Pembrolizumab Plus Niraparib Shows Promise in Ovarian Cancer

Panagiotis A. Konstantinopoulos, MD, PhD

Patients with platinum-resistant/refractory ovarian cancer had durable responses with the combination of the PARP inhibitor niraparib (Zejula) and the PD-1 inhibitor pembrolizumab (Keytruda), data from a phase I/II trial showed.

Overall, 15 of 60 evaluable patients had objective responses, and the combination achieved disease control (response plus stable disease) in 68% of the cohort. A subgroup analysis showed consistent activity across biomarker-selected groups.

The safety of the combination was consistent with the profiles of the individual drugs, and no new or unexpected toxicities occurred, Panagiotis A. Konstantinopoulos, MD, PhD, reported at the 2018 Society of Gynecologic Oncology Annual Meeting.

“The combination activity was higher than previously reported for single-agent activity of a PARP inhibitor or pembrolizumab,” said Konstantinopoulos, an attending oncologist at Dana-Farber Cancer Institute. “We observed activity in platinum-resistant and platinum-refractory patients and in patients with BRCA-mutated platinum-refractory disease. The combination offers a possible alternative to chemotherapy, and prolonged duration of treatment up to 18 months has been observed.”

Patients with recurrent platinum-resistant ovarian cancer have few treatment options. Combined chemotherapy increases toxicity with no increase in efficacy. Monotherapy with PARP inhibitors leads to objective responses in 25% to 30% of patients with BRCA-mutant disease but has demonstrated limited activity outside that subgroup, said Konstantinopoulos. PD-1/PD-L1 inhibitors produce response rates of 10% to 15%, irrespective of PD-L1 expression.

Studies involving preclinical models of ovarian cancer suggested therapeutic synergy between PARP inhibitors and anti—PD-1 agents, regardless of BRCA mutation status or PD-L1 expression. To investigate the combination clinically, investigators at more than a dozen US centers conducted a phase I/II trial involving patients with platinum-resistant ovarian cancer and triple-negative breast cancer. Konstantinopoulos reported findings from the ovarian cancer cohort.

Investigators defined platinum resistance as a response lasting <6 months to the most recent platinum-containing regimen. Patients with primary platinum-refractory disease (progression during or within 1 month of initial platinum therapy) were excluded, but patients with disease that was platinum refractory in subsequent lines of platinum-based chemotherapy were eligible. Additionally, patients with platinum-sensitive disease were eligible if they had exhausted treatment options.

Patients who had received as many as 5 prior lines of therapy were eligible.

Phase I of the trial included 9 patients and resulted in recommended phase II doses of 200 mg of niraparib daily and 200 mg every 3 weeks of pembrolizumab. During phase II, investigators enrolled an additional 53 patients, 2 of whom discontinued after less than 9 weeks and did not have post-baseline scans. Investigators acquired comprehensive biomarker data for 83% of the patients.

The patients had a median age of 60, had received a median of 2 prior therapies, and the cohort had exposure to almost all chemotherapeutic agents used to treat ovarian cancer, said Konstantinopoulos.

Biomarker studies showed that 11 patients had BRCA mutations, 45 were BRCA wild-type, and 6 had unknown BRCA status. Testing for homologous recombination deficiency (HRD) yielded positive results in 22 patients, negative in 31, and unknown in 9. PD-L1 assessment was positive in 33 patients, negative in 21, and unknown in 8.

The most common adverse events (all grades, >20% of patients) were fatigue, nausea, constipation, anemia, thrombocytopenia, and decreased appetite. The most frequently occurring grade 3/4 adverse events were anemia (19%), thrombocytopenia (9%), decreased platelet count (6%), and fatigue (4%).

Across all 60 evaluable patients, the objective response rate was 25% (including 2 complete responses), and the disease control rate was 68%. In an analysis of 46 biomarker-selected patients, the combination led to objective responses in 2 of 7 patients with BRCA mutations, 4 of 15 who were HRD positive, 9 of 34 who had BRCA wild-type tumors, and 7 of 24 who were HRD negative.

“The addition of pembrolizumab to niraparib in BRCA wild-type and HRD negative patients led to an objective response rate similar to PARP inhibitor efficacy in the BRCA-mutated population,” said Konstantinopoulos. “HRD status does not correlate with response to this combination in platinum-resistant or -refractory disease.”

The combination led to objective responses in 24% of 29 patients with platinum-resistant disease and disease control in 72%. Among 17 patients with platinum-refractory disease, the objective response rate was 24% and disease control rate 59%.

Konstantinopoulos PA, Munster P, Forero-Torres A, et al. TOPACIO: preliminary activity and safety in patients (pts) with platinum-resistant ovarian cancer in a phase 1/2 study of niraparib in combination with pembrolizumab. Presented at: SGO Annual Meeting; March 24-27, 2018; New Orleans, LA. Late-breaking abstract.

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