ASCO GU 2024: ASCERTAIN: An Open-Label, Randomized, Phase 1, Window-of-Opportunity Study to Investigate the Biological Effects of Saruparib (AZD5305) and Darolutamide Alone or in Combination in Men with Prostate Cancer Eligible for Radical Prostatectomy

(UroToday.com) The 2024 GU ASCO annual meeting included a prostate cancer session featuring trials in progress and a presentation by Dr. Simon Pacey discussing the trial design of ASCERTAIN, an open-label, randomized, phase 1, window-of-opportunity study to investigate the biological effects of saruparib (AZD5305) and darolutamide alone or in combination in men with prostate cancer eligible for radical prostatectomy. Novel hormonal agents, such as darolutamide, are the standard of care for the treatment of metastatic prostate cancer. There is emerging evidence that combining PARP inhibitors with novel hormonal agents can further improve benefit in patients with metastatic prostate cancer. AZD5305 is a potent and selective PARP inhibitor that specifically targets and inhibits PARP1 while sparing other PARP family enzymes and has the potential to demonstrate 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 over abiraterone alone in patients with metastatic castration-resistant prostate cancer (mCRPC) (HR 0.66, 95% CI 0.54 to 0.81).¹ Similarly, the Phase 3 TALAPRO-2 study showed that first-line talazoparib with enzalutamide resulted in statistically significant improvement in radiographic progression-free survival over enzalutamide alone in patients with mCRPC (HR 0.63, 95% CI 0.51 to 0.78).² Both PARP1 and the androgen receptor are involved in DNA repair, which may explain the additional benefit of combining PARP inhibitors with novel hormonal agents. However, a direct demonstration of the mechanism behind the benefit of combination treatment has 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 novel hormonal agents, further supporting their use in clinical practice.

ASCERTAIN is a phase 1 multi-center study enrolling patients aged ≥18 years with localized, unfavorable-intermediate, or high-risk prostate cancer who are eligible for radical prostatectomy. The study design is as follows:

Key inclusion criteria included:

Male patients aged >= 18 years
Suitable for radical prostatectomy
Must have localized unfavorable-intermediate risk or high-risk prostate cancer eligible for prostatectomy
Adequate organ and bone marrow function
Available formalin-fixed paraffin-embedded diagnostic tumor biopsy samples

Patients with prior treatment with any systemic or local anti-cancer treatment for localized prostate cancer are excluded. Eligible patients will either be randomly allocated to receive AZD5305 alone or in combination with darolutamide 600 mg twice daily or darolutamide alone (600 mg twice daily), for a period of 21 days. Additional patients will be recruited into a no-treatment arm, and patients 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
Evaluate the effects of the study treatment on the percent change in Ki-67-positive cells from baseline in tumor samples

Exploratory analysis using comprehensive omics approaches is planned to elucidate further insights into the mechanism of action of combination therapy:

Enrollment began in September 2023 among sites across North America, Europe, and Australia and will enroll up to 120 patients:

Clinical trial information: NCT05938270.

Presented by: Simon Pacey, Cambridge University Hospitals NHS Foundation Trust & University of Cambridge, Cambridge, UK

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25^th – January 27^th, 2024

References:

Login