Phase 2 study

Reproduced exactly, unedited. Written for researchers rather than for patients.

Key Inclusion Criteria:

• 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

• Prior ADT: Participants must have started ADT at least 1 month (at least 28 days) but no more than 12 months before study entry and be willing to continue ADT during treatment

• Prior taxane use for mHSPC is permitted:

  • Phase I and II: Participants may have received, but not progressed on, one prior taxane-based therapy.
  • Phase II: Limited to 25% participants with prior taxane use.

• Prior ARPI is allowed in both Phase I and Phase II:

  • Prior ARPI use in biochemical recurrence (BCR) or curative treatment is allowed for any duration, provided therapy was discontinued and participant had no evidence of conventional imaging positive metastatic disease at that time

  • Prior ARPI use in mHSPC is permitted but not mandated. If participants meet all study eligibility criteria, they are required to stop their prior ARPI after providing informed consent and remain off ARPI until Cycle 1 Day 1, when study treatment is initiated.

    • Phase I: Allowed for any duration.
    • Phase II: Allowed prior exposure to ARPI is ≤4 months. Participants with ongoing use of darolutamide are not eligible.

Participants with ongoing ARPI are eligible for a switch from their ongoing ARPI therapy if they have not progressed to CRPC disease, and meet any of the criteria, indicative of suboptimal biochemical response, or intolerability, as assessed by the Investigator:

• Evidence of insufficient PSA control or suboptimal PSA response, defined as PSA ≥ 0.2 ng/mL after 6-12 months ADT and no more than 4 months of current ARPI therapy in mHSPC with declining or stable PSA trend. Eligibility based on biochemical progression should be supported by objective evidence (e.g. PSA results).

• Intolerance and non-compliance: Participant's inability to tolerate or comply with the prescribed ARPI. The site should maintain documentation to support the appropriateness of therapy changes resulting from intolerance or non-compliance.

  • Other permitted prior local therapy for mHSPC:

• Phase I and II: Prior prostate-directed radiation or surgical intervention. Radiation must be completed before study entry; surgery at least 2 weeks prior.

Key Exclusion Criteria:

• 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.

• Participants with CNS metastases are excluded unless:

  • 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.

• Concurrent use of first-generation anti-androgens (like bicalutamide). Prior use of a first-generation anti-androgen drug in the context of ADT initiation with a GNRH analog is allowed, provided it was administered for ≤14 days and the last dose was administered ≥7 days from the study entry.

• Systemic ketoconazole is used as antineoplastic treatment for prostate cancer.

• Previous exposure to radioligand therapy.

• Treatment with any investigational agent within 28 days (or 5 half-lives, whichever is longer) prior to study entry.

• Previous treatment with any Polycomb Repressive Complex 2 (PRC2) inhibitor, including but not limited to Enhancer of Zeste Homolog 2 (EZH2) inhibitors, EZH2/1 inhibitors, or embryonic ectoderm development (EED) inhibitors.

• Herbal products that may decrease PSA levels within 4 weeks prior to the start of study drug treatment and while on study.

• Participants taking prohibited medication(s) (e.g., strong CYP3A4 inducers or strong or moderate CYP3A4 inhibitors that cannot be stopped within 7 days or 5 half-lives (whichever is longer) prior to study treatment and for the duration of the study treatment or prohibited herbal product(s) that cannot be stopped 7 days prior to study treatment.

• Have a history of a concurrent or second malignancy except for adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 3 years. Participants with a history of leukemia/lymphoma and/or MDS are not eligible.

Other inclusion/exclusion criteria may apply