Conference Coverage

Combined PARP, checkpoint inhibitor regimens show ovarian cancer activity



– Results from the first two trials to assess the efficacy of combined treatment with a PARP inhibitor plus an immune checkpoint inhibitor in patients with ovarian cancer showed promising results in both phase 2.

Dr. Panagiotis A. Konstantinopoulos Mitchel L. Zoler/MDedge News

Dr. Panagiotis A. Konstantinopoulos

One trial treated 53 patients resistant to, refractory to, or ineligible for platinum treatment with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib (Zejula) and the immune checkpoint inhibitor pembrolizumab (Keytruda) and showed an objective response rate of 25% and a disease control rate of 67%, Panagiotis A. Konstantinopoulos, MD, said at the annual meeting of the Society of Gynecologic Oncology.

The second trial treated 34 patients with platinum-sensitive ovarian cancer with a “chemotherapy-sparing” combination of the PARP inhibitor olaparib (Lynparza) and the immune checkpoint inhibitor durvalumab (Imfinzi) and showed an objective response rate of 72% and a disease control rate of 81%, reported Yvette Drew, MD, of the Northern Institute for Cancer Research in Newcastle upon Tyne, England.

These responses in the two uncontrolled series appeared to exceed historical rates on monotherapy with a PARP inhibitor or immune checkpoint inhibitor, leading both Dr. Konstantinopoulos and Dr. Drew to suggest possible synergy between the two drug classes. The response rates “were higher than previously reported” with either drug alone in platinum-resistant or -refractory ovarian cancer patients, noted Dr. Konstantinopoulos, the director of translational research in the Gynecologic Oncology Program at the Dana-Farber Cancer Institute in Boston.

Dr. Yvette Drew Mitchel L. Zoler/MDedge News

Dr. Yvette Drew

“The preclinical data suggest synergy,” noted Dr. Drew; she suggested that PARP inhibitors could be triggering increased production of the PD-L1 protein that is part of the pathway targeted by immune checkpoint inhibitors.

In both phase 2 studies, the drugs were generally well tolerated, with grade 3 or higher adverse effects roughly matching what’s been reported using monotherapy with each of the tested drugs. The most common was anemia, in 12%-19% of patients. The data on niraparib plus pembrolizumab that Dr. Konstantinopoulos reported also included nine patients in a phase 1 study that had compared the dosages used in the phase 2 study against a second regimen that used a higher niraparib dosage.

The TOPACIO (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial enrolled ovarian cancer patients who had been on a platinum regimen for at least 6 months and had received no more than five prior lines of treatment. The phase 1/2 study MEDIOLA (MEDI4736 in Combination With Olaparib in Patients With Advanced Solid Tumors) enrolled only patients with a BRCA mutation and at least two prior lines of treatment. The substantial differences in response and control rates between the two studies can be at least partially attributed to differences in their enrollment criteria and other study details, commented Amir A. Jazaeri, MD, director of the Gynecologic Cancer Immunotherapy Program at the University of Texas MD Anderson Cancer Center in Houston.

Dr. Amir A. Jazaeri Mitchel L. Zoler/MDedge News

Dr. Amir A. Jazaeri

The two different combinations tested in TOPACIO and MEDIOLA are both on track for testing in phase 3 studies that will soon begin, the researchers said.

TOPACIO was funded by Tesaro and Merck. MEDIOLA was funded by AstraZeneca. Dr. Konstantinopoulos is an adviser to AstraZeneca, Merck, and Pfizer. Dr. Drew is an adviser to AstraZeneca and Clovis. Dr. Jazaeri is an adviser to Areva, has received travel support from AstraZeneca and Genentech as well as research funding from AstraZeneca, Bristol-Myers Squibb, Iovance, and Pfizer.

SOURCE: Konstantinopoulos PA and Drew Y. SGO 2018.

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