The role of PARP inhibition and HRR alterations in mHSPC: current evidence and future perspectives

Prostate cancer (PC) represents a heterogeneous disease with variable clinical outcomes. Despite most cases being diagnosed at localized stage, 20%–40% of patients experience disease recurrence, progressing to metastatic hormone-sensitive prostate cancer (mHSPC), and without effective intervention, lethal metastatic castration-resistant disease. Homologous recombination repair (HRR) gene mutations, particularly BRCA1/2 alterations, are identified in over 20% of metastatic PC patients and confer significantly worse prognosis, including shorter time to castration resistance and inferior overall survival. Following demonstrated efficacy in metastatic castration-resistant prostate cancer, poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) are now being evaluated in earlier disease settings. The phase III trials AMPLITUDE and TALAPRO-3 are investigating PARPi combined with androgen receptor pathway inhibitors in HRR-mutated mHSPC, with preliminary results from AMPLITUDE demonstrating significant improvement in radiographic progression-free survival. Additional trials are exploring PARPi in HRR-proficient disease and neoadjuvant settings. However, there are critical questions regarding optimal treatment sequencing, long-term survival benefit, and gene-specific response patterns, particularly given minimal benefit in ATM/CHEK2-mutant populations. This review aims to investigate the role of PARPi and HRR mutations in patients with mHSPC, addressing this evolving therapeutic landscape.