ZEN003694 + Enzalutamide for Prostate Cancer

Recruiting at 28 trial locations

Overseen By Zenith Study Team

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Zenith Epigenetics

Must not be taking: Enzalutamide, Apalutamide

Disqualifiers: Brain metastases, Seizure history, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 28-day cycles up to 30 months

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination treatment for men with advanced prostate cancer that hasn't responded well to abiraterone. Researchers aim to determine if adding ZEN003694 (an experimental treatment) to enzalutamide (a standard treatment) is more effective than using enzalutamide alone. Participants will be divided into two groups based on their previous response to abiraterone. Men whose prostate cancer worsened after abiraterone treatment and who aren't suitable for chemotherapy are ideal candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you have not received any systemic anti-cancer therapy within 2 weeks or five half-lives before starting the study drug. It does not specify about other medications, so you should discuss your current medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of ZEN003694 and enzalutamide has been tested for safety in men with advanced prostate cancer. Some studies have found that this combination is generally well-tolerated. Earlier research identified tiredness and nausea as the most common side effects, which are typical and usually manageable in cancer treatments.

Enzalutamide alone is already approved for treating prostate cancer and is known to be safe. Common side effects include tiredness, hot flashes, and joint pain, which are also generally manageable.

Overall, both treatments have demonstrated safety, but side effects can occur. It is important to consult a healthcare provider about potential risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ZEN003694 in combination with enzalutamide for prostate cancer because it offers a new approach to treatment. Most standard treatments target androgen receptors to slow cancer growth, but ZEN003694 works differently by inhibiting BET proteins, which are involved in gene regulation that contributes to cancer progression. This dual-action strategy could potentially enhance the effectiveness of enzalutamide, offering hope for improved outcomes in patients with advanced prostate cancer. Additionally, this combination could be beneficial for patients who have developed resistance to traditional androgen receptor-targeting therapies.

What evidence suggests that this trial's treatments could be effective for prostate cancer?

Research has shown that combining ZEN003694 with enzalutamide might help patients with prostate cancer unresponsive to other treatments. In this trial, some participants will receive the combination of ZEN003694 and enzalutamide, while others will receive enzalutamide alone. Early studies found that the combination was generally well-tolerated and could benefit patients whose cancer did not improve with previous medications. Specifically, some patients experienced a significant drop in PSA levels, a marker used to monitor prostate cancer. This suggests that adding ZEN003694 to enzalutamide might help manage prostate cancer that other drugs have not controlled. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

Men over 18 with metastatic, castration-resistant prostate cancer that worsened after abiraterone treatment. They must have low testosterone levels and not be candidates for chemotherapy or refuse it. There are two groups: one had a poor response to abiraterone, the other had a better response.

Inclusion Criteria

I cannot or do not want to undergo chemotherapy.

I have prostate cancer and did not respond well to abiraterone treatment.

I have been on hormone therapy for prostate cancer for at least 8 weeks, and my testosterone levels are low.

Exclusion Criteria

I haven't had cancer treatment within the last 2 weeks or five half-lives before starting the study drug.

I have been treated with newer prostate cancer drugs but not with the older ones.

I still have side effects from previous treatments, except for hair loss and nerve issues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in

Participants are administered enzalutamide (160 mg) orally once daily for 21 days to reach steady state concentration prior to Cycle 1

3 weeks

1 visit (in-person)

Treatment

Participants receive ZEN003694 in combination with enzalutamide or enzalutamide monotherapy for 28-day cycles

28-day cycles up to 30 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Enzalutamide
• ZEN003694

Trial Overview This study is testing ZEN003694 combined with enzalutamide against enzalutamide alone in men whose prostate cancer has progressed despite previous treatment with abiraterone. It's an open-label trial where patients know which treatment they're getting.

How Is the Trial Designed?

Group I: Cohort B - ZEN003694 + Enzalutamide Experimental Treatment 2 Interventions

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.

Group II: Cohort A - ZEN003694 + Enzalutamide Experimental Treatment 2 Interventions

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.

Group III: Cohort B - Enzalutamide Active Control 1 Intervention

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.

