EvoPAR-PR01: Saruparib (AZD5305) Phase III Trial in Metastatic Castration-Sensitive Prostate Cancer

Saruparib (AZD5305), a next-generation PARP1-selective inhibitor, represents a promising evolution in prostate cancer therapy, particularly for metastatic castration-sensitive disease (mCSPC), through the ongoing phase III EvoPAR-PR01 trial.

Unlike first-generation PARP inhibitors (PARPi) such as olaparib that target both PARP1 and PARP2, saruparib specifically inhibits and traps PARP1 on DNA damage sites, sparing PARP2 to potentially deliver stronger antitumor effects with fewer hematologic toxicities and better tolerability for combinations. This selectivity could widen the therapeutic window, allowing patients to stay on optimal doses longer, while enhancing efficacy in homologous recombination repair-mutated (HRRm) tumors and extending benefits to non-HRRm cases. Examples of HRR mutations are BRCA1/2, ATM, PALB2, CHEK2, BARD1, RAD51C, RAD51D, CDK12.

Preclinical studies underscore saruparib’s superior potency: in patient-derived xenograft (PDX) models of BRCA1/2-associated cancers, it achieved a 75% complete response rate versus 37% for olaparib, with median progression-free survival exceeding 386 days compared to 90 days. It also delayed resistance in PARPi-sensitive models and resensitized some resistant ones when paired with carboplatin or the ATR inhibitor ceralasertib, showing profound responses in up to 100% of tested cases. In prostate-specific models, saruparib combined with androgen receptor pathway inhibitors (ARPIs) like enzalutamide demonstrated activity in both HRRm and non-HRRm settings, addressing the synthetic lethality gap where HRD tumors struggle to repair DNA single-strand breaks, leading to replication fork collapse and cell death.

EvoPAR-PR01 tests this potential by randomizing ~1,800 men with first-line mCSPC, split into HRRm (~550) and non-HRRm (~1,250) cohorts, to saruparib plus physician’s choice NHA (abiraterone, darolutamide, or enzalutamide) on androgen deprivation therapy (ADT) versus placebo plus NHA. The primary endpoint, radiographic PFS, aims to prove superiority, with overall survival as a key secondary, alongside patient-reported outcomes like pain progression and quality of life. Early phase I/IIa PETRANHA data support feasibility, reporting objective response rates of 88.5% in mCSPC, 73.3% in ARPI-naive mCRPC, and even 25% in prior-ARPI mCRPC, with a favorable safety profile enabling safe NHA combos.

Clinical trial.