Saruparib (formerly AZD5305), a first-in-class, next-generation PARP inhibitor selectively targeting PARP1, is generating excitement in the treatment of advanced solid tumors. Preclinical and early clinical data suggest that saruparib may offer a more favorable safety profile compared to first-generation dual PARP1/2 inhibitors, potentially reducing hematologic toxicities while maintaining therapeutic efficacy.
Rationale for PARP1 Selectivity
PARP inhibitors have become established treatments for various cancers, including ovarian, breast, prostate, and pancreatic cancers, particularly in patients with homologous recombination repair (HRR) deficiencies. However, first-generation PARP inhibitors, which inhibit both PARP1 and PARP2, are associated with adverse events such as anemia, thrombocytopenia, and neutropenia, limiting their use, especially in earlier disease settings.
According to Timothy A. Yap, MBBS, PhD, FRCP, only PARP1 trapping is required for synthetic lethality in HRR deficiency settings. Saruparib was rationally designed to be highly selective for PARP1 with increased potency and improved physiochemical properties compared to the first-generation FDA-approved PARP inhibitors.
PETRA Trial: Promising Early Results
The ongoing phase 1/2 PETRA trial (NCT04644068) is evaluating saruparib monotherapy and in combination with other anticancer agents in patients with advanced/metastatic solid tumors, including HER2-negative breast, ovarian, pancreatic, and prostate cancer, harboring BRCA1/2, PALB2, RAD51C, or RAD51D mutations.
At the American Association for Cancer Research Annual Meeting 2024, Yap presented preliminary findings from the dose escalation (part A) and dose expansion (part B) portions of PETRA. In part B, patients with HER2-negative breast cancer (n = 31) achieved an objective response rate (ORR) of 48.4% (95% CI, 35.7%-61.3%), a median duration of response (DOR) of 7.3 months (95% CI, 5.6-7.6), and a median progression-free survival (PFS) of 9.1 months (95% CI, 5.7-9.3).
Patients treated at the 60-mg daily dose level (n = 141) experienced infrequent dose reductions (14.2%) and discontinuations (3.5%). The rates of grade 3 or higher anemia (11.3%), neutropenia (10.6%), and thrombocytopenia (5.7%) were all below 15%. The recommended phase 2 dose (RP2D) of saruparib was determined to be 60 mg once daily.
Yap noted that saruparib demonstrated a very favorable safety and tolerability profile, with no unexpected safety findings. The adverse effects were mainly grade 1 to 2, and adverse events leading to dose reductions or discontinuations were highly infrequent. Saruparib pharmacokinetics were linear, achieving much higher target pharmacokinetic coverage vs all the approved PARP inhibitors.
EvoPAR-Prostate01: Phase 3 Trial in Metastatic Castration-Sensitive Prostate Cancer
Building on the encouraging results from PETRA, the phase 3 EvoPAR-Prostate01 trial (NCT06120491) has been initiated to evaluate saruparib in combination with next-generation hormonal agents in patients with metastatic castration-sensitive prostate cancer (CSPC). This double-blind, placebo-controlled, multicenter global trial is enrolling patients with de novo or recurrent metastatic CSPC with or without HRR mutations.
The study includes two cohorts: one with HRR mutations (BRCA1/2, ATM, CDK12, PALB2, RAD51B, RAD51C, RAD51D, and/or BARD1) and one without HRR mutations. Patients will be randomized 1:1 to receive saruparib at the RP2D in combination with physician’s choice of a next-generation hormonal agent (abiraterone acetate, darolutamide, or enzalutamide) or placebo plus a next-generation hormonal agent.
The primary endpoint is radiographic PFS per RECIST v1.1 criteria and/or Prostate Cancer Working Group 3 criteria. Key secondary endpoints include overall survival, time to second progression, health-related quality of life, pharmacokinetics, and safety and tolerability. Enrollment in EvoPAR-Prostate01 began in November 2023 and is ongoing.
PETRANHA Study: Saruparib in Combination with Androgen Receptor Pathway Inhibitors
Saruparib is also being investigated in combination with androgen receptor (AR) pathway inhibitors in the phase 1/2 PETRANHA study (NCT05367440) in patients with metastatic CRPC or CSPC, irrespective of HRR mutation status. Patients are receiving saruparib at the RP2D in combination with enzalutamide, abiraterone plus prednisone, or darolutamide.
Interim safety findings from PETRANHA, presented at the 2024 Genitourinary Cancers Symposium, demonstrated that saruparib can be safely combined with enzalutamide, abiraterone, or darolutamide. No significant drug-drug interactions were reported. Serious adverse events occurred at rates of 25% in metastatic CRPC and 6.3% in metastatic CSPC, with treatment-related serious adverse events at 3.1% and 6.3%, respectively.
Andrew J. Armstrong, MD, MSc, noted the interest in expanding the PARP-AR combination successes into other settings, such as nonmetastatic CRPC and even nonmetastatic high-risk hormone-sensitive prostate cancer, with ongoing study designs around earlier disease settings.
