Saruparib Plus ARPI Shows Promising Efficacy in Metastatic Prostate Cancer

Combining the PARP1-selective inhibitor saruparib with an androgen receptor pathway inhibitor (ARPI) demonstrated promising efficacy and safety in patients with metastatic prostate cancer, according to results from the phase 1/2 PETRANHA trial presented at the 2025 ESMO Congress.¹

Data from the efficacy-evaluable population showed that objective response rates were 88.5% (23/26) in patients with metastatic castration-sensitive prostate cancer (mCSPC), 25% (2/8) in patients with metastatic castration-resistant prostate cancer (mCRPC) who had prior ARPI, and 73.3% (11/15) in patients with ARPI-naive mCRPC. Rates of prostate specific antigen (PSA) reduction >90% were 100%, 5.6%, and 53.3% in the 3 groups, respectively, and rates of undetectable PSA (<0.2 ng/mL), were 83.3%, 5.3%, and 29.0%, respectively.

“Saruparib plus ARPI has promising safety and preliminary efficacy in patients with mCSPC and ARPI-naïve mCRPC,” first study author Arun A. Azad, MBBS, FRACP, PhD, Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, said when presenting the data at ESMO. “Exploratory analyses demonstrated PSA responses in pts irrespective of whether their tumor harbored an HRRm or not,” added Azad.

What Was the Safety Profile for Saruparib in the PETRANHA Trial?

Across the overall population, the median duration of exposure to saruparib was 12.8 months (range, 0.2-28.2). The median duration of saruparib exposure among patients with mCSPC, mCRPC and prior ARPI, and ARPI-naive mCRPC was 17.8 months (range, 0.2-28.2), 5.5 months (range, 1.2-17.7), and 14.7 months (range, 0.3-24.8), respectively. The median exposure to ARPI in these 3 groups was 19.7 months (range, 0.2-28.2), 5.5 months (range, 1.1-17.7), and 15.7 months (range, 0.4-24.8), respectively.

Among the mCSPC, prior ARPI mCRPC, and ARPI-naive mCRPC groups, any grade adverse events (AEs) occurred at rates of 96.3%, 94.7%, and 100%, respectively. AEs specifically related to saruparib occurred at rates of 85.2%, 84.2%, and 90.3%, respectively. Grade ≥3 AEs were experienced by 51.9%, 31.6%, and 51.6% of the 3 groups, respectively, and serious AEs were reported in 14.8%, 21.1%, 32.3% of patients, respectively.

Across the entire population, AEs led to saruparib discontinuation in 10.4% of patients. AE-related discontinuation of saruparib and ARPI occurred in 11.1% and 3.7% of mCSPC patients, respectively, 5.3% and 5.3% of prior-ARPI mCRPC patients, and 12.9% and 3.2% of ARPI-naive mCRPC patients. AE-related dose reductions of saruparib and ARPI occurred in 29.6% and 0% of mCSPC patients, respectively, 26.3% and 21.1% of prior-ARPI mCRPC patients, and 35.5% and 12.9% of ARPI-naïve mCRPC patients.

Lastly, AE-related treatment interruption of saruparib and ARPI occurred in 51.9% and 44.4% of mCSPC patients, respectively, 36.8% and 31.6% of prior-ARPI mCRPC patients, and 67.7% and 51.6% of ARPI-naïve mCRPC patients.

What Was the Study Design and Rationale for the 1/2 PETRANHA Trial?

The rationale for the phase 1/2 PETRANHA trial was to explore the potential of improving upon the established metastatic prostate cancer treatment of combination therapy with a PARP inhibitor and ARPI for selected patients with mCRPC. The researchers were specifically evaluating whether combining a PARP1-selective inhibitor, such as saruparib, could enhance efficacy and safety outcomes compared with the standard approach of combining a non-selective PARP inhibitor with ARPI.

The study design had patients assigned by investigator choice to 1 of 4 treatment arms defined by the ARPI used. Patients in the analysis presented at ESMO received 60 mg of saruparib once daily combined with enzalutamide (Xtandi) at 160 mg once daily (Arm 1; n = 18), abiraterone acetate (Zytiga) at 1000 mg once daily plus 5 mg of prednisone once daily (Arm 2; n = 23), or darolutamide (Nubeqa; n = 36) at 600 mg twice daily (Arm 3). Data from arm 4 of the study, in which patients are receiving saruparib at the same dose plus apalutamide (Erleada) at 240 mg once daily, were not available for this analysis.

All treatment is being administered until disease progression or intolerable toxicity. The primary end points are safety and tolerability, with efficacy outcomes being the secondary end points.

What Are the Patient Characteristics of the PETRANHA Trial?

At the data cutoff of October 28, 2024, the phase 1/2 PETRANHA trial included 77 patients with metastatic prostate cancer. Of these patients, 65% (n = 50) had mCRPC and 35% (n = 27) had mCSPC. A little over one-third (n = 19) of the mCRPC population had previously received ARPI and about two-thirds (n = 31) were ARPI-naive. Across the whole population, 20.8% (n = 16) had tumors harboring a homologous recombination repair mutation.

What Are the Next Steps with Saruparib in Metastatic Prostate Cancer?

The ongoing, double-blinded, randomized phase 3 EvoPAR-PR01 trial (NCT06120491) is comparing saruparib vs placebo, both given in combination with physician’s choice of ARPI in patients with mCSPC.² The study will explore this comparison in both populations of patients with HRR mutations (550 patient target) and those without mutations (1250 patient target). The primary outcome measure is radiographic progression-free survival (PFS) and key secondary outcomes measures are overall survival, PFS2, and symptomatic skeletal event–free survival.

DISCLOSURES: Azad declared associations with following companies: Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Telix, Merck Serono, Janssen, Bristol Myers Squibb, Ipsen, Bayer, Pfizer, Amgen, Noxopharm, Merck Sharpe Dohme, Daiichi Sankyo, Arvinas; Financial Interests, Personal, Other, Consultant: Aculeus Therapeutics; Exelixis; Aptevo , Hinova, Glaxo Smith Kline, SYNthorx, Bionomics, Lilly, Gilead Sciences.

REFERENCES:

1. Azad AA, Joshua AM, Voskoboynik M, et al. First interim efficacy analysis of the phase I/II PETRANHA trial of saruparib + androgen receptor pathway inhibitors (ARPI) in patients (pts) with metastatic prostate cancer (mPC). Presented at: ESMO 2025 Congress; October 17-20, 2025; Berlin, Germany. Abstract 2384MO.

2.Saruparib (AZD5305) vs Placebo in Men With Metastatic Castration-Sensitive Prostate Cancer Receiving Physician's Choice New Hormonal Agents (EvoPAR-PR01). ClinicalTrials.gov. Last updated October 10, 2025. Accessed October 17, 2025. https://clinicaltrials.gov/study/NCT06120491