A phase II study of luxdegalutamide in combination with abiraterone in adult patients with metastatic hormone-sensitive prostate cancer (mHSPC).

TPS275 Background: Androgen deprivation therapy (ADT) remains the cornerstone of mHSPC treatment, yet patients with high-volume disease experience poorer outcomes and faster progression. Combining agents that target androgen receptor (AR) signaling at multiple steps has been demonstrated to improve overall survival (OS) among patients with mHSPC. Luxdegalutamide is a novel potent oral proteolysis-targeting chimera (PROTAC) AR degrader that has shown complementary antitumor activity when combined with abiraterone in preclinical models. In a prior phase I/II study (NCT05067140), luxdegalutamide combined with abiraterone showed promising antitumor activity with manageable safety in patients with metastatic prostate cancer and no prior AR pathway inhibitor (ARPI) exposure. This phase II, randomized, open-label, multicenter study will evaluate the efficacy and safety of luxdegalutamide at 2 doses (100 mg and 300 mg once daily [QD]) combined with abiraterone in patients with mHSPC (NCT06991556). Methods: Patients are considered eligible if they have high-volume mHSPC (visceral metastases and/or ≥4 bone lesions, with ≥1 lesion located outside the vertebral column and/or pelvis) and no prior ARPI in the metastatic setting. Using the stratified Miettinen and Nurminen method, a sample size of 150 patients randomized in a 1:1:1 ratio is considered appropriate to obtain the minimum response rates required for the lower bound of 90% confidence interval of PSA90 (proportion of patients achieving ≥90% reduction in prostate-specific antigen [PSA] from baseline) difference to exceed 0% (clinical benefit) and 10% (strong clinical benefit) between the pooled combination arm and control arm. The patients will be randomized into 3 treatment arms: Arm 1: Luxdegalutamide 100 mg QD + abiraterone 1000 mg QD. Arm 2: Luxdegalutamide 300 mg QD + abiraterone 1000 mg QD. Arm 3 (control): Abiraterone 1000 mg QD or enzalutamide 160 mg QD (Investigator’s choice). All patients will receive concomitant ADT. Randomization will be stratified by visceral metastases (yes vs no) and Gleason score at diagnosis (<8 vs ≥8). The primary objectives are to (1) determine the recommended phase III dose of luxdegalutamide combined with abiraterone and (2) evaluate the efficacy, safety, and tolerability of the combination versus standard therapy. The primary efficacy endpoint is PSA90 rate. Secondary endpoints include radiographic response, PSA0 (PSA level <0.2 ng/mL at any timepoint), progression-free survival, OS, and pharmacokinetics. Exploratory endpoints include assessment of biomarkers associated with treatment response and/or resistance. As of October 9, 2025, 4 patients have been enrolled. Clinical trial information: NCT06991556 .