Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2

Abstract

PURPOSE Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved as maintenance therapy for patients with advanced pancreatic cancer (PC) and a germline BRCA1 or BRCA2 pathogenic variant (PV). This investigator-initiated, single-arm phase II study assessed the role of the PARPi rucaparib as maintenance therapy in advanced PC with germline or somatic PV in BRCA1, BRCA2, or PALB2. PATIENTS AND METHODS Eligible patients had advanced PC; germline (g) or somatic (s) PVs in BRCA1, BRCA2, or PALB2, and received at least 16 weeks of platinum-based chemotherapy without evidence of platinum resistance. Chemotherapy was discontinued and patients received rucaparib 600 mg orally twice a day until progression. The primary end point was the progression-free survival (PFS) rate at 6 months (PFS6). Secondary end points included safety, ORR, disease control rate, duration of response, and overall survival. RESULTS Of 46 enrolled patients, 42 were evaluable (27 g BRCA2, seven g BRCA1, six g PALB2, and two s BRCA2). PFS6 was 59.5% (95% CI, 44.6 to 74.4), median PFS was 13.1 months (95% CI, 4.4 to 21.8), and median overall survival was 23.5 months (95% CI, 20 to 27). The PFS at 12 months was 54.8%. ORR of the 36 patients with measurable disease was 41.7% (3 complete responses; 12 partial responses; 95% CI, 25.5 to 59.2), and disease control rate was 66.7% (95% CI, 49.0 to 81.4). Median duration of response was 17.3 months (95% CI, 8.8 to 25.8). Responses occurred in patients with gBRCA2 (41%, 11 out of 27), gPALB2 (50%, 3 out of 6), and sBRCA2 (50%, 1 out of 2). No new safety signals were noted. CONCLUSION Maintenance rucaparib is a safe and effective therapy for platinum-sensitive, advanced PC with a PV in BRCA1, BRCA2, or PALB2. The finding of efficacy in patients with g PALB2 and s BRCA2 PVs expands the population likely to benefit from PARPi beyond g BRCA1/ 2 PV carriers.

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

“…Further, the association between platinum sensitivity and PARPi responsiveness is seen regardless of BRCA status in ovarian cancer [128,129]. As we highlighted in prior sections, patient selection using platinum-sensitivity plus BRCA or PALB2 mutation status identifies a subset of patients with pancreatic cancer who benefit from PARPi maintenance [58,59]. Further, in patients with pancreatic cancer, regardless of HR gene mutation status, PFS to olaparib monotherapy is longer in platinum-sensitive disease as compared to platinum-resistant disease [60].…”

“…The maintenance PARPi paradigm has been confirmed and extended in a single-arm phase II clinical trial showing activity of rucaparib as a viable maintenance treatment in advanced pancreatic cancer. This second study included patients with somatic BRCA2 and germline PALB2 mutations [59]. The trial was notable for a PFS of 13.1 months, and an ORR of 41.7%, with responses seen in 3/6 patients with PALB2 variants and in 1/2 patients with somatic BRCA variants.…”

“…The trial was notable for a PFS of 13.1 months, and an ORR of 41.7%, with responses seen in 3/6 patients with PALB2 variants and in 1/2 patients with somatic BRCA variants. High disease burden was associated with poor outcomes, suggesting that additional tumorspecific biology interacts with HR mutations to drive HRD in pancreatic cancer [59].…”

“…Growing evidence for a dynamic relationship between PARPi and inflammation in the TME further highlights the importance of tumor extrinsic factors in mediating the response to treatments [115]. A relatively small but persistent group of patients with BRCA-related pancreatic cancer demonstrate complete and durable responses with PARPi treatment [58,59]. This type of prolonged tumor control is reminiscent of durable responses to immunotherapy [116].…”

BRCAness as a Biomarker of Susceptibility to PARP Inhibitors in Glioblastoma Multiforme

“…As a result, olaparib was approved (May 2020) as a monotherapy for metastatic castration-resistant prostate cancer, for carriers of deleterious mutations in ATM and PALB2 [81,83]. Rucaparib increased overall survival of pancreatic cancer patients carriers of PALB2 in a phase II trial, hence potentially broadening the population that could be benefited by PARPi treatment [84].…”