Group IV: Cohort A - Enzalutamide Active Control 1 Intervention

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.

Enzalutamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Approved in European Union as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Approved in Canada as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Approved in Japan as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Who Is Running the Clinical Trial?

Zenith Epigenetics

Lead Sponsor

Trials

10

Recruited

590+

Newsoara BHK BioPharma Co. Ltd.

Industry Sponsor

Newsoara HYK Biopharmaceutical (Shanghai) Co., Ltd.

Industry Sponsor

Newsoara Biopharma Co., Ltd.

Industry Sponsor

Trials

9

Recruited

1,100+

Astellas Pharma Inc

Industry Sponsor

Trials

700

Recruited

236,000+

Headquarters

Tokyo, Japan

Top Products

- Xtandi (enzalutamide) for prostate cancer, - Xospata (gilteritinib) for AML, - Padcev (enfortumab vedotin) for bladder cancer, - Prograf (tacrolimus) for organ rejection prevention

Tadaaki Taniguchi

Astellas Pharma Inc

Chief Medical Officer since 2023

MD, PhD

Naoki Okamura

Astellas Pharma Inc

Chief Executive Officer since 2023

University of Tokyo, Faculty of Pharmacy

Published Research Related to This Trial

Enzalutamide is an effective androgen receptor inhibitor that improves overall survival in patients with metastatic castration-resistant prostate cancer, showing a 4.8-month survival benefit in those previously treated with docetaxel, as demonstrated in the Phase III AFFIRM trial.

The FDA has expanded enzalutamide's approval to include first-line treatment for metastatic castration-resistant prostate cancer in patients who have not yet received chemotherapy, and it is associated with an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide for patients with metastatic castration-resistant prostate cancer. Ramadan, WH., Kabbara, WK., Al Basiouni Al Masri, HS.[2020]

Enzalutamide (XTANDI) is an FDA-approved treatment for castration-resistant prostate cancer (CRPC) that effectively targets androgen receptor signaling, which is crucial for cancer progression.

In a Phase III clinical trial involving men with CRPC after chemotherapy, enzalutamide was well tolerated and significantly improved overall survival by 4.8 months, as indicated by reduced serum prostate-specific antigen (PSA) levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide: a novel anti-androgen with prolonged survival rate in CRPC patients. Dhingra, R., Sharma, T., Singh, S., et al.[2021]

In a phase 3 trial involving 1401 men with nonmetastatic, castration-resistant prostate cancer, enzalutamide significantly improved median overall survival to 67.0 months compared to 56.3 months for placebo, indicating a 27% lower risk of death.

The safety profile of enzalutamide was consistent with previous studies, with a similar rate of serious adverse events compared to placebo, primarily involving fatigue and musculoskeletal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. Sternberg, CN., Fizazi, K., Saad, F., et al.[2021]

A 76-year-old man developed severe thrombocytopenia after 13 days of enzalutamide treatment for castration-resistant prostate cancer, indicating that this side effect can occur early in therapy.

After discontinuing enzalutamide, the patient's platelet count recovered, and he was able to restart the medication without recurrence of thrombocytopenia; however, he later experienced a seizure, suggesting that enzalutamide may also be associated with neurological adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide-induced severe thrombocytopenia complicated by a seizure in a 76-year-old man with castration-resistant prostate cancer. Murata, M., Takizawa, I., Maruyama, R., et al.[2022]

Enzalutamide is a second-generation androgen receptor inhibitor that has shown greater affinity for the androgen receptor without causing agonistic effects, making it a promising treatment for metastatic castration-resistant prostate cancer.

The review discusses the drug's safety profile and its role among other agents that improve survival outcomes, highlighting the need for strategic sequencing and combination therapies to enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide, a second generation androgen receptor antagonist: development and clinical applications in prostate cancer. Menon, MP., Higano, CS.[2021]

Enzalutamide effectively inhibits androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) by blocking multiple steps, including androgen binding and nuclear translocation, without exhibiting AR agonistic activity, which is a significant advantage over bicalutamide.

