Niraparib-Pembrolizumab Combo May Have Benefit in Ovarian, Breast Cancers

By Will Boggs MD

June 23, 2019

NEW YORK (Reuters Health) - Niraparib in combination with pembrolizumab may show promise in women with recurrent platinum-resistant ovarian carcinoma (PROC) and in those with advanced or metastatic triple-negative breast cancer (TNBC), according to results from two industry-sponsored phase 2 trials.

But outside experts were not convinced, saying the results were not all that different from those seen with monotherapy with either agent.

Niraparib, a PARP inhibitor, is approved in the U.S. and Europe for maintenance treatment of recurrent ovarian carcinoma, and preclinical models have demonstrated synergistic antitumor effects against ovarian and breast carcinomas when the drug is combined with anti-PD-1 inhibitors like pembrolizumab.

In the first study (TOPACIO/KEYNOTE-162), Dr. Panagiotis A. Konstantinopoulos from Dana-Farber Cancer Institute, Harvard Medical School, in Boston, and colleagues evaluated the objective response rate (ORR) of niraparib in combination with pembrolizumab in 62 women with recurrent platinum-resistant ovarian carcinoma.

Overall, three women had confirmed complete responses, eight had confirmed partial responses, 28 had stable disease, 20 had progressive disease, and three were not evaluable, for an ORR of 18% and a disease control rate (DCR) of 65%.

Eight women with partial or complete responses had response durations exceeding six months, including four whose responses were maintained longer than nine months. Nine women with stable disease received treatment for longer than six months, including two who received treatment for more than 12 months.

The ORRs appeared to be similar for all biomarker-identified populations.

Median progression-free survival (PFS) was 3.4 months, with estimated PFS of 31% at six months and 12% at 12 months.

In the second study (also part of TOPACIO), Dr. Shaveta Vinayak of the University of Washington School of Medicine, Seattle Cancer Care Alliance, and colleagues evaluated ORR, DCR and PFS associated with niraparib combined with pembrolizumab in 55 women with advanced or metastatic TNBC.

Overall, five women had confirmed complete responses, five had confirmed partial responses, 13 had stable disease, and 24 had disease progression, for an ORR of 21% and a DCR of 49%.

Response durations in women with a confirmed complete or partial response ranged from 4.6 to 15.9 months.

Among all treated patients, the median PFS was 2.3 months, and estimated PFS was 28% at six months and 14% at 12 months.

ORR and median PFS appeared to be greater in women with tBRCA mutation (47% and 8.3 months, respectively) than in women with wild-type tBRCA (11% and 2.1 months, respectively).

Response rates were also nominally higher in women with PD-L1-positive tumors 32%) than in women with PD-L1-negative tumors (8%).

The most common treatment-related adverse events in the two studies were fatigue, nausea, anemia, thrombocytopenia and constipation.

Both reports appeared online June 13 in JAMA Oncology.

Dr. Ela Senkus of the Medical University of Gdansk, in Poland, who studies breast-cancer treatment, told Reuters Health by email, "I'm a bit disappointed with this study. The response rates and PFS are not that much different from (what) one would expect from monotherapy with niraparib in BRCA mutant and from pembrolizumab in BRCA wild-type tumors. The only promising result is the impressive duration of response, but this has been observed earlier with immune checkpoint inhibitors. It's also worrisome to see such a high early dropout rate due to adverse events."

"Definitely it's worth proceeding with trials combining PARP inhibitors and immunotherapy, but based on this study, I would limit them only to BRCA mutant tumors," she said.

"It's definitely too early to pronounce the success of this combination, in particular in view of the efficacy of the combination of PD-L1 inhibition and chemotherapy, as demonstrated in the IMpassion 130 study (https://bit.ly/2KwpkNQ), " Dr. Senkus said.

"The TOPACIO clinical studies are clearly steps in the right direction for patients with PROC and TNBC," write Dr. Kunle Odunsi from Roswell Park Comprehensive Cancer Center, in Buffalo, New York, and Dr. Tanja Pejovic from Knight Cancer Institute, Oregon Health and Science University, in Portland, in a linked editorial. "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. Konstantinopoulos and Dr. Vinayak did not respond to a request for comments.

The studies were supported by TESARO: A GSK Company and Merck and Co., and the authors include several employees and others with financial ties to the company. Both authors of the editorial also report such conflicts of interest.

SOURCE: https://bit.ly/2IsOkTR, https://bit.ly/2L2g2so and https://bit.ly/2Y2qfbO

JAMA Oncol 2019.

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