired them through their struggles with chemotherapy, radiation, despair, and frayed hopes and dreams.

In response to a friend’s Facebook posting, one wrote, "... You should side with Lance. As a person who’s had cancer ... winning any bicycle race, let alone the Tour de France 7, 7, 7 times ... I am so angry and upset by this that I think I need another day to respond. I am so saddened by our country’s need to build someone up and tear them down. This is sick behavior. I probably have the chemo present in MY blood after 7 years."

Came one response, "Even if he IS guilty, it looks like they were ALL doping."

Then, meekly, another, "I want to side with him too, but if someone were making false accusations about me, I would fight to the death."

Social psychologists have an array of explanations (backed up by confirmatory data) for why we, as human beings, hold even more tightly to our beliefs about people, once they are challenged. We also harbor favorable biases about celebrities of all sorts, and unconsciously believe that a person we admire for one trait (good looks, for example, or, ahem, undeniable athletic prowess) must also be smart and honorable.

In the case of cancer patients, who felt befriended by Armstrong and inspired by his amazing story, the loyalty will likely hold strong, which makes the specter of betrayal – if it is so – particularly sad.

Of course, I have no way of knowing that Lance Armstrong doped to win, but I did cringe at the recollection, in a scathing profile in February’s Outside Magazine, of a 2009 Nike ad featuring Armstrong saying, "They say I’m arrogant ... a doper ... washed up ... a fraud." Following images of cancer patients struggling to regain their strength, he adds, referring to his critics: "I’m not back on my bike for them."

The Outside piece’s central theme is that Armstrong’s money-making enterprises are fuzzily distinguished from his nonprofit foundation, which has ceased funding basic cancer research.

Fair enough, but the foundation does do genuine good, from offering financial counseling, clinical trial referrals, fertility preservation awareness, support for young adults and survivors of all ages, YMCA-linked exercise programs, anti-stigma campaigns, and psychosocial support to direct monetary support for patients.

It prides itself on spending 82 cents of every dollar on programs, and the website Charity Navigator gives it a rating of 63 points out of 70, 4 stars. (By way of comparison, the American Cancer Society receives 2.)

I do hope that cancer survivors don’t suffer in the long run, once the fireworks die down and sponsors quietly consider how closely they want to be tied to an athlete celebrity stripped of his ribbons and authenticity. Forbes.com reported that he personally stands to lose at least $7 million in prize money he must return and perhaps $50 million in product endorsements over time.

And that’s just the sports money.

It seems likely that charitable enthusiasm may wane as well, as the reality sets in that Lance Armstrong, the invincible hero, was always just a man, and one who many must conclude compromised his ethics (and ironically, the sanctity of his cancer-free body) to win.

Dr. Freed is a psychologist in Santa Barbara, Calif., and a medical journalist.

It only took a day.

On Aug. 16, seven-time Tour de France–winning cyclist Lance Armstrong became just cyclist Lance Armstrong by announcing he was giving up his fight to disprove doping charges leveled in what he contended was an unfair investigation by the U.S. Anti-Doping Agency.

By Aug. 17, on Amazon.com, the most recent reader review for "It’s Not About the Bike: My Journey Back to Life," Lance Armstrong’s inspirational story about recovering from metastatic testicular cancer, read, "It’s not about the bike, it’s about the EPO."

"Naive, but still heartbroken," posted one fan on San Francisco’s Storify social media website.

"Burned by another fraud masquerading as a hero," scoffed Yahoo sports columnist Les Carpenter.

Reader Tom Noll, posting a comment in response to a story in USA Today, wrote, "You are a disgrace to all competitive athletes, and will forever be synonymous with cheating, mr dopestrong."

But these were not cancer survivors, wearers of the yellow bracelet, participants in Armstrong’s fundraising rides, and in some cases, recipients of the largess of Armstrong’s nearly 15-year-old charity, which has grown to a staff of 88 and annual revenues of roughly $50 million.

For the most part, cancer survivors would hear none of it.

In the wake of Armstrong’s announcement, donations soared, according to the Lance Armstrong Foundation at livestrong.org (not to be confused with livestrong.com, the Armstrong-approved fitness and vitamin site that shares the name). In just one day, $174,000 poured in, compared with $3,000 on an average day at the Austin, Tex.–based headquarters.

Money wasn’t the only symbol of impassioned support for Armstrong. Survivors took to the airwaves, to Facebook, and to blogs to defend a hero who inspired them through their struggles with chemotherapy, radiation, despair, and frayed hopes and dreams.

In response to a friend’s Facebook posting, one wrote, "... You should side with Lance. As a person who’s had cancer ... winning any bicycle race, let alone the Tour de France 7, 7, 7 times ... I am so angry and upset by this that I think I need another day to respond. I am so saddened by our country’s need to build someone up and tear them down. This is sick behavior. I probably have the chemo present in MY blood after 7 years."

Came one response, "Even if he IS guilty, it looks like they were ALL doping."

Then, meekly, another, "I want to side with him too, but if someone were making false accusations about me, I would fight to the death."

Social psychologists have an array of explanations (backed up by confirmatory data) for why we, as human beings, hold even more tightly to our beliefs about people, once they are challenged. We also harbor favorable biases about celebrities of all sorts, and unconsciously believe that a person we admire for one trait (good looks, for example, or, ahem, undeniable athletic prowess) must also be smart and honorable.

In the case of cancer patients, who felt befriended by Armstrong and inspired by his amazing story, the loyalty will likely hold strong, which makes the specter of betrayal – if it is so – particularly sad.

Of course, I have no way of knowing that Lance Armstrong doped to win, but I did cringe at the recollection, in a scathing profile in February’s Outside Magazine, of a 2009 Nike ad featuring Armstrong saying, "They say I’m arrogant ... a doper ... washed up ... a fraud." Following images of cancer patients struggling to regain their strength, he adds, referring to his critics: "I’m not back on my bike for them."

The Outside piece’s central theme is that Armstrong’s money-making enterprises are fuzzily distinguished from his nonprofit foundation, which has ceased funding basic cancer research.

