(UroToday.com) The 2025 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Annual Symposium held in San Francisco, CA, between February 13–15, 2025, was host to a trials in progress prostate cancer poster session. Dr. Guru Sonpavde presented an ongoing phase 1/1b trial of neoadjuvant darolutamide + relugolix prior to radical prostatectomy for high-risk localized and locally advanced prostate cancer.
Treatment options for patients with high-risk localized prostate cancer (PCa) include upfront radical prostatectomy (RP) or radiation therapy (XRT), either alone or in combination with androgen blockade therapies. Multiple phase II trials have suggested that neoadjuvant intensive androgen blockade incorporating novel hormonal agents (NHA) for high-risk hormone sensitive non-metastatic PCa may demonstrate efficacy in this setting.1-3
Phase III trials evaluating a combination of neoadjuvant + adjuvant androgen deprivation therapy (ADT) + NHA have been conducted, and data are awaited, e.g. PROTEUS. However, these trials do not employ post-op PSA nadir in a non-castrate state to guide adjuvant therapy.
What is the rationale to evaluate the neoadjuvant combination of darolutamide + relugolix? Darolutamide is an oral potent androgen receptor (AR) inhibiting NHA. Relugolix is an oral LHRH antagonist characterized by rapid onset of castration upon initiation and rapid resolution of castration after discontinuation. Both are approved for various settings of advanced PCa. Drug-drug interactions between these agents are likely to be clinically insignificant. Dr. Sonpavde and colleagues hypothesized that deep and intensive androgen blockade employing darolutamide + relugolix, an all-oral regimen, will likely be feasible, convenient, rapidly reversible and efficacious as neoadjuvant therapy preceding RP for high-risk PCa. Additionally, the rapid reversibility of androgen blockade upon discontinuation will 1) allow reliable determination of efficacy of RP by assessing the post-operative PSA nadir in the presence of normal testosterone levels, and 2) the nadir PSA may be utilized to risk-stratify and inform post-operative therapy.
The trial design is summarized below:
Patients with localized, high-risk prostate cancer will receive relugolix 120 mg orally once daily (360 mg orally on Cycle 1, Day 1) plus darolutamide 600 mg orally twice daily for 12 weeks. Initially, 10 patients will be recruited for pharmacokinetic studies. If ≥7/10 patients experience no therapy-related severe adverse events, the trial will be expanded to include an additional 20 patients (total=30).
The key eligibility criteria are as follows:
- Histologically or cytologically confirmed adenocarcinoma of the prostate
- Clinical stage cT1-4, N0-1
- High-risk PCa defined as one of the following-
- Gleason score (GS) ≥ 4 + 3 with ≥ 6 positive systematic biopsies (SB)
- GS ≥ 4 + 3 with ≥ 3 SB and PSA ≥ 20 ng/mL
- GS ≥ 9 in ≥ 1 SB or TB
- ≥ 2 SB or TB with continuous GS ≥ 8, each with ≥ 80% involvement
- Must be a candidate for RP
- Mandatory to identify tumor availability
- ECOG performance Status 0-1
- Participants who have previously received darolutamide, relugolix, LHRH agonist/antagonist, or another novel androgen blocking therapy (abiraterone, apalutamide, enzalutamide) within 1 year are excluded (prior bicalutamide that was discontinued ≥14 days prior to planned cycle 1 day 1 is allowed).
The study objectives are as follows:
- Primary objective:
- Safety and feasibility of neoadjuvant darolutamide + relugolix followed by RP for local/locally advanced, high-risk prostate cancer
- Secondary objectives:
- Objective radiographic response (in those with measurable disease)
- PSA response
- Pathologic complete response and residual cancer burden
- PSA undetectable & Testosterone recovery to normal 4-8 weeks after RP
- Post-operative complications within 4 weeks after RP
- Pharmacokinetic studies (Phase I component of 10 patients only)
- Exploratory objectives are molecular profiling correlative studies of pre- and post-therapy prostate tumor tissue to evaluate biomarkers of sensitivity and mechanisms of resistance.
Presented by: Guru Sonpavde, MD, Medical Director of Genitourinary (GU) Oncology, Assistant Director of the Clinical Research Unit and Christopher K. Glanz Chair for Bladder Cancer Research, AdventHealth Cancer Institute, Orlando, Fl
Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.
References:
- McKay RR, Xie W, Ye H, et al. Results of a Randomized Phase II Trial of Intense Androgen Deprivation Therapy prior to Radical Prostatectomy in Men with High-Risk Localized Prostate Cancer. J Urol. 2021; 206(1):80-7.
- Efstathiou E, Davis JW, Pisters L, et al. Clinical and Biological Characterisation of Localised High-risk Prostate Cancer: Results of a Randomised Preoperative Study of a Luteinising Hormone-releasing Hormone Agonist with or Without Abiraterone Acetate plus Prednisone. Eur Urol. 2019; 76(4):418-24.
- Montgomery B, Tretiakova M, Joshua AM, et al. Neoadjuvant Enzalutamide Prior to Prostatectomy. Clin Cancer Res. 2016; 23(9):2169-76.