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

Trial Summary

What is the purpose of this trial?

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

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.

What data supports the effectiveness of the drug Enzalutamide for prostate cancer?

Research shows that Enzalutamide, a drug used for prostate cancer, significantly improves survival in men with metastatic castration-resistant prostate cancer (a type of prostate cancer that continues to grow despite low testosterone levels). It has been shown to increase survival rates and reduce prostate-specific antigen (PSA) levels, which are markers of prostate cancer activity. ^{1 2 3 4 5}

Is the combination of ZEN003694 and Enzalutamide safe for humans?

Enzalutamide, also known as Xtandi, has been used for prostate cancer and is generally well-tolerated, but it can cause side effects like severe low platelet count (thrombocytopenia) and skin reactions. Safety data for ZEN003694 specifically is not provided in the available research. ^{1 2 4 6 7}

What makes the drug Enzalutamide unique for prostate cancer treatment?

Enzalutamide is unique because it is a powerful inhibitor of the androgen receptor signaling pathway, which is crucial for the growth of prostate cancer cells. It works by blocking multiple steps in this pathway, helping to stop the cancer from growing and spreading, and has been shown to improve survival in patients with advanced prostate cancer. ^{1 2 8 9 10}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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 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

Findings from Research

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, 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]

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]

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]

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]

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 (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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Enzalutamide for patients with metastatic castration-resistant prostate cancer. [2020]

2. Poland pubmed.ncbi.nlm.nih.gov

Enzalutamide induced acute generalized exanthematous pustulosis. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Enzalutamide: a novel anti-androgen with prolonged survival rate in CRPC patients. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of enzalutamide in men with metastatic, castration-resistant prostate cancer. [2021]

6. Australia pubmed.ncbi.nlm.nih.gov

Enzalutamide-induced severe thrombocytopenia complicated by a seizure in a 76-year-old man with castration-resistant prostate cancer. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

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

8. United States pubmed.ncbi.nlm.nih.gov

Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration-resistant prostate cancer. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Enzalutamide as a Fourth- or Fifth-Line Treatment Option for Metastatic Castration-Resistant Prostate Cancer. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Enzalutamide Bests Older NSAAs in mHSPC. [2021]