Fair enough, but the foundation does do genuine good, from offering financial counseling, clinical trial referrals, fertility preservation awareness, support for young adults and survivors of all ages, YMCA-linked exercise programs, anti-stigma campaigns, and psychosocial support to direct monetary support for patients.

It prides itself on spending 82 cents of every dollar on programs, and the website Charity Navigator gives it a rating of 63 points out of 70, 4 stars. (By way of comparison, the American Cancer Society receives 2.)

I do hope that cancer survivors don’t suffer in the long run, once the fireworks die down and sponsors quietly consider how closely they want to be tied to an athlete celebrity stripped of his ribbons and authenticity. Forbes.com reported that he personally stands to lose at least $7 million in prize money he must return and perhaps $50 million in product endorsements over time.

And that’s just the sports money.

It seems likely that charitable enthusiasm may wane as well, as the reality sets in that Lance Armstrong, the invincible hero, was always just a man, and one who many must conclude compromised his ethics (and ironically, the sanctity of his cancer-free body) to win.

Dr. Freed is a psychologist in Santa Barbara, Calif., and a medical journalist.

Dr. Chris Parker of Royal Marsden Hospital in London discusses the ALSYMPCA trial of radium-223 (Alpharadin), the first agent to improve prostate cancer survival by targeting bone metastases.

Dr. Chris Parker of Royal Marsden Hospital in London discusses the ALSYMPCA trial of radium-223 (Alpharadin), the first agent to improve prostate cancer survival by targeting bone metastases.

Dr. Chris Parker of Royal Marsden Hospital in London discusses the ALSYMPCA trial of radium-223 (Alpharadin), the first agent to improve prostate cancer survival by targeting bone metastases.

Pretreatment lactate dehydrogenase levels predict how well poor-risk patients with advanced kidney cancer respond to temsirolimus, according to a retrospective analysis of a phase-III trial.

If further studies confirm the finding, a low-cost blood test for the enzyme could make it the first biomarker for clinical prediction of kidney cancer patients’ response to a mammalian target of rapamycin (mTOR) inhibitor, such as temsirolimus (Torisel).

© Duke Medicine

"Being able to direct these patients to a treatment we know will help them would be a major advancement in their care," Dr. Andrew J. Armstrong of the Duke Cancer Institute, Durham, N.C, said in a written statement. "At the same time, patients who would not benefit from the treatment would be spared from undergoing a drug regimen with potential side effects that could diminish their quality of life."

Temsirolimus is approved for treatment of advanced kidney cancer. Alternatives to mTOR inhibition for this disease include cytokine therapy and agents targeting the vascular endothelial growth factor.

A widely expressed metabolic enzyme in tissues, lactate dehydrogenase (LDH) is a well-known prognostic biomarker in various types of cancers, including prostate cancer, lymphoma, melanoma, and renal cell carcinoma (RCC). Prognostic biomarkers help evaluate patient outcomes irrespective of treatment. No predictive biomarkers have been identified that can help select treatments for genitourinary malignancies, including RCC, Dr. Armstrong and his associates wrote in the Journal of Clinical Oncology.

The researchers used data from a phase-III randomized study (N. Engl. J. Med. 2007;356:2271-81) to compare 404 poor-risk patients with advanced RCC who were randomly assigned to temsirolimus (201 patients) or interferon alfa-2a (IFN-alpha) (203 patients). Overall survival rates among patients treated with temsirolimus were 53.7% at 6 months and 34.3% at 12 months, compared with 39.5% and 12.7 %, respectively, in the IFN-alpha group.

Stratifying patients by high LDH (defined as greater than 1 × the upper limit of normal [ULN]) and normal LDH (up to 1 × ULN), investigators calculated the multivariable hazard ratio for death was 2.81with high vs. normal LDH at baseline (P less than .001), they reported (J. Clin. Oncol. Aug. 13 [doi: 10.1200/JCO.2011.40.9631]).

The analysis showed that, within the high-LDH group, median overall survival was significantly longer in those treated with temsirolimus than in those treated with IFN-alpha (6.9 v. 4.2 months; HR=0.56; P less than .002.) Among patients with normal LDH, median overall survival was not significantly improved by temsirolimus, however (11.7 months vs. 10.4 months).

As secondary end points, the authors examined the predictive value of baseline LDH for progression-free survival and clinical benefit rate, but they found no predictive interaction.

Dr. Armstrong said in an interview that the study statistically proves that LDH is a predictive biomarker for advanced RCC, but the results have to be validated before major practice changes take place.

"The advantage of LDH as a predictive and prognostic biomarker rests in its ease of collection, cost, and its routine assessment as part of routine medical care in patients with RCC," the authors wrote.

The study has several limitations, they noted. For one, it was limited to poor-risk patients with RCC. Also, temsirolimus was only compared with IFN-alpha, which is no longer in widespread use. Also, the study was limited to temsirolimus, an mTOR/TORC1 inhibitor.

"Although other TORC1 inhibitors may have anticancer activity, it is unknown at this time whether LDH is predictive of improved outcomes with these agents," the authors wrote.

Dr. Armstrong has received honoraria and research funding from Pfizer, which makes temsirolimus and funded the study.

Pretreatment lactate dehydrogenase levels predict how well poor-risk patients with advanced kidney cancer respond to temsirolimus, according to a retrospective analysis of a phase-III trial.

If further studies confirm the finding, a low-cost blood test for the enzyme could make it the first biomarker for clinical prediction of kidney cancer patients’ response to a mammalian target of rapamycin (mTOR) inhibitor, such as temsirolimus (Torisel).

© Duke Medicine

"Being able to direct these patients to a treatment we know will help them would be a major advancement in their care," Dr. Andrew J. Armstrong of the Duke Cancer Institute, Durham, N.C, said in a written statement. "At the same time, patients who would not benefit from the treatment would be spared from undergoing a drug regimen with potential side effects that could diminish their quality of life."

Temsirolimus is approved for treatment of advanced kidney cancer. Alternatives to mTOR inhibition for this disease include cytokine therapy and agents targeting the vascular endothelial growth factor.

