(UroToday.com) The 2025 GU ASCO annual meeting featured a prostate cancer trials in progress session and a presentation by Dr. Richard Cathomas discussing SAKK 08/23, a randomized open label phase II trial of the addition of darolutamide to first line treatment of metastatic castration-resistant prostate cancer (mCRPC). The implementation of androgen-receptor pathway inhibitors +/- docetaxel in addition to ADT in metastatic hormone sensitive prostate cancer (mHSPC) has limited the therapeutic options in the mCRPC setting. Maintenance androgen receptor pathway inhibitor therapy in mCRPC has demonstrated efficacy in previous trials in later lines, and darolutamide’s favorable safety profile and combination with different systemic therapies used in mCRPC is safe.
In the SAKK 08/16 trial, darolutamide maintenance demonstrated prolonged radiographic progression-free survival compared to placebo in patients with mCRPC who had received prior androgen-receptor pathway inhibitors and did not progress during taxane therapy.1 This benefit was more pronounced in patients with response to the prior androgen-receptor pathway inhibitors. Continuing enzalutamide in addition to docetaxel versus a switch to docetaxel alone after progression on enzalutamide in later line mCRPC has been demonstrated to prolong progression free survival in a phase 3 trial. The continued maximal androgen-receptor (AR) blockage in the mCRPC first-line setting in addition to a standard of care could potentially control persistent AR-pathway sensitive clones. Darolutamide is an optimal drug for use as androgen-receptor pathway inhibitor maintenance because of its favorable safety profile and low potential for drug-drug interactions. Dr. Cathomas and colleagues hypothesized that the addition of darolutamide to a first-line standard of care in mCRPC in patients with a prior long response to ADT and androgen-receptor pathway inhibitor in mHSPC improves radiographic progression-free survival.
SAKK 08/23 is an international open-label randomized phase 2 trial enrolling patients with ECOG 0-2 having progressed to mCRPC with a response to prior ADT-androgen-receptor pathway inhibitors combination for at least 18 months showing at least a 50% PSA response or partial remission according to RECIST. Patients must not have received treatment for mCRPC, however, pretreatment with docetaxel in mHSPC is allowed. Patients will be randomized 1:1 to receive physician’s choice standard of care (standard of care: docetaxel, cabazitaxel, 177lutetium-PSMA, radium-223 or olaparib) or standard of care with darolutamide. Treatment with darolutamide will be continued until progression according to PCWG3. Stratification factors include country and treatment with taxanes versus radium-223 versus 177Lutetium-PSMA versus olaparib:
The primary endpoint is radiographic progression-free survival. Secondary endpoints include:
- Overall survival
- Time to symptomatic/clinical progression
- Event-free survival
- Time to PSA progression by PCWG3
- Objective response rate according to RECIST
- PSA response
- PSA response duration
Without darolutamide the investigators expect a median radiographic progression-free survival of 6 months for taxanes, radium-223, and olaparib and 8 months for 177Lutetium-PSMA. Assuming a three month increase in median radiographic progression-free survival with the addition of darolutamide 121 events are needed (one-sided type I error of 10%, power of 80%) which leads to a sample size of 162 patients (including 10% dropout after one year). The trial will enroll patients in Switzerland and Spain. Accrual to the study is currently ongoing.
Presented by: Richard Cathomas, Division of Oncology/Hematology, Cantonal Hospital Grisons, Chur, Switzerland
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md 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:
- Gillessen S, Procopio G, Hayoz S, et al. Darolutamide maintenance in patients with metastatic castration-resistant prostate cancer with nonprogressing disease after taxane treatment (SAKK 08/16). J Clin Oncol. 2023 Jul 10;41(20):3608-3615.