In an unusual move, the US Food & Drug Administration on May 15, 2020, granted accelerated approval to Clovis Oncology for the oral PARP inhibitor rucaparib as a treatment for metastatic castration-resistant prostate cancer (mCRPC), based on objective tumor and prostate-specific antigen (PSA) response rates from a single-arm phase 2 trial (TRITON2; Identifier NCT02952534).1,2

The study included only 115 patients with germline or somatic BRCA-altered mCRPC — and overall response rate (ORR) was evaluable in just 62 of those patients, who had measurable tumors.2 Full FDA approval will be contingent on demonstration of safety and efficacy in the ongoing multicenter, randomized, open-label phase 3 TRITON3 trial; findings are expected in the second half of 2021.3

The following week, on May 20, 2020, the FDA also announced approval of olaparib for mCRPC harboring deleterious germline or somatic mutations in any of 14 homologous recombination repair genes, including BRCA1 and BRCA2, based on improved radiographic response duration (rPFS) findings from the randomized phase 3 PROfound study ( Identifier: NCT02987543).4

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The rucaparib approval was surprising but justified, according to Emmanuel Antonarakis, MD, professor of oncology and urology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland. (Dr Antonarakis has received honoraria and consultancy payments from Clovis Oncology.)

“While the FDA’s decision was surprising to me, and unprecedented in prostate cancer, it makes sense in retrospect given the strong rationale behind PARP inhibitors and the impressive objective response rate seen with rucaparib in prostate cancer patients with BRCA1/2 mutations,” Dr Antonarakis told Cancer Therapy Advisor.

Rucaparib was relatively well tolerated, noted Eddy S. Yang, MD, PhD, professor and vice chair for translational sciences, department of radiation oncology, the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, and deputy director and associate director for precision oncology at the Hugh Kaul Precision Medicine Institute, in Birmingham, Alabama. (Dr Yang has served on several pharmaceutical companies’ advisory boards, including Clovis Oncology.)

A quarter of TRITON2 patients experienced grade 3 or higher treatment-emergent anemia; more than 20% of patients experienced fatigue, nausea, increased alanine transaminase/aspartate transaminase, decreased appetite, rash, constipation, thrombocytopenia, vomiting, or diarrhea.1,2