PARP Inhibitors in Metastatic Castration-resistant Prostate Cancer: Rationale, Mechanisms, and Clinical Applications

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Metastatic prostate cancer (PC) remains a significant cause of cancer death, with limited survival rates for castration-resistant PC (CRPC).
• Advances include chemotherapy, androgen receptor pathway inhibitors (ARPIs), and radium-223, but personalized treatment is evolving.
• Poly (ADP-ribose) polymerase inhibitors (PARPi) target DNA repair deficiencies in cancer cells, offering a new therapeutic avenue.

Purpose of the Study:

• To review the literature on PARPi treatment for CRPC.
• To synthesize evidence on the evolving treatment landscape of PARPi in metastatic CRPC.
• To evaluate the efficacy and patient selection criteria for PARPi in CRPC management.

Main Methods:

• Literature review of PARPi treatment for CRPC.
• Narrative synthesis of evidence from clinical studies.
• Analysis of Phase 3 trial data for PARPi agents (olaparib, niraparib, rucaparib, talazoparib).

Main Results:

• PARPi agents prolong overall survival (OS) in metastatic CRPC, particularly in patients with BRCA1/2 mutations.
• Combination therapy with PARPi and ARPIs demonstrates improved radiological progression-free survival and OS.
• Treatment response to PARPi varies based on specific gene alterations, with greater benefit observed in BRCA1/2, CDK12, and PALB2 mutations.

Conclusions:

• PARPi agents are approved as monotherapy or in combination with ARPIs for selected CRPC patients.
• These therapies offer a valuable alternative when chemotherapy is not indicated.
• Further research is needed to optimize patient selection and treatment sequencing strategies.