A widely expressed metabolic enzyme in tissues, lactate dehydrogenase (LDH) is a well-known prognostic biomarker in various types of cancers, including prostate cancer, lymphoma, melanoma, and renal cell carcinoma (RCC). Prognostic biomarkers help evaluate patient outcomes irrespective of treatment. No predictive biomarkers have been identified that can help select treatments for genitourinary malignancies, including RCC, Dr. Armstrong and his associates wrote in the Journal of Clinical Oncology.

The researchers used data from a phase-III randomized study (N. Engl. J. Med. 2007;356:2271-81) to compare 404 poor-risk patients with advanced RCC who were randomly assigned to temsirolimus (201 patients) or interferon alfa-2a (IFN-alpha) (203 patients). Overall survival rates among patients treated with temsirolimus were 53.7% at 6 months and 34.3% at 12 months, compared with 39.5% and 12.7 %, respectively, in the IFN-alpha group.

Stratifying patients by high LDH (defined as greater than 1 × the upper limit of normal [ULN]) and normal LDH (up to 1 × ULN), investigators calculated the multivariable hazard ratio for death was 2.81with high vs. normal LDH at baseline (P less than .001), they reported (J. Clin. Oncol. Aug. 13 [doi: 10.1200/JCO.2011.40.9631]).

The analysis showed that, within the high-LDH group, median overall survival was significantly longer in those treated with temsirolimus than in those treated with IFN-alpha (6.9 v. 4.2 months; HR=0.56; P less than .002.) Among patients with normal LDH, median overall survival was not significantly improved by temsirolimus, however (11.7 months vs. 10.4 months).

As secondary end points, the authors examined the predictive value of baseline LDH for progression-free survival and clinical benefit rate, but they found no predictive interaction.

Dr. Armstrong said in an interview that the study statistically proves that LDH is a predictive biomarker for advanced RCC, but the results have to be validated before major practice changes take place.

"The advantage of LDH as a predictive and prognostic biomarker rests in its ease of collection, cost, and its routine assessment as part of routine medical care in patients with RCC," the authors wrote.

The study has several limitations, they noted. For one, it was limited to poor-risk patients with RCC. Also, temsirolimus was only compared with IFN-alpha, which is no longer in widespread use. Also, the study was limited to temsirolimus, an mTOR/TORC1 inhibitor.

"Although other TORC1 inhibitors may have anticancer activity, it is unknown at this time whether LDH is predictive of improved outcomes with these agents," the authors wrote.

Dr. Armstrong has received honoraria and research funding from Pfizer, which makes temsirolimus and funded the study.

Pretreatment lactate dehydrogenase levels predict how well poor-risk patients with advanced kidney cancer respond to temsirolimus, according to a retrospective analysis of a phase-III trial.

If further studies confirm the finding, a low-cost blood test for the enzyme could make it the first biomarker for clinical prediction of kidney cancer patients’ response to a mammalian target of rapamycin (mTOR) inhibitor, such as temsirolimus (Torisel).

© Duke Medicine

"Being able to direct these patients to a treatment we know will help them would be a major advancement in their care," Dr. Andrew J. Armstrong of the Duke Cancer Institute, Durham, N.C, said in a written statement. "At the same time, patients who would not benefit from the treatment would be spared from undergoing a drug regimen with potential side effects that could diminish their quality of life."

Temsirolimus is approved for treatment of advanced kidney cancer. Alternatives to mTOR inhibition for this disease include cytokine therapy and agents targeting the vascular endothelial growth factor.

A widely expressed metabolic enzyme in tissues, lactate dehydrogenase (LDH) is a well-known prognostic biomarker in various types of cancers, including prostate cancer, lymphoma, melanoma, and renal cell carcinoma (RCC). Prognostic biomarkers help evaluate patient outcomes irrespective of treatment. No predictive biomarkers have been identified that can help select treatments for genitourinary malignancies, including RCC, Dr. Armstrong and his associates wrote in the Journal of Clinical Oncology.

The researchers used data from a phase-III randomized study (N. Engl. J. Med. 2007;356:2271-81) to compare 404 poor-risk patients with advanced RCC who were randomly assigned to temsirolimus (201 patients) or interferon alfa-2a (IFN-alpha) (203 patients). Overall survival rates among patients treated with temsirolimus were 53.7% at 6 months and 34.3% at 12 months, compared with 39.5% and 12.7 %, respectively, in the IFN-alpha group.

Stratifying patients by high LDH (defined as greater than 1 × the upper limit of normal [ULN]) and normal LDH (up to 1 × ULN), investigators calculated the multivariable hazard ratio for death was 2.81with high vs. normal LDH at baseline (P less than .001), they reported (J. Clin. Oncol. Aug. 13 [doi: 10.1200/JCO.2011.40.9631]).

The analysis showed that, within the high-LDH group, median overall survival was significantly longer in those treated with temsirolimus than in those treated with IFN-alpha (6.9 v. 4.2 months; HR=0.56; P less than .002.) Among patients with normal LDH, median overall survival was not significantly improved by temsirolimus, however (11.7 months vs. 10.4 months).

As secondary end points, the authors examined the predictive value of baseline LDH for progression-free survival and clinical benefit rate, but they found no predictive interaction.

Dr. Armstrong said in an interview that the study statistically proves that LDH is a predictive biomarker for advanced RCC, but the results have to be validated before major practice changes take place.

"The advantage of LDH as a predictive and prognostic biomarker rests in its ease of collection, cost, and its routine assessment as part of routine medical care in patients with RCC," the authors wrote.

The study has several limitations, they noted. For one, it was limited to poor-risk patients with RCC. Also, temsirolimus was only compared with IFN-alpha, which is no longer in widespread use. Also, the study was limited to temsirolimus, an mTOR/TORC1 inhibitor.

"Although other TORC1 inhibitors may have anticancer activity, it is unknown at this time whether LDH is predictive of improved outcomes with these agents," the authors wrote.

Dr. Armstrong has received honoraria and research funding from Pfizer, which makes temsirolimus and funded the study.

A new quality of life analysis adds fuel for both sides in the ongoing debate over benefit versus harm of routine PSA screening for prostate cancer in asymptomatic men, according to a report in the New England Journal of Medicine.

Researchers applied complex modeling to the European Randomized Study of Screening for Prostate Cancer (ERSPC), which reported screening cuts prostate cancer mortality by 29%. They agreed that screening saves lives but found that the benefit was undercut by long-term effects of overdiagnosis and overtreatment.