In preclinical models, enzalutamide not only reduced tumor volume in CRPC xenografts but also induced apoptosis in prostate cancer cells, suggesting its potential as a powerful treatment option for patients with advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration-resistant prostate cancer. Guerrero, J., Alfaro, IE., Gómez, F., et al.[2022]

Enzalutamide, a treatment for metastatic castration-resistant prostate cancer, was linked to a case of acute generalized exanthematous pustulosis (AGEP) in a 62-year-old male patient, indicating a potential skin-related side effect of this medication.

The patient's skin reaction occurred shortly after starting enzalutamide and resolved within four weeks, suggesting that the long half-life of enzalutamide (5.8 days) may contribute to the prolonged duration of symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide induced acute generalized exanthematous pustulosis. Alberto, C., Konstantinou, MP., Martinage, C., et al.[2020]

Enzalutamide significantly improves overall survival and radiographic progression-free survival in men with metastatic, castration-resistant prostate cancer (mCRPC), as shown in two major randomized trials (AFFIRM and PREVAIL) involving patients who had previously undergone chemotherapy and those who were chemotherapy naive.

While enzalutamide is generally safe and effective, it can cause side effects like fatigue and has specific safety concerns, such as an increased risk of seizures and falls, particularly in older patients (≥ 75 years).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of enzalutamide in men with metastatic, castration-resistant prostate cancer. Graff, JN., Gordon, MJ., Beer, TM.[2021]

Enzalutamide (Enz) was evaluated in a retrospective study of 47 men with heavily pretreated metastasized castration-resistant prostate cancer (mCRPC), showing a 23% response rate with significant PSA declines, indicating its potential efficacy even in later treatment lines.

The treatment was generally well tolerated, with common side effects like fatigue and nausea, and resulted in a median overall survival of 40.1 weeks and a median progression-free survival of 12.1 weeks, suggesting it can be a viable option for patients who have exhausted other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide as a Fourth- or Fifth-Line Treatment Option for Metastatic Castration-Resistant Prostate Cancer. Badrising, SK., van der Noort, V., Hamberg, P., et al.[2021]

The ENZAMET phase III trial demonstrated that adding enzalutamide to standard treatment significantly prolongs survival in men with metastatic hormone-sensitive prostate cancer.

Enzalutamide is more effective than older nonsteroidal antiandrogen drugs, highlighting its potential as a superior treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide Bests Older NSAAs in mHSPC. [2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32694156/

A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in ... ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04986423?term=AREA%5BBasicSearch%5D(pcwg3)&rank=1

NCT04986423 | ZEN003694 and Enzalutamide Versus ... This is an open-label, randomized, Phase 2b study of ZEN003694 in combination with enzalutamide vs. enzalutamide monotherapy in patients with mCRPC who have ...

3. annalsofoncology.org annalsofoncology.org/article/S0923-7534(22)03741-3/fulltext

1404P A phase II study of ZEN-3694 (ZEN), enzalutamide ... The primary objective was to determine the recommended phase 2 dose (RP2D); key efficacy endpoints included PSA50 response.

4. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT04471974

UCSF Prostate Cancer Trial → ZEN-3694, Enzalutamide ... This phase II trial investigates how well ZEN-3694, enzalutamide, and pembrolizumab work in treating patients with castration-resistant prostate cancer.

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS5123

A randomized, open-label, phase 2b study of the BET ... A randomized, open-label, phase 2b study of the BET bromodomain inhibitor (BETi) ZEN-3694 plus enzalutamide vs. enzalutamide in patients with ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7572827/

A Phase 1b/2a Study of the Pan-BET Bromodomain ... The safety and efficacy of ZEN-3694 plus enzalutamide (ENZ) was evaluated in a phase 1b/2a study in metastatic castration-resistant prostate cancer (mCRPC).

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04471974

Study Details | NCT04471974 | ZEN-3694, Enzalutamide, ... The purpose of this study is to find out the effects ZEN-3694, enzalutamide, and pembrolizumab on patients with metastatic castration-resistant prostate cancer ...

8. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/298142

ZEN003694 and Enzalutamide Versus ... This is an open-label, randomized, Phase 2b study of ZEN003694 in combination with enzalutamide vs. enzalutamide monotherapy in patients with mCRPC.