Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma

Abstract

IMPORTANCE Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. OBJECTIVE To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. DESIGN, SETTING, AND PARTICIPANTS The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to Ն23.0 months). Data were collected from

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

“…PARP inhibition promotes differentiation of naïve T cells to Foxp3 + regulatory T cells [104], which suppress immune responses, and upregulates in tumor cells the expression of PD-L1 [139,140], which by engaging PD1 dampens anti-tumor T cell responses favoring tumor immune-evasion. Combined therapy using anti-PD-L1/anti-PD-1 blocking antibodies and PARPis showed synergic effects in mouse models [140] and promising antitumor activity in clinical trials [141].…”

New strategies in ovarian cancer treatment

“…25 Such neoantigen release and high tumor mutational burden have been shown to be associated with clinical response to immune checkpoint inhibition in some solid tumors. A 72% response rate (RR) has been reported for durvalumab and olaparib in patients with germline BRCA-mutant, platinum-sensitive ovarian cancer 28 ; a 25% RR has been reported for niraparib and pembrolizumab in patients with platinum-resistant ovarian cancer 29 ; and a 14% RR has been reported for durvalumab and olaparib in heavily pretreated patients with ovarian cancer, predominantly composed of those with platinum-resistant BRCA wildtype disease. To our knowledge to date, limited clinical data are available from 3 active PARP inhibitor and PD-1 and/or PD-L1 blockade combination trials demonstrating early clinical activity in subsets of patients with recurrent ovarian cancer.…”

“…To our knowledge to date, limited clinical data are available from 3 active PARP inhibitor and PD-1 and/or PD-L1 blockade combination trials demonstrating early clinical activity in subsets of patients with recurrent ovarian cancer. A 72% response rate (RR) has been reported for durvalumab and olaparib in patients with germline BRCA-mutant, platinum-sensitive ovarian cancer 28 ; a 25% RR has been reported for niraparib and pembrolizumab in patients with platinum-resistant ovarian cancer 29 ; and a 14% RR has been reported for durvalumab and olaparib in heavily pretreated patients with ovarian cancer, predominantly composed of those with platinum-resistant BRCA wildtype disease. 30 In support, several phase 3 randomized trials of multipathway modulation (immune checkpoint inhibitor with or without PARP inhibition with or without VEGF inhibition) currently are being investigated in the frontline setting for ovarian cancer.…”

Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: Still promising?

“…26,27 This biological observation has been tested clinically in 3 phase 2 studies. 30 The combination of PARPi and CPIs is considered a promising strategy in patients with ovarian cancer and is being explored in patients with recurrent disease for whom platinum is an option (ENGOT-OV41/GEICO ENGOT-OV41/GEICO 69-O/ANITA is an ongoing trial that includes patients with recurrent ovarian, fallopian tube, or peritoneal cancer for whom platinum is an option, and requires a platinum-free interval of >6 months and the receipt of ≤2 prior lines of therapy. 28 The same combination was studied in a population of 32 patients, with the majority of patients with platinum-resistant disease recurrences (83%) achieving an ORR of 14%.…”

“…The ORR was 18% (5% CR rate and 13% PR rate) and the median duration of response had not been reached at the time of the data cutoff (range, 4.2 to ≥14.5 months). 30 The combination of PARPi and CPIs is considered a promising strategy in patients with ovarian cancer and is being explored in patients with recurrent disease for whom platinum is an option (ENGOT-OV41/GEICO Table 2.…”