The new analysis calculates the ERSPC results in quality-adjusted life-years (QALYs), a measure the investigators based on health states ranging from "death or worst imaginable health" to full health and on treatment-related complications such as urinary incontinence, bowel dysfunction, and sexual dysfunction.

"Our model predicts that there would be nine fewer prostate cancer deaths and 73 life-years gained over the lifetime of 1,000 men who underwent annual screening between the ages of 55 and 69 years," write Dr. Eveline A.M. Heijnsdijk of Erasmus Medical Center, Rotterdam, the Netherlands, and her coauthors.

"The harms caused by the introduction of such screening would be the overdiagnosis and overtreatment of 45 cases and the loss of 1,134 life-years free of prostate cancer (i.e., lead-time years). After adjustment of the number of life-years gained from screening by consideration of quality-of-life effects, 56 QALYs would be gained, which is a 23% reduction from the predicted number of life-years gained."

Extending screening to men aged 74 years would increase the number of unadjusted life-years gained to 82, but QALYs would stay the same at 56, according to the authors (N. Engl. J. Med. 2012;367:595-605 [doi: 10.1056/NEJMoa1201637]).

"The predicted adjustment for quality of life is due to the long-term side effects from treatment. Men in whom cancer has been overdiagnosed and those in whom cancer has not been overdiagnosed will live many years with the adverse effects of treatment," they write.

The U.S. Preventive Services Task Force (USPSTF) set off a furor in May when it took a stand against PSA screening for prostate cancer in healthy men, arguing that the harms outweigh the benefits. Debate has centered on interpretation of data from the ERSPC trial (N. Engl. J. Med. 2012;366:981-90) and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (N. Engl. J. Med. 2009;360:1310-9), with proponents of universal screening arguing that it saves lives.

Dr. Heijnsdijk and her coauthors did not take a stand on screening, proposing instead that more long-term data are needed along with more research and more modeling to calculate cost-effectiveness.

"It is essential to await longer follow-up data from the ERSPC, as well as longer-term data on how treatment and active surveillance affect long-term quality of life, before more general recommendations can be made regarding mass PSA screening," they conclude.

The analysis was supported by grants from the Netherlands Organization for Health Research and Development, Europe Against Cancer, the European Union; agencies or health authorities in participating countries; and by unconditional grants from Beckman Coulter.

Dr. Heijnsdijk disclosed receiving consulting fees from Beckman Coulter and her coauthors reported relationships with various companies. Dr. Sox is a former chair of the U.S. Preventive Services Task Force and serves on the board of the Informed Medical Decisions Foundation, which makes decision aids for prostate cancer screening.

A new quality of life analysis adds fuel for both sides in the ongoing debate over benefit versus harm of routine PSA screening for prostate cancer in asymptomatic men, according to a report in the New England Journal of Medicine.

Researchers applied complex modeling to the European Randomized Study of Screening for Prostate Cancer (ERSPC), which reported screening cuts prostate cancer mortality by 29%. They agreed that screening saves lives but found that the benefit was undercut by long-term effects of overdiagnosis and overtreatment.

The new analysis calculates the ERSPC results in quality-adjusted life-years (QALYs), a measure the investigators based on health states ranging from "death or worst imaginable health" to full health and on treatment-related complications such as urinary incontinence, bowel dysfunction, and sexual dysfunction.

"Our model predicts that there would be nine fewer prostate cancer deaths and 73 life-years gained over the lifetime of 1,000 men who underwent annual screening between the ages of 55 and 69 years," write Dr. Eveline A.M. Heijnsdijk of Erasmus Medical Center, Rotterdam, the Netherlands, and her coauthors.

"The harms caused by the introduction of such screening would be the overdiagnosis and overtreatment of 45 cases and the loss of 1,134 life-years free of prostate cancer (i.e., lead-time years). After adjustment of the number of life-years gained from screening by consideration of quality-of-life effects, 56 QALYs would be gained, which is a 23% reduction from the predicted number of life-years gained."

Extending screening to men aged 74 years would increase the number of unadjusted life-years gained to 82, but QALYs would stay the same at 56, according to the authors (N. Engl. J. Med. 2012;367:595-605 [doi: 10.1056/NEJMoa1201637]).

"The predicted adjustment for quality of life is due to the long-term side effects from treatment. Men in whom cancer has been overdiagnosed and those in whom cancer has not been overdiagnosed will live many years with the adverse effects of treatment," they write.

The U.S. Preventive Services Task Force (USPSTF) set off a furor in May when it took a stand against PSA screening for prostate cancer in healthy men, arguing that the harms outweigh the benefits. Debate has centered on interpretation of data from the ERSPC trial (N. Engl. J. Med. 2012;366:981-90) and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (N. Engl. J. Med. 2009;360:1310-9), with proponents of universal screening arguing that it saves lives.

Dr. Heijnsdijk and her coauthors did not take a stand on screening, proposing instead that more long-term data are needed along with more research and more modeling to calculate cost-effectiveness.

"It is essential to await longer follow-up data from the ERSPC, as well as longer-term data on how treatment and active surveillance affect long-term quality of life, before more general recommendations can be made regarding mass PSA screening," they conclude.

The analysis was supported by grants from the Netherlands Organization for Health Research and Development, Europe Against Cancer, the European Union; agencies or health authorities in participating countries; and by unconditional grants from Beckman Coulter.

Dr. Heijnsdijk disclosed receiving consulting fees from Beckman Coulter and her coauthors reported relationships with various companies. Dr. Sox is a former chair of the U.S. Preventive Services Task Force and serves on the board of the Informed Medical Decisions Foundation, which makes decision aids for prostate cancer screening.

A new quality of life analysis adds fuel for both sides in the ongoing debate over benefit versus harm of routine PSA screening for prostate cancer in asymptomatic men, according to a report in the New England Journal of Medicine.

Researchers applied complex modeling to the European Randomized Study of Screening for Prostate Cancer (ERSPC), which reported screening cuts prostate cancer mortality by 29%. They agreed that screening saves lives but found that the benefit was undercut by long-term effects of overdiagnosis and overtreatment.

