PARP1-selective inhibitor/ARPI combination is well tolerated in advanced prostate cancer

Combination treatment with saruparib, an investigational PARP1-selective inhibitor, and an androgen receptor pathway inhibitor (ARPI) appears to be safe and associated with promising early efficacy in patients with metastatic castration-sensitive prostate cancer (mCSPC) as well as ARPI-naïve metastatic castration-resistant prostate cancer (mCRPC).¹

The data, from the phase 1/2 PETRANHA trial (NCT05367440), were presented at the 2025 European Society for Medical Oncology Congress in Berlin, Germany by Arun Azad, PhD, MBBS, a urologic oncologist at Peter MacCallum Cancer Centre and an associate professor at the University of Melbourne in Australia.

“The combination of androgen receptor pathway inhibitors and non-selective PARP inhibitors has shown clinically meaningful activity in patients with both metastatic castration-resistant prostate cancer^2,3 and metastatic castration-sensitive prostate cancer.⁴ Saruparib is a new-generation PARP inhibitor that selectively inhibits and traps PARP1. In preclinical studies, saruparib shows improved targeted engagement, efficacy, and safety compared with non-selective PARP inhibitors”⁵

Adult patients with histologically confirmed metastatic prostate cancer (either mCRPC or mCSPC), and ECOG performance status of 0 or 1 were eligible for the study. Patients could be included regardless of HRR mutation status.

Investigators allocated patients into 1 of 4 treatment arms:

• Arm 1: saruparib plus enzalutamide (Xtandi, 18 patients)

• Arm 2: saruparib plus abiraterone acetate (Zytiga) plus prednisone (23 patients)

• Arm 3: saruparib plus darolutamide (Nubeqa, 36 patients)

• Arm 4: saruparib plus apalutamide (Erleada). Recruitment in this arm was ongoing at data cut-off and was not included in the present analysis due to the low number of recruited patients.

The study’s primary end point was incidence of adverse events (AEs). Key secondary end points included objective response rate (ORR), duration of response, and prostate-specific antigen (PSA) response.

Azad called the baseline patient characteristics “typical of an advanced prostate cancer population.” Of patients with mCRPC who had received prior treatment with an ARPI, 8 (42.1%) had high-volume disease; in patients with mCRPC who were ARPI naïve, 18 (58.1%) had high-volume disease. In patients with mCSPC, 12 (44.4%) had high-volume disease. Five (26.3%) patients with mCRPC who had received prior ARPI treatment had an HRR mutation, 7 (22.6%) patients with mCRPC who were ARPI naïve had an HRR mutation, and 5 (18.5%) patients with mCSPC had an HRR mutation.

“Overall, the combination of saruparib plus an ARPI was well tolerated. The median treatment exposure to saruparib was 13 months, and to an ARPI was 15 months,” Azad reported.

Grade 3 or higher AEs were observed in 46.8% of patients.

“Importantly, grade 3 or higher anemia occurred in just under 20% of patients. In comparison to non-selective PARP inhibitors, this appears [to be a] similar rate to that seen with olaparib [Lynparza] but lower than that seen with some other non-selective PARP inhibitors. Also importantly, grade 3 or higher GI [gastrointestinal] toxicity was uncommon. Treatment discontinuation due to adverse events was relatively infrequent, occurring in 10% of cases with saruparib and 4% of cases with an ARPI. No cases of myelodysplastic syndrome have been reported,” Azad said.

Turning to efficacy, Azad said that the majority of patients responded to saruparib plus an ARPI, and their response was independent of HRR mutation status. For patients with mCRPC who had received a prior ARPI, ORR was 25.0%; in patients with mCRPC who were ARPI naïve, ORR was 73.3%. In patients with mCSPC, ORR was 100.0%. The investigators also assessed reduction in 90% or greater of PSA level from baseline (PSA-90) and undetectable PSA rates. For patients with mCRPC who had received a prior ARPI, the PSA-90 rate was 5.6%, and the rate of undetectable PSA was 5.3%. In patients with mCRPC who were ARPI naïve, the PSA-90 rate was 55.2%, and the rate of undetectable PSA was 30.0%. In patients with mCSPC, the PSA-90 rate was 100.0%, and the rate of undetectable PSA was 83.3%.

“In conclusion, saruparib in combination with different ARPIs had manageable toxicity, with comparable or lower incidence of grade 3 or higher adverse events than similar combinations with nonselective PARP inhibitors. Interim efficacy results were promising, with high rates of response independent of HRR mutation status…Collectively, these data provide strong support for the ongoing phase 3 EvoPAR-Prostate01 trial (NCT06120491), which is evaluating saruparib in combination with ARPIs in mCSPC, and unlike other mHSPC trials with PARP inhibitors, enrolling patients with and without HRR mutations,” Azad said.

DISCLOSURES: Azad noted disclosures from Aculeus Therapeutics, Amgen, Arvinas, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix, Tolmar, Hinova, Aptevo Therapeutics, Bionomics, Eli Lilly, Exelixis, Gilead Sciences, GSK, MedImmune, and SYNthorx.

REFERENCES

1. Azad A, 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: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract 2384MO. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/2384MO.html.pdf

2. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9). doi:10.1056/EVIDoa2200043

3. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402(10398):291-303. doi:10.1016/S0140-6736(23)01055-3

4. Attard G, Agarwal N, Graff JN, et al. Phase 3 AMPLITUDE trial: Niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes. J Clin Oncol. 2025;43;(Number 17_suppl):LBA5006-LBA5006(2025). doi:10.1200/JCO.2025.43

5. Illuzzi G, Staniszewska AD, Gill SJ, et al. Preclinical characterization of AZD5305, a next-generation, highly selective PARP1 inhibitor and trapper. Clin Cancer Res. 2022;28(21):4724-4736. doi:10.1158/1078-0432.CCR-22-0301