From the Journals

Niraparib-pembrolizumab combo finds niche in breast, ovarian cancers

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Biomarker panel needed to identify those most likely to benefit

“Targeting DNA repair and immune checkpoint pathways has emerged as an important concept in cancer therapy, well supported by preclinical and clinical data in ovarian cancer and TNBC. However, there are some limitations to the two studies presented herein,” maintain editorialists Kunle Odunsi, MD, PhD, and Tanja Pejovic, MD, PhD.

Patients varied considerably with respect to number of prior chemotherapy regimens, they elaborate. Also, there may have been some misclassification of patients into DNA damage repair (DDR) groups, and small sample sizes precluded rigorous subgroup analyses.

“Because DDR and, by extension, tumor mutational burden and PD-L1 status do not fully explain the effects of the combination of PARP inhibitors and anti–PD-1 therapy, additional predictive biomarkers based on tumor intrinsic or adaptive mechanisms of resistance are needed for both cancer types,” the editorialists contend. In particular, knowledge of the tumor microenvironment could be used to tailor therapy for individual patients.

“The TOPACIO clinical studies are clearly steps in the right direction for patients with [platinum-resistant ovarian carcinoma] and TNBC,” they conclude. “However, larger confirmatory randomized clinical trials are needed that use panels of integrated biomarkers that would allow identification of patients most likely to respond.”

Dr. Odunsi is the deputy director and chair of the department of gynecologic oncology, executive director of the Center for Immunotherapy, and co-leader of the Tumor Immunology and Immunotherapy Research Program–Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Dr. Pejovic is associate professor, division of gynecologic oncology, department of obstetrics & gynecology, Knight Cancer Institute, Oregon Health & Science University, Portland, Ore. These remarks are adapted from a related editorial (JAMA Oncol. 2019 Jun 13. doi: 10.1001/jamaoncol.2019.1009 ).



The strategy of simultaneously exploiting deficient DNA damage repair and unleashing the immune response could expand treatment options for hard-to-treat breast and ovarian cancers, findings of the TOPACIO/KEYNOTE-162 trial suggest.

Triple-negative breast cancer (TNBC) and high-grade serous ovarian carcinoma share a number of genomic features, including a high frequency of BRCA1 and BRCA2 inactivation (Nature. 2012;490:61-70), as well as potential immunoreactivity (Lancet Oncol. 2018;19:40-50).

The open-label, single-arm phase 1/2 trial therefore tested the combination of niraparib (Zejula), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, and pembrolizumab (Keytruda), an antibody to programmed death 1 (PD-1), among more than 100 patients with advanced or metastatic TNBC or recurrent platinum-resistant ovarian carcinoma. Patients were enrolled irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression.

Main results, reported in JAMA Oncology, showed that the combination was safe, and about a fifth of patients with each type of cancer had an objective response. Median progression-free survival (PFS) was about 2 months in those with TNBC overall (although it exceeded 8 months in the subset with a tumor BRCA mutation) and about 3 months in those with ovarian cancer.

TNBC cohort

Investigators led by Shaveta Vinayak, MD, of the division of oncology at Fred Hutchinson Cancer Research Center, and University of Washington School of Medicine, Seattle Cancer Care Alliance, Seattle, studied 55 patients with TNBC treated with niraparib-pembrolizumab in the trial.

In the efficacy-evaluable population of 47 patients, the objective response rate (ORR) was 21%, and the disease control rate (DCR) was 49%. With a median duration of follow-up of 14.8 months, the median duration of response was not reached.

Activity of the combination varied by tumor BRCA mutation status. Compared with counterparts having BRCA wild-type tumors, patients having tumors with BRCA mutations had a numerically higher ORR (47% vs. 11%), DCR (80% vs. 33%), and PFS (8.3 vs. 2.1 months).

Some 18% of patients had treatment-related anemia, 15% thrombocytopenia, and 7% fatigue. In addition, 15% of patients had immune-related adverse events, with 4% having grade 3 immune-related adverse events.

“Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations,” Dr. Vinayak and colleagues conclude. “The combination therapy was safe with a tolerable safety profile, warranting further investigation.”


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