The new analysis calculates the ERSPC results in quality-adjusted life-years (QALYs), a measure the investigators based on health states ranging from "death or worst imaginable health" to full health and on treatment-related complications such as urinary incontinence, bowel dysfunction, and sexual dysfunction.

"Our model predicts that there would be nine fewer prostate cancer deaths and 73 life-years gained over the lifetime of 1,000 men who underwent annual screening between the ages of 55 and 69 years," write Dr. Eveline A.M. Heijnsdijk of Erasmus Medical Center, Rotterdam, the Netherlands, and her coauthors.

"The harms caused by the introduction of such screening would be the overdiagnosis and overtreatment of 45 cases and the loss of 1,134 life-years free of prostate cancer (i.e., lead-time years). After adjustment of the number of life-years gained from screening by consideration of quality-of-life effects, 56 QALYs would be gained, which is a 23% reduction from the predicted number of life-years gained."

Extending screening to men aged 74 years would increase the number of unadjusted life-years gained to 82, but QALYs would stay the same at 56, according to the authors (N. Engl. J. Med. 2012;367:595-605 [doi: 10.1056/NEJMoa1201637]).

"The predicted adjustment for quality of life is due to the long-term side effects from treatment. Men in whom cancer has been overdiagnosed and those in whom cancer has not been overdiagnosed will live many years with the adverse effects of treatment," they write.

The U.S. Preventive Services Task Force (USPSTF) set off a furor in May when it took a stand against PSA screening for prostate cancer in healthy men, arguing that the harms outweigh the benefits. Debate has centered on interpretation of data from the ERSPC trial (N. Engl. J. Med. 2012;366:981-90) and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (N. Engl. J. Med. 2009;360:1310-9), with proponents of universal screening arguing that it saves lives.

Dr. Heijnsdijk and her coauthors did not take a stand on screening, proposing instead that more long-term data are needed along with more research and more modeling to calculate cost-effectiveness.

"It is essential to await longer follow-up data from the ERSPC, as well as longer-term data on how treatment and active surveillance affect long-term quality of life, before more general recommendations can be made regarding mass PSA screening," they conclude.

The analysis was supported by grants from the Netherlands Organization for Health Research and Development, Europe Against Cancer, the European Union; agencies or health authorities in participating countries; and by unconditional grants from Beckman Coulter.

Dr. Heijnsdijk disclosed receiving consulting fees from Beckman Coulter and her coauthors reported relationships with various companies. Dr. Sox is a former chair of the U.S. Preventive Services Task Force and serves on the board of the Informed Medical Decisions Foundation, which makes decision aids for prostate cancer screening.

HOUSTON  – An experimental drug significantly improved physical function in men with cancer-related muscle wasting, compared with placebo – and more so in the men with low testosterone levels – in a secondary analysis of a randomized, double-blind, phase II clinical trial.

In all, 60% of the 93 men for whom baseline testosterone levels were available had hypogonadism when the patients were randomized to treatment with daily placebo or 1 mg or 3 mg of enobosarm for 16 weeks. Before treatment, the eugonadal males showed significantly better physical function, as measured by stair-climb power, compared with the hypogonadal patients (174 W vs. 147 W). Lower testosterone levels correlated with lower physical function.

Enobosarm significantly improved physical function (a secondary end point in the trial) with an average 17% increase in stair-climb power in hypogonadal men, and a 12% increase in power in eugonadal men, compared with baseline, Dr. Adrian Dobs and her associates reported at the annual meeting of the Endocrine Society.

Among men on placebo, stair-climb power increased by about 10% in hypogonadal men and by roughly 1% in eugonadal men, compared with baseline, but the changes were not statistically significant, said Dr. Dobs, professor of medicine and oncology at Johns Hopkins University, Baltimore.

Adverse events included fatigue in 21% of both treatment groups, anemia in 19% of those on enobosarm and 15% in those on placebo, nausea in 18% on enobosarm and 14% on placebo, diarrhea in 16% on enobosarm and 14% on placebo, vomiting in 12% of each treatment group, weight decrease in 12% on enobosarm and 10% on placebo, and constipation in 14% on enobosarm and 4% on placebo.

The investigators defined hypogonadism as a testosterone level below 300 ng/dL.

Enobosarm is a nonsteroidal SARM (selective androgen receptor modulator) that produces anabolic effects in bone and muscle without causing the prostate effects in men or hair growth in women that is seen with steroids.

The analysis used data from a larger trial in 159 people with cancer (65% of whom were men) who had lost at least 2% (and an average of 8%) of their weight in the previous 6 months. The men were older than 45 years of age, the women were postmenopausal, and each had a body mass index less than 35 mg/kg².

The multicenter study as a whole met its primary end point of increasing lean body mass (muscle) and its secondary end point of improving physical function, Dr. Dobs said in an interview. Those results were reported on the website of the company that is developing the drug, GTx Inc., and at previous medical meetings, according to an interview in the Los Angeles Times.

Dr. Dobs did not report results for lean body mass in the current analysis based on gonadal status.

Cancer diagnoses included colorectal cancer, non–small cell lung cancer, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and breast cancer. Patients participated in the study prior to or between courses of chemotherapy. Rates of hypogonadism were similar for each type of cancer. Patients with hypogonadism were less likely to complete the study than were eugonadal men.

Patients with cancer develop cachexia (muscle wasting) because of reduced anabolic activity, increased catabolic activity, or both, accounting for a progressive catabolic state. Up to 50% of patients with lung cancer show severe cachexia at the time of diagnosis, and the muscle wasting increases throughout the course of the malignancy, Dr. Dobs said.

Two phase III clinical trials are underway to study effects of 3 mg/day of enobosarm for the prevention and treatment of muscle wasting in patients with non–small cell lung cancer.

GTx Inc., the company that is developing enobosarm, funded the current study. Dr. Dobs reported having no other financial disclosures.

HOUSTON  – An experimental drug significantly improved physical function in men with cancer-related muscle wasting, compared with placebo – and more so in the men with low testosterone levels – in a secondary analysis of a randomized, double-blind, phase II clinical trial.

