ASCERTAIN: an Open-Label, Randomized, Phase 1, Window-of-opportunity Study to Investigate the Biological Effects of AZD5305 and Darolutamide Alone or in Combination in Men with Prostate Cancer Eligible for Radical Prostatectomy.

TPS356 Background: Novel hormonal agents (NHAs), such as darolutamide, are the standard of care for treatment of metastatic prostate cancer (mPC). There is emerging evidence that combining PARP inhibitors with NHAs can further improve benefit in patients with mPC. AZD5305 is a potent and selective PARP inhibitor that specifically targets and inhibits PARP1 while sparing other PARP family enzymes and has the potential for demonstrating a better therapeutic index compared to first-generation PARP inhibitors that block both PARP1 and PARP2. The Phase 3 PROpel study showed that first-line combination treatment with olaparib and abiraterone significantly improved radiographic progression-free survival (rPFS) over abiraterone alone in pts with metastatic castration-resistant PC (mCRPC) (hazard ratio [HR], 0.66; 95% CI, 0.54 to 0.81; p<0.001). Similarly, the Phase 3 TALAPRO-2 study showed that first-line talazoparib with enzalutamide resulted in statistically significant improvement in rPFS over enzalutamide alone in pts with mCRPC (HR, 0.63; 95% CI, 0.51 to 0.78; p<0.0001). Both PARP1 and androgen receptor are involved in DNA repair, which may explain the additional benefit of combining PARP inhibitors with NHAs; however, direct demonstration of the mechanism behind the benefit of combination treatment have not been established in humans. ASCERTAIN is a window-of-opportunity study that will provide insights into the mechanism of action of combination treatment with PARP inhibitors and NHAs, further supporting their use in clinical practice. Methods: ASCERTAIN (NCT05938270) is a Phase 1 multi-center study enrolling pts aged ≥18 years with localized, unfavorable-intermediate or high-risk PC who are eligible for radical prostatectomy. Pts with prior treatment with any systemic or local anti-cancer treatment for localized PC are excluded. Eligible pts will either be randomly allocated to receive AZD5305 alone or in combination with darolutamide 600 mg twice daily (BD) or darolutamide alone (600 mg BD), for a period of 21 days; additional pts will be recruited into a no-treatment arm. Pts will undergo surgery on Day 22. The primary objective is to assess the fold change from baseline in the percentage of cells with phosphorylated-Ser139 histone H2AX, a marker of DNA damage, in tumor biopsy samples at diagnosis and in the surgical specimen. Key secondary objectives include safety and tolerability; surgery outcomes; and the change in percentage of Ki-67-positive cells in tumor samples. Exploratory analysis using comprehensive omics approaches are planned to elucidate further insights into the mechanism of action of combination therapy. Enrollment began in September 2023; sites across North America, Europe and Australia will enroll up to 120 patients. Clinical trial information: NCT05938270 .