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Maintenance Rucaparib for Platinum-Sensitive Pancreatic Adenocarcinoma with HRD-Associated Mutations

Results of a phase II study in patients with germline or somatic pathogenic variants in BRCA1/2 or PALB2
17 May 2021
Anticancer agents & Biologic therapy;  Gastrointestinal cancers;  Personalised medicine

Maintenance rucaparib is a safe and effective treatment for patients with platinum-sensitive pancreatic adenocarcinoma and germline or somatic pathogenic variants in BRCA1/2 or PALB2. Dr Kim A. Reiss of the Abramson Cancer Center, Perelman School of Medicine, and Department of Medicine, University of Pennsylvania in Philadelphia, PA, US and colleagues observed activity in patients with germline PALB2 pathogenic variants and somatic BRCA2 pathogenic variants and in a patient with squamous cell carcinoma, suggesting that the role of poly ADP-ribose polymerase (PARP) inhibitors might be expanded in clinical practice. The study team published the findings on 10 May 2021 in the Journal of Clinical Oncology.

Patients with pancreatic adenocarcinoma and pathogenic germline BRCA1/2 and PALB2 alterations are sensitive to platinum chemotherapy. Olaparib, the PARP inhibitor is approved by US Food and Drug Administration as maintenance treatment for patients with germline BRCA1/2 pathogenic variants and platinum-sensitive, metastatic pancreatic adenocarcinoma. There is a need to expand the group of patients who may benefit from PARP inhibition beyond those with germline BRCA pathogenic variants.

Recent study demonstrated that patients with metastatic breast cancer and germline PALB2 or somatic BRCA pathogenic variants benefit from olaparib. Previous studies in prostate and ovarian cancer have shown activity of PARP inhibitors in patients with homologous recombination deficiency (HRD) beyond germline BRCA pathogenic variants.

The authors wrote in the study background that it is critical to refine clinical and biological biomarkers that might predict for benefit from PARP inhibition in patients with pancreatic adenocarcinoma. They designed a single-arm phase II study to test the hypothesis that maintenance treatment with rucaparib in patients with platinum-sensitive advanced pancreatic adenocarcinoma and a germline or somatic pathogenic variant in BRCA1/2 or PALB2 can result in progression-free survival (PFS) rate at 6 months (PFS6) of at least 60%.

Eligible patients received at least 16 weeks of platinum-based chemotherapy without evidence of platinum resistance. Chemotherapy was discontinued and patients received rucaparib until progression. The primary endpoint was the PFS6. Secondary endpoints included safety, overall response rate (ORR), disease control rate (DCR), duration of response (DoR), and overall survival (OS).

Of 46 enrolled patients, 42 were evaluable, of whom 27 with germline BRCA2, 7 with germline BRCA1, 6 with germline PALB2 and 2 with somatic BRCA2.

The PFS6 was 59.5% (95% confidence interval [CI] 44.6 to 74.4). Median PFS was 13.1 months (95% CI 4.4 to 21.8), and median OS was 23.5 months (95% CI 20 to 27). The PFS at 12 months was 54.8%.

The ORR in the 36 patients with measurable disease was 41.7% with 3 complete responses and 12 partial responses (95% CI 25.5 to 59.2); DCR was 66.7% (95% CI 49.0 to 81.4). Median DoR was 17.3 months (95% CI 8.8 to 25.8).

Responses occurred in 11 of 27 patients with germline BRCA2 (41%), 3 of 6 patients with germline PALB2 (50%) and in 1 of 2 patients with somatic BRCA2 (50%).

No new safety signals were observed.

The authors wrote that the results of their study provide promising evidence, complementing and furthering findings reported in the POLO study, that PARP inhibition may be an effective maintenance treatment for a broader range of patients with pancreatic adenocarcinoma with both, somatic and germline HRD–associated mutations.

This investigator-initiated study was supported by Clovis Oncology.

Reference

Reiss KA, Mick R, O’Hara M, et al. Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1BRCA2, or PALB2. JCO; Published online 10 May 2021. DOI: 10.1200/JCO.21.00003.

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