TulmiSTAR-02: A phase I/II open-label study of dose escalation and expansion of tulmimetostat in combination with darolutamide versus darolutamide, and tulmimetostat with abiraterone in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

TPS302 Background: Patients (pts) with mHSPC, especially those with high-volume disease, have a poor prognosis due to progression to castration-resistance, highlighting a substantial unmet need for more effective therapies. Androgen receptor pathway inhibitors (ARPIs) including darolutamide and abiraterone, have demonstrated clinical activity in pts with mHSPC. Inhibition of enhancer of zeste homolog 2 (EZH2) improves the effects of ARPIs by increasing sensitivity to AR inhibition through upregulation of AR signaling, further corroborating the rationale that EZH2 inhibition could deepen the response elicited by ARPIs and delay resistance. Tulmimetostat is an investigational, novel, oral, next-generation dual inhibitor of EZH2/EZH1. This phase I/II study evaluates the safety, tolerability and preliminary efficacy of tulmimetostat in combination with darolutamide or abiraterone in pts with de novo or recurrent mHSPC (NCT07190300). Methods: This two-part, open-label, global, multicenter, phase I/II, dose escalation and expansion study includes male pts (≥18 years) who may have received one prior taxane-based therapy without progression and/or prior ARPI (≤6 months in mHSPC). The phase I study will enroll ~30 pts in each part and phase II, a randomized part of the study (5:5:3), will enroll ~143 pts with ECOG performance status 0-2, and life expectancy >6 months. In the phase II study, randomization will be stratified by combining disease volume and prior use of taxane. Study details are described in the table below. Dose escalation will be guided by Bayesian logistic regression model with overdose control. The prostate-specific antigen <0.2 ng/mL rate will be assessed by stratified Miettinen and Nurminen method. The time-to-event efficacy endpoints will be estimated by Kaplan–Meier method. Clinical trial information: NCT07190300 . Phase Parts Treatment Objectives I 1 Tulmimetostat PO QD escalating doses + darolutamide 600 mg PO BID Primary: RDE, safety, tolerability Secondary: PK 2 Tulmimetostat PO QD escalating doses + abiraterone 1000 mg PO QD II Tulmimetostat dose 1 PO QD + darolutamide 600 mg PO BID Primary: BCR (defined as PSA decline <0.2 ng/mL at 6 months) Secondary: rPFS, OS, OR, BOR, DOR, PSA50 response, BCR of <0.1 ng/mL, time to CRPC, safety, tolerability, PK, TTSSE Tulmimetostat dose 2 (optional) + darolutamide 600 mg PO BID Control arm (darolutamide 600 mg PO BID) BCR, biochemical response rate; BID, Twice a day; BOR, best overall response; CRPC, castration–resistant prostate cancer; DOR, duration of response; QD, once a daily; OR, objective response; OS, overall survival; PK, pharmacokinetics, PSA, prostate-specific antigen; PO, oral; RDE, recommended dose for expansion; rPFS, radiographic progression-free survival; TTSSE, time to first symptomatic skeletal event.