Dr. Tagawa on the Evolution and Selection of PARP Inhibitors in mCRPC

Scott Tagawa, MD, MS, FACP, professor, medicine and urology, medical director, Genitourinary Oncology Research Program, Weill Cornell Medical College, attending physician, New York Presbyterian Hospital, discusses the evolution of PARP inhibitor use in metastatic castration-resistant prostate cancer (mCRPC) and available PARP inhibitors for molecularly-selected patients in this space.

Therapeutic approaches targeting the androgen receptor (AR) proliferation pathway have been a mainstay in the treatment armamentarium for prostate cancer for several years and were an effective option for the general patient population, Tagawa begins. However, the discovery of prevalent germline alterations, in addition to the widespread use of somatic testing platforms, contributed to the use of molecularly-selected regimens in this space, Tagawa explains.

This effort has been reflected in the increasing use of PARP inhibitors for patients with specific genomic alterations, he adds. Germline or somatic BRCA1/2 mutations are commonly seen in this tumor type, and patients who express these mutations are highly sensitive to PARP inhibitors, Tagawa notes.

These patients could benefit from the use of olaparib (Lynparza) or rucaparib (Rubraca), Tagawa continues. Both agents received FDA approval in mCRPC for patients with homologous recombination repair (HRR) gene mutations who progressed on standard hormonal treatments based on results from the phase 3 PROfound (NCT02987543) and TRITON2 (NCT02952534) trials, respectively.

Findings from the PROFOUND trial showed that olaparib increased median radiographic progression-free survival (rPFS) from 3.6 months with abiraterone acetate (Zytiga) or enzalutamide (Xtandi) to 7.4 months. The agent also reduced the risk of disease progression or death by 66% in this population. In TRITON2, rucaparib produced an objective response rate (ORR) of 44% in patients with BRCA-mutated mCRPC. Subsequent data from the phase 3 TRITON3 trial (NCT02975934) confirmed the efficacy of rucaparib monotherapy by showing that the agent improved rPFS vs chemotherapy or second-line androgen deprivation therapy in chemotherapy-naïve patients with BRCA- or ATM-mutated mCRPC.

The approval of these agents not only revolutionized the treatment of patients with mCRPC but indicated the viability of molecular-selected therapeutic approaches in this space, Tagawa emphasizes.

Regarding the optimal sequencing of therapy, single-agent PARP inhibitors are likely to be utilized after prior treatment with an AR pathway inhibitor, Tagawa adds. Selection often depends on individual patient factors and any molecular alterations that may be expressed, he concludes.

Disclosures: Dr Tagawa reports received institutional research support from Sanofi, Medivation, Astellas, Janssen, Amgen, Progenics, Dendreon, Lilly, Genentech, Newlink, BMS, Inovio, AstraZeneca, Immunomedics, Aveo, Rexahn, Atlab, Boehringer Ingelheim, Millennium, Bayer, Merck, Abbvie, Karyopharm, Endocyte, Clovis, Seattle Genetics, Novartis, Gilead, POINT Biopharma, Ambrx; he worked as a paid consultant for Sanofi, Medivation, Astellas, Dendreon, Janssen, Genentech, Bayer, Endocyte, Eisai, Immunomedics, Karyopharm, Abbvie, Tolmar, Seattle Genetics, Amgen, Clovis, QED, Pfizer, AAA/Novartis, Clarity, Genomic Health, POINT Biopharma, Blue Earth, AIkido Pharma, Telix Pharma, Convergent Therapeutics, EMD Serono, Myovant, Merck, Daiichi Sankyo; he was an unpaid consultant for Atlab Pharma, Phosplatin Therapeutics, Amgen, Ambrx; he has a patent filed with Immunomedics / Gilead / Weill Cornell for Biomarkers for sacituzumab govitecan therapy.