The purpose of this study is to evaluate the safety, tolerability, and efficacy of two different treatment combinations of tulmimetostat in participants with de novo or recurrent metastatic hormone-sensitive prostate cancer (mHSPC). Phase I aims to determine the recommended dose(s) for expansion (RDE) of tulmimetostat in combination with darolutamide or abiraterone. Phase II is designed to further evaluate the efficacy and safety of tulmimetostat in combination with darolutamide compared with darolutamide alone in participants with mHSPC.
Adult men ≥ 18 years old with de novo or recurrent mHSPC (without neuroendocrine or small cell features). The tumor lesion(s) may be located in the bone, soft tissue/visceral region, or both.
Participants must have castrate levels of testosterone, i.e., ≤ 50 ng/dL (≤ 1.7 nM).
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
Adequate bone marrow and organ function
Participants with evidence of mCRPC or biochemical recurrence / PSA only disease or asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy and with normal PSA for ≥ 1 year prior to the start of study treatment.
Participants who have not received ARPI treatment for mHSPC and present with PSA levels of ≤0.5 ng/mL or those with prior/ongoing ARPI treatment presenting with PSA levels of ≤ 0.2 ng/mL prior to treatment assignment/randomization.
they have received prior therapy (e.g. surgery, radiotherapy, gamma knife), are neurologically stable and asymptomatic.
they are not receiving corticosteroid for the purpose of maintaining neurologic integrity and have baseline and subsequent radiological imaging of the brain.
Parallel
Tulmimetostat
DrugTulmimetostat is an oral dual EZH1/EZH2 inhibitor administered once daily. In Phase I, escalating dose levels will be evaluated in combination with darolutamide or abiraterone. In Phase II, one or two dose levels selected from Phase I will be evaluated in combination with darolutamide.
Darolutamide
DrugDarolutamide 600 mg administered orally twice daily (BID).
Abiraterone
DrugAbiraterone 1000 mg administered orally once daily (QD) in combination with prednisone/prednisolone according to local prescribing information.
Prednisone/Prednisolone
DrugOral corticosteroid administered with abiraterone in Phase I Group B according to local prescribing information.
Androgen Deprivation Therapy (ADT)
DrugBackground therapy consisting of a gonadotropin-releasing hormone (GnRH) agonist/antagonist or prior orchiectomy to maintain castrate testosterone levels (\<50 ng/dL \[\<1.7 nmol/L\]). All participants will continue ADT throughout study participation.
Phase I (Group A and Group B): Dose-limiting toxicities (DLTs)
A dose-limiting toxicity was defined as an adverse event or abnormal laboratory value that was not clearly attributable to the underlying disease or an extraneous cause, occurred during the first 28 days of treatment with tulmimetostat, and met the protocol-defined dose-limiting toxicity criteria. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Dose-limiting toxicities were included in the Bayesian Logistic Regression Model used to support dose-escalation decisions.
Phase I (Group A and Group B): Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)
The incidence, type, frequency, seriousness, and severity of adverse events and serious adverse events will be summarized. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.
Phase I (Group A and Group B): Number of Participants with dose adjustments
The number of participants with dose reductions, dose interruptions, or permanent discontinuations, including the reasons for the dose adjustments, will be summarized by treatment group and dose cohort.
Phase I (Group A and Group B): Dose Intensity
Dose intensity, calculated as the actual cumulative dose received divided by the actual duration of exposure, and relative dose intensity, calculated as the dose intensity divided by the planned dose intensity, will be summarized using descriptive statistics for each study drug.
Phase I (Group A): Plasma concentrations of Tulmimetostat and Darolutamide
Plasma concentrations of tulmimetostat and darolutamide will be evaluated using pharmacokinetic samples collected from participants across the evaluated dose levels in Phase I, Group A.
Phase I (Group A): AUC of Tulmimetostat and Darolutamide
The area under the concentration-time curve from time zero to the last quantifiable concentration, the area under the concentration-time curve from time zero extrapolated to infinity, and the area under the concentration-time curve over a dosing interval at steady state will be derived, as applicable, and summarized using descriptive statistics.
Phase I (Group A): Maximum Observed Plasma Concentration (Cmax) of Tulmimetostat and Darolutamide
The maximum observed plasma concentration of tulmimetostat and darolutamide will be derived, as applicable, and summarized using descriptive statistics.
Phase I (Group B): Plasma concentrations of Tulmimetostat and Abiraterone
Plasma concentrations of tulmimetostat and abiraterone will be evaluated using pharmacokinetic samples collected from participants across the evaluated dose levels in Phase I, Group B.
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