Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial.

BACKGROUND

Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane.

METHODS

In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0-2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436.

FINDINGS

Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6-13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7-46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment.

INTERPRETATION

Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations.

FUNDING

Janssen Research & Development.

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests MRS has received grants or contracts to their institution from Bayer, Janssen, Pfizer, AstraZeneca, and Lilly; has received consulting fees from Astellas Pharma, Novartis, Janssen, AstraZeneca, Bayer, Lilly, and Pfizer; and has participated on data safety monitoring boards, advisory boards, or both for Janssen, Pfizer, and AstraZeneca. HIS has a leadership role in Asterias Biotherapeutics; holds stock and other ownership interests in Asterias Biotherapeutics; received grants or contracts to their institution from Epic Sciences, Illumina, Menarini Silicon Biosystems, ThermoFisher, and AIQ Pharma; provided consulting to Ambry Genetics Corporation/Konica Minolta, Amgen (uncompensated), Bayer, ESSA Pharma (uncompensated), Menarini Silicon Biosystems (uncompensated), Pfizer, Sun Pharmaceuticals, and WCG Oncology; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Sidney Kimmel Cancer Center—Jefferson Health; has received support for attending meetings or travel from Amgen, Bayer, ESSA Pharma, Menarini Silicon Biosystems, Epic Sciences, Pfizer, WCG Oncology, and Phosplatin; has patents planned, issued, or pending via their institution with BioNTech, Elucida Oncology, MabVax Therapeutics, and Y-mAbs Therapeutics; and has other financial or non-financial interests in Elsevier, Prostate Cancer Foundation (via institution), National Cancer Institute (via institution), Department of Defense (via institution), MabVax Therapeutics, and BioNTech. SS has received grants from Amgen, Advanced Accelerator Applications (a Novartis company), Merck Sharp & Dohme, AstraZeneca, and Genentech; has received grants and personal fees from AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme; and participated on a data safety monitoring board for Advanced Accelerator Applications (a Novartis company). EE has received grants or contracts, consulting fees, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Sanofi, Astellas, Pfizer, Myovant, Merck Sharp & Dohme, AstraZeneca, and Novartis, and has participated on data safety monitoring boards, advisory boards, or both for Sanofi, Astellas, Pfizer, Myovant, Merck Sharp & Dohme, AstraZeneca, and Novartis. PNL Jr has received grants or contracts from Janssen to their institution. EYY has received grants or contracts from Bayer, Dendreon, Merck Sharp & Dohme, Seagen, Taiho, Blue Earth, and Lantheus; and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Clovis, Janssen, Merck Sharp & Dohme, Seagen, Sanofi, AbbVie, Advanced Accelerator Applications (a Novartis company), and Exelixis. DJG has received grants or contracts to their institution from Astellas, Bristol Myers Squibb, Calithera, Exelixis, Janssen, Novartis, Pfizer, and Sanofi; has received consulting fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Constellation, Exelixis, Flatiron, IdeoOncology, Janssen, Merck, Myovant Sciences, Physician Education Resource, Pfizer, PlatformQ, Propella, RevHealth, Sanofi, Seattle Genetics, WebMD, and Xcures; has received payment or honoraria for lectures, presentation, speakers bureaus, manuscript writing, or educational events from Bayer, EMD Serono, Exelixis, Ipsen, Michael J Hennessey, Pfizer, Sanofi, UroGPO, and UroToday; has received payment for expert testimony from Wilmer Hale Attorneys; has received support for attending meetings or travel from Bayer, Exelixis, Sanofi, and UroToday; has participated on data safety monitoring boards, advisory boards, or both for Astellas, AstraZeneca, Janssen, and Modra; and holds a leadership or fiduciary role in the American Association for Cancer Research (senior editor), AstraZeneca (CAPI-281 study coordinator), Bristol Myers Squibb (study coordinator), Capio Biosciences (scientific advisory board), Millennium Medical Publishing (co-editor-in-chief, Clinical Advances in Hematology & Oncology), NCI Genitourinary (study coordinator), Nektar Therapeutics (study coordinator), and Pfizer (study coordinator). KNC has received grants or contracts to their institution from Janssen, AstraZeneca, Merck, Novartis, and Point Biopharma; has received consulting fees from Astellas, AstraZeneca, Janssen, Merck Sharp & Dohme, Novartis, Point Biopharma, and Roche; and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Janssen, Merck Sharp & Dohme, AstraZeneca, and Novartis. FS has received grants or contracts, consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, and has received equipment, materials, drugs, medical writing, gifts, or other services from Janssen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Myovant, Sanofi, Novartis, and Pfizer; and has participated on data safety monitoring boards, advisory boards, or both for Janssen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Myovant, Sanofi, Novartis, and Pfizer. DO has received grants or contracts from AstraZeneca, Bayer, and Janssen; has received consulting fees from Clovis, Daiichi Sankyo, AstraZeneca, Bayer, Roche, Merck Sharp & Dohme, and Janssen; has received support for attending meetings or travel from AstraZeneca, Janssen, and Roche; and has participated on data safety monitoring boards, advisory boards, or both for Janssen, AstraZeneca, and Bayer. DCD has received consulting fees from Angle, Axiom, Janssen, Astellas, Medivation, Pfizer, Genzyme, and Agensys; and has other financial or non-financial interests (research support) in the US Department of Defense, the American Society of Clinical Oncology, the Prostate Cancer Foundation, Stand Up to Cancer, Janssen, Astellas, Medivation, Agensys, Genentech, and CreaTV. GEM, BME, KAU, PF, and AL-G are employees of Janssen Research & Development. GEM and PF own stocks with Janssen. XZ was an employee of Janssen at the time of this study. KAU has been listed as an inventor on a patent as an employee of Janssen Research & Development. KF has received consulting fees from AAA, Astellas, AstraZeneca, Bayer, Novartis, Janssen, Amgen, Pfizer, Orion, Curevac, and Sanofi; has received payment or honoraria from lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, AstraZeneca, Bayer, Janssen, Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, and Orion; and has participated on data safety monitoring boards, advisory boards, or both for Astellas, AstraZeneca, Bayer, Novartis, Janssen, Amgen, Pfizer, Sanofi, Orion, and Curevac. OS declares no competing interests.