Testosterone + ZEN-3694 + Enzalutamide for Prostate Cancer

Overseen By Sin Chan, MS

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must be taking: Androgen ablative therapy

Must not be taking: Opioid pain medications, Anticoagulants

Disqualifiers: Seizure history, Uncontrolled infection, 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

Compensation: Varies

Number of Visits: Unknown

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for prostate cancer that no longer responds to standard therapies. Researchers aim to determine if starting with testosterone (specifically testosterone cypionate, a form of hormone therapy) and ZEN-3694 (an experimental treatment), followed by enzalutamide and ZEN-3694, can shrink tumors more effectively. Men with prostate cancer that has spread beyond the prostate and whose cancer has grown despite other treatments may be suitable candidates for this study. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

Participants must stop taking second-generation AR-axis inhibitors like Abiraterone, Enzalutamide, Darolutamide, or Apalutamide for at least 2 weeks before starting the trial. Attempts should also be made to reduce or stop prednisone, but if symptoms persist, the lowest possible dose can be continued.

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

Research has shown that combining ZEN-3694 with enzalutamide has been studied in patients with advanced prostate cancer. This combination is generally well-tolerated, though some patients have experienced side effects such as tiredness and nausea.

Enzalutamide, already approved by the FDA for treating prostate cancer, is widely used and considered safe. Common side effects include headaches, hot flashes, and high blood pressure.

Testosterone cypionate is also used in treatment and replacement therapy. It has been linked to a slight increase in prostate cancer risk, particularly in older men, but studies have not demonstrated a direct increase in cancer risk due to testosterone therapy. Some men may experience side effects like a higher red blood cell count or acne.

Overall, these treatments have been tested in many patients with prostate cancer and are generally considered safe, though side effects can occur. Consulting a healthcare professional is important to understand the potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine novel approaches to tackle prostate cancer. While traditional treatments often focus on hormone therapy to lower testosterone, the BATZEN treatment arm uniquely uses testosterone cypionate injections alongside ZEN-3694, a bromodomain inhibitor that targets cancer cell growth. This combination could potentially disrupt cancer progression by leveraging testosterone in a way that challenges conventional methods. On the other hand, the ZENZA treatment arm escalates the dose of ZEN-3694 when disease progression is detected, aiming to directly interfere with cancer cell mechanisms more aggressively. These innovative strategies offer hope for more effective management of prostate cancer compared to standard hormone deprivation therapies.

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

Research has shown that combining ZEN-3694 with enzalutamide, as studied in the ZENZA arm of this trial, may help treat prostate cancer unresponsive to standard treatments. Studies have found that this combination can prevent testosterone from reaching cancer cells, potentially stopping tumor growth. Early results suggest this combination is manageable for patients and could be effective. Additionally, initial data indicates that using testosterone with ZEN-3694, as explored in the BATZEN arm of this trial, might also help reduce tumor size. These treatments target prostate cancer cells in different ways, potentially increasing their effectiveness when used together. ^{6 7 8 9 10}

Who Is on the Research Team?

Samuel Denmeade, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for men with prostate cancer that's resistant to castration and other treatments. Participants should have a certain level of PSA in their blood, be healthy enough for the study drugs, and not have brain metastases or uncontrolled illnesses.

Inclusion Criteria

Documented castrate level of serum testosterone (<50 ng/dl)

Screening PSA ≥ 1.0 ng/mL

I stopped taking second-gen AR inhibitors over 2 weeks ago.

Exclusion Criteria

Allergy to sesame seed oil or cottonseed oil

I need help with my daily activities due to my health condition.

I had major surgery less than 3 weeks ago or haven't fully recovered yet.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - BATZEN

Participants receive ZEN-3694 and high dose testosterone in 28-day cycles until disease progression

Variable, based on disease progression

Monthly visits for testosterone injections and monitoring

Treatment - ZENZA

Participants receive ZEN-3694 and Enzalutamide daily after progression on BATZEN

Variable, based on disease progression

Regular visits for monitoring and medication adjustment

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Enzalutamide
• Testosterone cypionate
• ZEN-3694

Trial Overview The COSMYC Trial is testing if combining testosterone (cypionate) with ZEN-3694 can shrink tumors when followed by enzalutamide plus ZEN-3694 in castration-resistant prostate cancer. It also examines if pre-dosing with testosterone enhances the effectiveness.

How Is the Trial Designed?

Group I: ZENZA Experimental Treatment 3 Interventions

ZENZA cycles will begin once there is disease progression on bone and CT scans.ZEN-3694 dose will increase to 72 mg (one 48 mg and two 12 mg tablets) to be taken daily by mouth. Enzalutamide 160 mg (four 40 mg capsules) will be taken daily by mouth.

