ZEN003694 and Enzalutamide Versus Enzalutamide Monotherapy in Metastatic Castration-Resistant Prostate Cancer

Zenith Epigenetics

Status and phase: Enrolling; Phase 2

Conditions: Metastatic Castration-Resistant Prostate Cancer

Treatments: Drug: ZEN003694; Drug: Enzalutamide

Study type: Interventional

Funder types: Industry

Identifiers

NCT04986423

ZEN003694-201

Details and patient eligibility

About

This is an open-label, randomized, Phase 2b study of ZEN003694 in combination with enzalutamide vs. enzalutamide monotherapy in patients with mCRPC who have progressed on prior abiraterone by PCWG3 criteria. Disease must have progressed on only abiraterone by PCWG3 criteria prior to study entry.

The patient population will be separated into two cohorts:

Cohort A: Patients with poor response to prior abiraterone defined as:

• Abiraterone started in hormone-sensitive prostate cancer (HSPC) disease setting: < 12 months duration on abiraterone or failure to achieve PSA nadir of 0.2 ng/mL while taking abiraterone, or;
• Abiraterone started in castrate-resistant prostate cancer (CRPC) disease setting: < 6 months duration on abiraterone or failure to achieve PSA50 response while on abiraterone

Cohort B: Patients with response to prior abiraterone, defined as:

• Abiraterone started in hormone-sensitive prostate cancer (HSPC) disease setting: ≥ 12 months duration on abiraterone and nadir PSA < 0.2 ng/mL, or;
• Abiraterone started in castrate-resistant prostate cancer (CRPC) disease setting: ≥ 6 months duration on abiraterone and confirmed PSA50 response

Enrollment: 200 estimated patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Males age ≥ 18 years

2. Metastatic, castration-resistant, histologically confirmed prostate cancer

3. Surgical castration or continuous medical castration for ≥ 8 weeks prior to screening; serum testosterone < 50 ng/dL confirmed within 4 weeks of first administration of study drug

4. Have progressed on prior abiraterone treatment by PCWG3 criteria

5. Patients who are not candidates for chemotherapy in the opinion of the investigator or patients who decline chemotherapy

6. Cohort A only - Patient must meet definition of poor responder to abiraterone by one of the following:

   1. Abiraterone started in hormone-sensitive prostate cancer (HSPC) disease setting: < 12 months duration on abiraterone or failure to achieve PSA nadir of 0.2 ng/mL while taking abiraterone
   2. Abiraterone started in castrate-resistant prostate cancer (CRPC) disease setting: < 6 months duration on abiraterone or failure to achieve a PSA50 response

7. Cohort B only - Patient must meet definition of responder to abiraterone by one of the following:

   1. Abiraterone started in hormone-sensitive prostate cancer (HSPC) disease setting: ≥ 12 months duration on abiraterone and nadir PSA < 0.2 ng/mL
   2. Abiraterone started in castrate-resistant prostate cancer (CRPC) disease setting: ≥ 6 months duration on abiraterone and PSA50 response

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion criteria

1. Any history of brain metastases, prior seizure, conditions predisposing to seizure activity
2. Have previously received an investigational BET inhibitor (including previous participation in this study or a study of ZEN003694)
3. Receipt of prior second-generation androgen receptor inhibitors (e.g. enzalutamide, apalutamide, darolutamide, proxalutamide). Receipt of first-generation AR antagonists (e.g. bicalutamide, nilutamide, flutamide) does not count towards this limit.
4. Have received prior chemotherapy in the metastatic castration-resistant setting (prior chemotherapy in the hormone-sensitive setting is allowed provided last dose was at least 6 months prior to first dose of study drug)
5. Have received prior systemic anti-cancer therapy within 2 weeks or five half-lives, whichever is shorter, prior to the first administration of study drug
6. Have received exogenous administration of testosterone therapy since discontinuation of abiraterone.
7. Failure to recover to Grade 1 or lower toxicity related to prior systemic therapy (excluding alopecia and neuropathy) prior to study entry
8. Radiation therapy within 2 weeks of the first administration of study drug

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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200 participants in 4 patient groups

Cohort A - ZEN003694 + Enzalutamide

Experimental group

Description:

Patients will be administered enzalutamide (160 mg) orally once daily for 21 days prior to the initiation of the combination therapy (Lead-in) to reach steady state concentration (Css) prior to Cycle 1. After the Lead-in, ZEN003694 (72 mg) will be administered orally one daily in combination with daily enzalutamide for 28-day cycles.

Treatment:

Drug: Enzalutamide

Drug: ZEN003694

Cohort A - Enzalutamide

Active Comparator group

Description:

Patients will be administered enzalutamide (160 mg) orally once daily for 21 days prior to Cycle 1 Day 1 (Lead-in). After the Lead-in, patients will be administered enzalutamide 160 mg orally once daily for 28-day cycles. Active control patients will have the option to cross-over to treatment with ZEN003694 in combination with enzalutamide upon confirmed radiographic progression by PCWG3 criteria by independent central review.

Treatment:

Drug: Enzalutamide

Cohort B - ZEN003694 + Enzalutamide

Experimental group

Description:

Patients will be administered enzalutamide (160 mg) orally once daily for 21 days prior to the initiation of the combination therapy (Lead-in) to reach steady state concentration (Css) prior to Cycle 1. After the Lead-in, ZEN003694 (72 mg) will be administered orally one daily in combination with daily enzalutamide for 28-day cycles.

Treatment:

Drug: Enzalutamide

Drug: ZEN003694

Cohort B - Enzalutamide

Active Comparator group

Description:

Patients will be administered enzalutamide (160 mg) orally once daily for 21 days prior to Cycle 1 Day 1 (Lead-in). After the Lead-in, patients will be administered enzalutamide 160 mg orally once daily for 28-day cycles. Active control patients will have the option to cross-over to treatment with ZEN003694 in combination with enzalutamide upon confirmed radiographic progression by PCWG3 criteria by independent central review.

Treatment:

Drug: Enzalutamide