In all, 60% of the 93 men for whom baseline testosterone levels were available had hypogonadism when the patients were randomized to treatment with daily placebo or 1 mg or 3 mg of enobosarm for 16 weeks. Before treatment, the eugonadal males showed significantly better physical function, as measured by stair-climb power, compared with the hypogonadal patients (174 W vs. 147 W). Lower testosterone levels correlated with lower physical function.

Enobosarm significantly improved physical function (a secondary end point in the trial) with an average 17% increase in stair-climb power in hypogonadal men, and a 12% increase in power in eugonadal men, compared with baseline, Dr. Adrian Dobs and her associates reported at the annual meeting of the Endocrine Society.

Among men on placebo, stair-climb power increased by about 10% in hypogonadal men and by roughly 1% in eugonadal men, compared with baseline, but the changes were not statistically significant, said Dr. Dobs, professor of medicine and oncology at Johns Hopkins University, Baltimore.

Adverse events included fatigue in 21% of both treatment groups, anemia in 19% of those on enobosarm and 15% in those on placebo, nausea in 18% on enobosarm and 14% on placebo, diarrhea in 16% on enobosarm and 14% on placebo, vomiting in 12% of each treatment group, weight decrease in 12% on enobosarm and 10% on placebo, and constipation in 14% on enobosarm and 4% on placebo.

The investigators defined hypogonadism as a testosterone level below 300 ng/dL.

Enobosarm is a nonsteroidal SARM (selective androgen receptor modulator) that produces anabolic effects in bone and muscle without causing the prostate effects in men or hair growth in women that is seen with steroids.

The analysis used data from a larger trial in 159 people with cancer (65% of whom were men) who had lost at least 2% (and an average of 8%) of their weight in the previous 6 months. The men were older than 45 years of age, the women were postmenopausal, and each had a body mass index less than 35 mg/kg².

The multicenter study as a whole met its primary end point of increasing lean body mass (muscle) and its secondary end point of improving physical function, Dr. Dobs said in an interview. Those results were reported on the website of the company that is developing the drug, GTx Inc., and at previous medical meetings, according to an interview in the Los Angeles Times.

Dr. Dobs did not report results for lean body mass in the current analysis based on gonadal status.

Cancer diagnoses included colorectal cancer, non–small cell lung cancer, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and breast cancer. Patients participated in the study prior to or between courses of chemotherapy. Rates of hypogonadism were similar for each type of cancer. Patients with hypogonadism were less likely to complete the study than were eugonadal men.

Patients with cancer develop cachexia (muscle wasting) because of reduced anabolic activity, increased catabolic activity, or both, accounting for a progressive catabolic state. Up to 50% of patients with lung cancer show severe cachexia at the time of diagnosis, and the muscle wasting increases throughout the course of the malignancy, Dr. Dobs said.

Two phase III clinical trials are underway to study effects of 3 mg/day of enobosarm for the prevention and treatment of muscle wasting in patients with non–small cell lung cancer.

GTx Inc., the company that is developing enobosarm, funded the current study. Dr. Dobs reported having no other financial disclosures.

HOUSTON  – An experimental drug significantly improved physical function in men with cancer-related muscle wasting, compared with placebo – and more so in the men with low testosterone levels – in a secondary analysis of a randomized, double-blind, phase II clinical trial.

In all, 60% of the 93 men for whom baseline testosterone levels were available had hypogonadism when the patients were randomized to treatment with daily placebo or 1 mg or 3 mg of enobosarm for 16 weeks. Before treatment, the eugonadal males showed significantly better physical function, as measured by stair-climb power, compared with the hypogonadal patients (174 W vs. 147 W). Lower testosterone levels correlated with lower physical function.

Enobosarm significantly improved physical function (a secondary end point in the trial) with an average 17% increase in stair-climb power in hypogonadal men, and a 12% increase in power in eugonadal men, compared with baseline, Dr. Adrian Dobs and her associates reported at the annual meeting of the Endocrine Society.

Among men on placebo, stair-climb power increased by about 10% in hypogonadal men and by roughly 1% in eugonadal men, compared with baseline, but the changes were not statistically significant, said Dr. Dobs, professor of medicine and oncology at Johns Hopkins University, Baltimore.

Adverse events included fatigue in 21% of both treatment groups, anemia in 19% of those on enobosarm and 15% in those on placebo, nausea in 18% on enobosarm and 14% on placebo, diarrhea in 16% on enobosarm and 14% on placebo, vomiting in 12% of each treatment group, weight decrease in 12% on enobosarm and 10% on placebo, and constipation in 14% on enobosarm and 4% on placebo.

The investigators defined hypogonadism as a testosterone level below 300 ng/dL.

Enobosarm is a nonsteroidal SARM (selective androgen receptor modulator) that produces anabolic effects in bone and muscle without causing the prostate effects in men or hair growth in women that is seen with steroids.

The analysis used data from a larger trial in 159 people with cancer (65% of whom were men) who had lost at least 2% (and an average of 8%) of their weight in the previous 6 months. The men were older than 45 years of age, the women were postmenopausal, and each had a body mass index less than 35 mg/kg².

The multicenter study as a whole met its primary end point of increasing lean body mass (muscle) and its secondary end point of improving physical function, Dr. Dobs said in an interview. Those results were reported on the website of the company that is developing the drug, GTx Inc., and at previous medical meetings, according to an interview in the Los Angeles Times.

Dr. Dobs did not report results for lean body mass in the current analysis based on gonadal status.

Cancer diagnoses included colorectal cancer, non–small cell lung cancer, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and breast cancer. Patients participated in the study prior to or between courses of chemotherapy. Rates of hypogonadism were similar for each type of cancer. Patients with hypogonadism were less likely to complete the study than were eugonadal men.

Patients with cancer develop cachexia (muscle wasting) because of reduced anabolic activity, increased catabolic activity, or both, accounting for a progressive catabolic state. Up to 50% of patients with lung cancer show severe cachexia at the time of diagnosis, and the muscle wasting increases throughout the course of the malignancy, Dr. Dobs said.

Two phase III clinical trials are underway to study effects of 3 mg/day of enobosarm for the prevention and treatment of muscle wasting in patients with non–small cell lung cancer.

