Dr Smith on Future Research Directions in Prostate Cancer

“We’re still finding our way with the best use of PARP inhibitors [for the treatment of patients with prostate cancer]. Unequivocally in metastatic castration-resistant prostate cancer, they’re appropriate therapy for patients with DNA repair mutations, particularly in BRCA1 or BRCA2.”

Matthew R. Smith, MD, PhD, the Claire and John Bertucci Endowed Chair in Genitourinary Cancers and the director of the Genitourinary Malignancies Program at Massachusetts General Hospital, as well as a professor of medicine at Harvard Medical School, discussed emerging research avenues in prostate cancer.

Smith began by noting that the most appropriate use of PARP inhibitors is still being elucidated by investigators. Among patients with metastatic castration-resistant prostate cancer, he noted that these agents are an especially good fit for those with DNA repair–mutated disease, specifically those with BRCA1 or BRCA2 mutations. In patients without these types of mutations, the role of PARP inhibitors in combination with androgen pathway receptor inhibitors remains more controversial, he noted.

During the 2025 ASCO Annual Meeting, findings from the phase 3 AMPLITUDE trial (NCT04497844) of niraparib (Zejula) in combination with abiraterone acetate (Zytiga) and prednisone for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) were presented, Smith noted. Data from the study confirmed the important role of PARP inhibition in this biomarker-selected patient population, he added. Specifically, findings from AMPLITUDE revealed that patients with mCSPC harboring homologous recombination repair gene alterations who received the combination (n = 348) achieved a significant benefit in radiographic progression–free survival (rPFS) compared with those who received placebo plus abiraterone acetate and prednisone (n = 348; HR, 0.63; 95% CI, 0.49-0.80; P = .0001).

Additional PARP inhibitors are being evaluated in this setting, with the potential to move the agents earlier in the course of therapy, especially for patients with disease harboring BRCA1 or BRCA2 mutations, he concluded.