Group II: BATZEN Experimental Treatment 3 Interventions

ZEN-3694 48 mg (one 48 mg tablet) will be taken once per day by mouth each cycle (each cycle is 28 days). On the first day of each cycle, testosterone cypionate (400 mg) injection will be administered into the buttocks. The participant will continue with additional 28-day cycles of ZEN-3694 pills and testosterone injections until there is disease progression on bone and CT scans.

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Zenith Epigenetics

Industry Sponsor

Trials

10

Recruited

590+

Published Research Related to This Trial

Enzalutamide significantly improves overall survival in men with metastatic, castration-resistant prostate cancer (mCRPC), showing a 37% reduced risk of death compared to placebo, with median survival times of 18.4 months versus 13.6 months.

The results from the phase III AFFIRM trial support the continued targeting of the androgen receptor as an effective treatment strategy for prostate cancer, even after patients have developed resistance to castration therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide (formerly MDV3100) as a new therapeutic option for men with metastatic castration-resistant prostate cancer. Aragon-Ching, JB.[2021]

In a study of 14 Japanese patients with castration-resistant prostate cancer (CRPC), enzalutamide (ENZ) demonstrated a high efficacy, with 92% of patients achieving a significant reduction in prostate-specific antigen (PSA) levels of 50% or more from baseline.

The safety profile of ENZ was favorable, with only mild adverse events occurring in more than 20% of patients, indicating that even reduced doses of ENZ (80 or 120 mg/day) are effective and safe for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Enzalutamide in a Real-World Cohort of Japanese Patients With Castration-resistant Prostate Cancer. Hori, A., Sahashi, H., Sano, S., et al.[2021]

In a study of 72 patients with metastatic castration-resistant prostate cancer (mCRPC), low serum testosterone levels during and before enzalutamide treatment were linked to significantly shorter progression-free survival (PFS) and failure-free survival (FFS), indicating that testosterone levels could serve as a predictive biomarker for treatment outcomes.

Patients with low testosterone levels (<0.217 nmol/L) during treatment had a median PFS of only 7.4 months compared to 20.8 months for those with higher levels, suggesting that monitoring testosterone could help identify patients at risk of treatment failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictive value of low testosterone concentrations during and prior to enzalutamide treatment in metastatic castration-resistant prostate cancer. van Winden, LJ., Lanfermeijer, M., Dezentje, V., et al.[2023]

Enzalutamide combined with androgen deprivation therapy (ADT) significantly reduces the risk of death in men with non-metastatic castration-resistant prostate cancer (nmCRPC), regardless of age or region, based on a study involving 1401 participants with a median age of 74 years.

The safety profile of enzalutamide was consistent across different age groups and regions, with treatment-emergent adverse events being more common in the placebo group, indicating that enzalutamide is a safe option for older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consistent survival benefit of enzalutamide plus androgen deprivation therapy in men with nonmetastatic castration-resistant prostate cancer: PROSPER subgroup analysis by age and region. De Giorgi, U., Hussain, M., Shore, N., et al.[2022]

In a study of 95 patients with castration-resistant prostate cancer (CRPC), higher serum testosterone levels before starting enzalutamide treatment were associated with better quality of life (QoL) scores during treatment, as measured by the FACT-P questionnaire.

Patients with low testosterone levels experienced a significant decline in QoL after 12 weeks of enzalutamide treatment, suggesting that baseline testosterone levels could be a predictive marker for QoL changes in CRPC patients undergoing this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective study of the relationship between CRPC patient's quality of life after enzalutamide and serum testosterone levels measured via LC-MS/MS. Miyazawa, Y., Nakamura, T., Takezawa, Y., et al.[2023]

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]

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 demonstrated significant efficacy in managing non-metastatic castration-resistant prostate cancer, with a median prostate-specific antigen-progression-free survival of 35.0 months in a study of 66 Japanese patients.

The treatment showed a high prostate-specific antigen response rate of 88.9%, with most patients experiencing manageable adverse events, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide in patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical treatment in Japan (Japanese research for patients with non-metastatic castration-resistant prostate cancer-enzalutamide: JCASTRE-zero)-a prospective single-arm interventional study. Sugimoto, M., Kato, T., Tohi, Y., 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]

Citations

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Study Details | NCT04471974 | ZEN-3694, Enzalutamide, ... Enzalutamide has been shown to block testosterone from reaching prostate cancer cells by binding to a receptor on prostate cancer cells, called androgen ...

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1404P A phase II study of ZEN-3694 (ZEN), enzalutamide ... Conclusions. The combination of ZEN, ENZ, and P had an acceptable safety profile. Preliminary clinical activity was observed, including responses in ENZ- ...

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ASCO 2025: A Randomized, Open-Label, Phase 2b Study ... A randomized, open-label, phase 2b study of the bromodomain inhibitor ZEN-3694 + enzalutamide versus enzalutamide in patients with metastatic castration ...

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Improved Outcomes with Enzalutamide in Biochemically ... In patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with ...