GTx Inc., the company that is developing enobosarm, funded the current study. Dr. Dobs reported having no other financial disclosures.

Enzalutamide – formerly known as MDV3100 – prolonged overall survival by a median of 4.8 months and reduced the risk of death by 37%, according to newly published data from the phase III, placebo-controlled AFFIRM study of men with metastatic, castration-resistant prostate cancer.

An experimental oral agent inhibiting signaling by the androgen receptor, enzalutamide is under priority review by the Food and Drug Administration with an action date of Nov. 22, 2012, trial sponsors Medivation and Astellas Pharma have announced.

The randomized, double-blind AFFIRM trial underpins their New Drug Application in men with castration-resistant prostate cancer previously treated with docetaxel (Taxotere)-based chemotherapy. Based on the findings, an independent data and safety monitoring committee halted the trial, and those receiving placebo were offered treatment with enzalutamide.

At the time of a planned interim analysis, median overall survival was 18.4 months among 800 men randomized to receive a daily 160-mg oral dose of enzalutamide. It was 13.6 months in 399 men who received a placebo, Dr. Howard I. Scher of Memorial Sloan-Kettering Cancer Center, New York, and his colleagues reported "online first" Aug. 15 in the New England Journal of Medicine.

The drug was also superior to placebo with respect to all secondary end points, including prostate-specific antigen (PSA) response rate (54% vs. 2%), soft-tissue response rate (29% vs. 4%), FACT-P quality of life response (43% vs. 18%), time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25), radiographic progression-free survival (8.3 vs. 2.9 months; HR, 0.40), and time to first skeletal-related event (16.7 vs. 13.3 months; HR, 0.69). The results were consistent across all subgroups, and were maintained after adjustment for stratification factors and baseline prognostic factors.

They confirm that the androgen receptor and androgen-receptor signaling have a central role in the progression of prostate cancer "throughout the spectrum of disease," the investigators said (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).

Participants in AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) were men with progressive prostate cancer that had been treated with one or two chemotherapy regimens, at least one of which included docetaxel. The subjects, who were enrolled at 156 sites in 15 countries between September 2009 and November 2010, had a histologically or cytologically confirmed diagnosis of prostate cancer and testosterone levels of less than 50 ng/dL.

Despite longer observation with enzalutamide, adverse event rates were generally similar between the treatment and control groups; of note, those in the enzalutamide group experienced a lower incidence of adverse events of grade 3 or above (45.3% vs. 53.1%).

"The median time to any initial adverse event of grade 3 or higher was 8.4 months longer in the enzalutamide group than in the placebo groups (12.6 vs. 4.2 months) owing to improved long-term control of disease-related symptoms without an increase in drug reactions of grade 3 or higher," the investigators said.

More patients in the treatment group, however, experienced fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache. In addition, seizures occurred in five (0.6%) patients in the treatment group, whereas no seizures were reported in those receiving placebo. Predisposing factors were present in several patients experiencing seizures, including brain metastases in two patients, inadvertent IV administration of lidocaine in one patient, and brain atrophy in one patient.

The findings of this study substantiate preclinical work showing that androgen-receptor signaling contributes to disease progression despite castrate levels of testosterone and despite prior treatment with conventional antiandrogen therapy, the investigators said. This – coupled with other recent findings – establishes that these tumors are not refractory to hormones as previously thought, even after chemotherapy has been administered, they added.

"This novel agent is anticipated to join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a survival benefit in men with castration-resistant prostate cancer. These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy," they concluded, noting that clinical trials of the drug in earlier-stage prostate cancer are ongoing.

Earlier studies of enzalutamide have been announced in patients with metastatic chemotherapy-naive prostate cancer.

This study was supported by Medivation, the maker of enzalutamide, and Astellas Pharma Global Development. Dr. Scher reported relationships with Aragon Pharmaceuticals, Centocor Ortho Biotech, and other companies. He holds stock or stock options in Johnson & Johnson. Other study authors also made disclosures; details are available with the full text of the article at NEJM.org.

Dr. Scher presented results from the AFFIRM trial at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium in February 2012.

Click here to see a 2009 video of Dr. Scher discussing the rationale behind MDV3100 efficacy in advanced prostate cancer.

Enzalutamide – formerly known as MDV3100 – prolonged overall survival by a median of 4.8 months and reduced the risk of death by 37%, according to newly published data from the phase III, placebo-controlled AFFIRM study of men with metastatic, castration-resistant prostate cancer.

An experimental oral agent inhibiting signaling by the androgen receptor, enzalutamide is under priority review by the Food and Drug Administration with an action date of Nov. 22, 2012, trial sponsors Medivation and Astellas Pharma have announced.

The randomized, double-blind AFFIRM trial underpins their New Drug Application in men with castration-resistant prostate cancer previously treated with docetaxel (Taxotere)-based chemotherapy. Based on the findings, an independent data and safety monitoring committee halted the trial, and those receiving placebo were offered treatment with enzalutamide.

At the time of a planned interim analysis, median overall survival was 18.4 months among 800 men randomized to receive a daily 160-mg oral dose of enzalutamide. It was 13.6 months in 399 men who received a placebo, Dr. Howard I. Scher of Memorial Sloan-Kettering Cancer Center, New York, and his colleagues reported "online first" Aug. 15 in the New England Journal of Medicine.

The drug was also superior to placebo with respect to all secondary end points, including prostate-specific antigen (PSA) response rate (54% vs. 2%), soft-tissue response rate (29% vs. 4%), FACT-P quality of life response (43% vs. 18%), time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25), radiographic progression-free survival (8.3 vs. 2.9 months; HR, 0.40), and time to first skeletal-related event (16.7 vs. 13.3 months; HR, 0.69). The results were consistent across all subgroups, and were maintained after adjustment for stratification factors and baseline prognostic factors.

They confirm that the androgen receptor and androgen-receptor signaling have a central role in the progression of prostate cancer "throughout the spectrum of disease," the investigators said (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).

Participants in AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) were men with progressive prostate cancer that had been treated with one or two chemotherapy regimens, at least one of which included docetaxel. The subjects, who were enrolled at 156 sites in 15 countries between September 2009 and November 2010, had a histologically or cytologically confirmed diagnosis of prostate cancer and testosterone levels of less than 50 ng/dL.

