The LuxAR-02 phase II study of luxdegalutamide in combination with [ ¹⁷⁷ Lu]Lu-PSMA-617 in patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration resistant prostate cancer (mCRPC).

Abstract

TPS278 Background: Patients with mCRPC have a poor prognosis and often experience rapid disease progression with current standard therapies. Treatment resistance in mCRPC is frequently driven by the reactivation of androgen receptor (AR) signaling pathways, despite castration or AR-targeted therapies. Luxdegalutamide is a potent oral proteolysis targeting chimera (PROTAC) AR degrader. In a phase I/II study, luxdegalutamide was well tolerated and showed encouraging antitumor activity in heavily pretreated patients with mCRPC (NCT05067140). Preclinically, luxdegalutamide shows additive activity when combined with 177 Lu-PSMA-617 in vivo in prostate cancer models, an effect that may be driven by prostate-specific membrane antigen (PSMA) upregulation. This phase II randomized, open-label, multi-center study aims to evaluate the efficacy, safety, and tolerability of two oral daily dose regimens of luxdegalutamide in combination with 177 Lu-PSMA-617 compared to 177 Lu-PSMA-617 alone in patients with PSMA-positive mCRPC (NCT07047118). Methods: Approximately 130 adult male patients with PSMA-positive (meeting criteria used in VISION trial) mCRPC and prior exposure to at least 1 androgen receptor pathway inhibitor and up to two taxanes will be randomized in a 5:5:3 ratio to one of the 3 arms: Arm 1: Luxdegalutamide 100 mg QD + 177 Lu-PSMA-617 (7.4 GBq q6 weeks). Arm 2: Luxdegalutamide 300 mg QD + 177 Lu-PSMA-617 (7.4 GBq q6 weeks). Arm 3 (control): 177 Lu-PSMA-617 (7.4 GBq q6 weeks). Randomization will be stratified by prior taxane (yes vs. no), and visceral metastases (yes vs. no). The primary objectives are to identify the recommended phase III dose of the combination based on efficacy (PSA50 response rate), safety, tolerability and PK data, and to compare the efficacy in arms 1 and 2 versus control. As of 07 October 2025, 15 patients have been enrolled. Clinical trial information: NCT07047118 .