Addition of darolutamide to first line treatment of metastatic castration-resistant prostate cancer (mCRPC): A randomized open label phase II trial (SAKK 08/23).

TPS280 Background: The implementation of androgen-receptor pathway inhibitors (ARPI) +/- docetaxel (doce) in addition to androgen deprivation therapy (ADT)in metastatic hormone sensitive prostate cancer (mHSPC) has limited the therapeutic options in the mCRPC setting. In the SAKK 08/16 trial, darolutamide (daro) maintenance demonstrated prolonged radiographic progression-free survival (rPFS) compared to placebo in patients (pts) with mCRPC who had received prior ARPI, and did not progress during taxane therapy. This benefit was more pronounced in pts with a response to the prior ARPI. Continuing enzalutamide in addition to doce versus a switch to doce alone after progression on enzalutamide in later line mCRPC has been demonstrated to prolong PFS 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. Daro is an optimal drug for the use as ARPI maintenance because of its favourable safety profile and a low potential for drug-drug interactions.We hypothesize that the addition of daro to a first-line SOC in mCRPC in pts with a prior long response to ADT and ARPI in mHSPC improves rPFS. Methods: SAKK 08/23 is an international open-label randomized phase 2 trial enrolling pts with ECOG 0-2 having progressed to mCRPC with a response to prior ADT-ARPI combination for at least 18 months showing at least a 50% PSA response or partial remission according to RECIST. Pts must not have received treatment for mCRPC. Pretreatment with doce in mHSPC is allowed. Patients will be randomized 1:1 to receive physician’s choice standard of care (SOC: doce, cabazitaxel, 177 lutetium-PSMA, radium-223 or olaparib) or SOC with daro. Treatment with daro will be continued until progression according to PCWG3. Stratification factors include country and treatment with taxanes versus radium-223 versus 177 lutetium-PSMA vs olaparib. The primary endpoint is rPFS. 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 and PSA response duration. Without daro we expect a median rPFS of 6 months for taxanes, radium-223 and Olaparib and 8 months for 177 lutetium-PSMA. Assuming a three months increase in median rPFS with the addition of daro 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 pts in Switzerland and Spain. Accrual to the study is currently ongoing. Clinical trial information: NCT06401980 .