Despite longer observation with enzalutamide, adverse event rates were generally similar between the treatment and control groups; of note, those in the enzalutamide group experienced a lower incidence of adverse events of grade 3 or above (45.3% vs. 53.1%).

"The median time to any initial adverse event of grade 3 or higher was 8.4 months longer in the enzalutamide group than in the placebo groups (12.6 vs. 4.2 months) owing to improved long-term control of disease-related symptoms without an increase in drug reactions of grade 3 or higher," the investigators said.

More patients in the treatment group, however, experienced fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache. In addition, seizures occurred in five (0.6%) patients in the treatment group, whereas no seizures were reported in those receiving placebo. Predisposing factors were present in several patients experiencing seizures, including brain metastases in two patients, inadvertent IV administration of lidocaine in one patient, and brain atrophy in one patient.

The findings of this study substantiate preclinical work showing that androgen-receptor signaling contributes to disease progression despite castrate levels of testosterone and despite prior treatment with conventional antiandrogen therapy, the investigators said. This – coupled with other recent findings – establishes that these tumors are not refractory to hormones as previously thought, even after chemotherapy has been administered, they added.

"This novel agent is anticipated to join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a survival benefit in men with castration-resistant prostate cancer. These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy," they concluded, noting that clinical trials of the drug in earlier-stage prostate cancer are ongoing.

Earlier studies of enzalutamide have been announced in patients with metastatic chemotherapy-naive prostate cancer.

This study was supported by Medivation, the maker of enzalutamide, and Astellas Pharma Global Development. Dr. Scher reported relationships with Aragon Pharmaceuticals, Centocor Ortho Biotech, and other companies. He holds stock or stock options in Johnson & Johnson. Other study authors also made disclosures; details are available with the full text of the article at NEJM.org.

Dr. Scher presented results from the AFFIRM trial at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium in February 2012.

Click here to see a 2009 video of Dr. Scher discussing the rationale behind MDV3100 efficacy in advanced prostate cancer.

Enzalutamide – formerly known as MDV3100 – prolonged overall survival by a median of 4.8 months and reduced the risk of death by 37%, according to newly published data from the phase III, placebo-controlled AFFIRM study of men with metastatic, castration-resistant prostate cancer.

An experimental oral agent inhibiting signaling by the androgen receptor, enzalutamide is under priority review by the Food and Drug Administration with an action date of Nov. 22, 2012, trial sponsors Medivation and Astellas Pharma have announced.

The randomized, double-blind AFFIRM trial underpins their New Drug Application in men with castration-resistant prostate cancer previously treated with docetaxel (Taxotere)-based chemotherapy. Based on the findings, an independent data and safety monitoring committee halted the trial, and those receiving placebo were offered treatment with enzalutamide.

At the time of a planned interim analysis, median overall survival was 18.4 months among 800 men randomized to receive a daily 160-mg oral dose of enzalutamide. It was 13.6 months in 399 men who received a placebo, Dr. Howard I. Scher of Memorial Sloan-Kettering Cancer Center, New York, and his colleagues reported "online first" Aug. 15 in the New England Journal of Medicine.

The drug was also superior to placebo with respect to all secondary end points, including prostate-specific antigen (PSA) response rate (54% vs. 2%), soft-tissue response rate (29% vs. 4%), FACT-P quality of life response (43% vs. 18%), time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25), radiographic progression-free survival (8.3 vs. 2.9 months; HR, 0.40), and time to first skeletal-related event (16.7 vs. 13.3 months; HR, 0.69). The results were consistent across all subgroups, and were maintained after adjustment for stratification factors and baseline prognostic factors.

They confirm that the androgen receptor and androgen-receptor signaling have a central role in the progression of prostate cancer "throughout the spectrum of disease," the investigators said (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).

Participants in AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) were men with progressive prostate cancer that had been treated with one or two chemotherapy regimens, at least one of which included docetaxel. The subjects, who were enrolled at 156 sites in 15 countries between September 2009 and November 2010, had a histologically or cytologically confirmed diagnosis of prostate cancer and testosterone levels of less than 50 ng/dL.

Despite longer observation with enzalutamide, adverse event rates were generally similar between the treatment and control groups; of note, those in the enzalutamide group experienced a lower incidence of adverse events of grade 3 or above (45.3% vs. 53.1%).

"The median time to any initial adverse event of grade 3 or higher was 8.4 months longer in the enzalutamide group than in the placebo groups (12.6 vs. 4.2 months) owing to improved long-term control of disease-related symptoms without an increase in drug reactions of grade 3 or higher," the investigators said.

More patients in the treatment group, however, experienced fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache. In addition, seizures occurred in five (0.6%) patients in the treatment group, whereas no seizures were reported in those receiving placebo. Predisposing factors were present in several patients experiencing seizures, including brain metastases in two patients, inadvertent IV administration of lidocaine in one patient, and brain atrophy in one patient.

The findings of this study substantiate preclinical work showing that androgen-receptor signaling contributes to disease progression despite castrate levels of testosterone and despite prior treatment with conventional antiandrogen therapy, the investigators said. This – coupled with other recent findings – establishes that these tumors are not refractory to hormones as previously thought, even after chemotherapy has been administered, they added.

"This novel agent is anticipated to join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a survival benefit in men with castration-resistant prostate cancer. These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy," they concluded, noting that clinical trials of the drug in earlier-stage prostate cancer are ongoing.

Earlier studies of enzalutamide have been announced in patients with metastatic chemotherapy-naive prostate cancer.

This study was supported by Medivation, the maker of enzalutamide, and Astellas Pharma Global Development. Dr. Scher reported relationships with Aragon Pharmaceuticals, Centocor Ortho Biotech, and other companies. He holds stock or stock options in Johnson & Johnson. Other study authors also made disclosures; details are available with the full text of the article at NEJM.org.

Dr. Scher presented results from the AFFIRM trial at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium in February 2012.

Click here to see a 2009 video of Dr. Scher discussing the rationale behind MDV3100 efficacy in advanced prostate cancer.