ZEN-3694 + Enzalutamide + Pembrolizumab for Prostate Cancer

Not currently recruiting at 2 trial locations

Overseen By UCSF Genitourinary Medical Oncology Recruitment

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Rahul Aggarwal

Must be taking: LHRH analogues

Must not be taking: Immune checkpoint inhibitors

Disqualifiers: Autoimmune disease, Cardiac condition, 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: 3

Duration: 21-day cycles, repeated

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining three treatments—ZEN-3694 (an experimental treatment), enzalutamide, and pembrolizumab—for individuals with prostate cancer that resists standard hormone therapy and has metastasized. ZEN-3694 blocks a specific gene that promotes tumor growth, enzalutamide prevents testosterone from fueling cancer cells, and pembrolizumab enhances the immune system's ability to attack cancer. The trial aims to determine if these treatments can slow or shrink cancer in patients with disease progression. This trial may suit those with metastatic castration-resistant prostate cancer whose condition has worsened despite previous treatments. 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 protocol does not specify if you must stop taking your current medications, but it does mention that patients receiving enzalutamide prior to the study may continue it without a washout period. It's best to discuss your specific 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 ZEN-3694, enzalutamide, and pembrolizumab is generally safe for patients with advanced prostate cancer that no longer responds to hormone therapy. Most patients can undergo the treatment without experiencing severe problems.

Enzalutamide is already approved for treating prostate cancer, indicating it is usually well-tolerated. Pembrolizumab, an immune therapy, helps the body fight cancer cells and is also approved for other types of cancer.

Overall, earlier studies suggest that patients can handle this treatment combination, with some showing positive results even if enzalutamide alone was not effective. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination because it targets prostate cancer from multiple angles. Unlike standard treatments that often focus solely on hormone therapy, this combo includes ZEN-3694, a BET bromodomain inhibitor, which disrupts cancer cell growth by targeting specific proteins involved in gene regulation. Additionally, the inclusion of pembrolizumab, an immune checkpoint inhibitor, boosts the immune system's ability to recognize and destroy cancer cells. This multi-faceted approach offers a promising alternative to traditional therapies by potentially overcoming resistance and improving outcomes for patients with advanced prostate cancer.

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

Studies have shown that enzalutamide can help men with advanced prostate cancer live longer by stopping testosterone from reaching cancer cells, thereby slowing their growth. In this trial, participants will receive a combination of treatments. Research suggests that ZEN-3694, when used with enzalutamide, may inhibit cancer cell growth by targeting a specific gene called MYC. Additionally, early findings indicate that pembrolizumab might enhance the immune system's ability to fight cancer in some patients. While each treatment shows promise, researchers are still studying their combined effectiveness in the various treatment cohorts of this trial. ^{6 7 8 9 10}

Who Is on the Research Team?

Rahul Aggarwal, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

Men with metastatic castration-resistant prostate cancer that has spread and shows progression despite low testosterone levels. Participants must have measurable disease, no prior chemotherapy for metastatic cancer within 6 months, and a maximum of two previous chemo treatments in this setting. They should not have used certain medications or had major surgery recently, nor should they have active infections or severe health conditions that could affect the trial.

Inclusion Criteria

My prostate cancer is spreading despite hormone therapy.

My testosterone levels are very low, and I'm on hormone therapy if not surgically treated.

I am mostly able to carry out my daily activities.

Exclusion Criteria

I haven't needed IV antibiotics for an infection in the last 7 days.

I have or had lung inflammation that needed steroids.

Has participated in a study of an investigational product and received study treatment or used an investigational device other than those specified in the protocol within 2 weeks of C1D1

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-in

A safety lead-in cohort of 6 patients with metastatic CRPC will be enrolled to assess dose-limiting toxicity during Cycle 1

3 weeks

1 visit (in-person)

Treatment

Patients receive pembrolizumab IV, BET bromodomain inhibitor ZEN-3694 PO, and enzalutamide PO in 21-day cycles

21-day cycles, repeated

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

30 days and every 90 days until death or study completion

1 visit at 30 days, then every 90 days

What Are the Treatments Tested in This Trial?

Interventions

• Enzalutamide
• Pembrolizumab
• ZEN-3694

Trial Overview The effectiveness of ZEN-3694 combined with enzalutamide and pembrolizumab is being tested on men with advanced prostate cancer resistant to hormonal therapy. The study aims to see if these drugs can slow down tumor growth by blocking specific genes and receptors involved in cancer cell proliferation while also enhancing the body's immune response against tumor cells.

How Is the Trial Designed?

Group I: Safety Cohort Experimental Treatment 3 Interventions

Patients receive 96mg pembrolizumab IV over 30 minutes on day 1, BET bromodomain inhibitor ZEN-3694 PO QD and enzalutamide PO QD on days 1-21. Patients not on enzalutamide prior to study enrollment or have previously discontinued enzalutamide receive BET bromodomain inhibitor ZEN-3694 beginning on day 1 of cycle 2. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group II: Cohort B: mCRPC without evidence of transdifferentiation Experimental Treatment 3 Interventions

Patients receive pembrolizumab IV over 30 minutes on day 1, BET bromodomain inhibitor ZEN-3694 PO QD and enzalutamide PO QD on days 1-21. Patients not on enzalutamide prior to study enrollment or have previously discontinued enzalutamide receive BET bromodomain inhibitor ZEN-3694 beginning on day 1 of cycle 2. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group III: Cohort A: Transdifferentiated mCRPC Experimental Treatment 3 Interventions

Patients receive pembrolizumab IV over 30 minutes on day 1, BET bromodomain inhibitor ZEN-3694 PO QD and enzalutamide PO QD on days 1-21. Patients not on enzalutamide prior to study enrollment or have previously discontinued enzalutamide receive BET bromodomain inhibitor ZEN-3694 beginning on day 1 of cycle 2. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

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?

Rahul Aggarwal

Lead Sponsor

Trials

13

Recruited

550+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Zenith Epigenetics

Industry Sponsor

Trials

10

Recruited

590+

U.S. Army Medical Research and Development Command

Collaborator

Trials

296

Recruited

249,000+

Published Research Related to This Trial

The KEYNOTE-641 study is a Phase III clinical trial designed to evaluate the safety and efficacy of combining the PD-1 inhibitor pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC).

This trial aims to determine if the combination therapy can improve outcomes compared to enzalutamide alone, addressing the need for more effective treatments in a patient population with a median survival of about 3 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-641: a Phase III study of pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer. Graff, JN., Liang, LW., Kim, J., et al.[2021]

In a study of 206 men with previously untreated metastatic castration-resistant prostate cancer (mCRPC) harboring PD-L1 staining, the combination of pembrolizumab (PEM) and enzalutamide (ENZ) significantly improved overall survival (25.1 months) and progression-free survival (6.1 months) compared to PEM alone (18.3 months and 4.9 months, respectively).

While the combination treatment had a higher rate of adverse events (72% for PE vs. 45.3% for PA), these side effects, including fatigue and musculoskeletal issues, were generally manageable, indicating a favorable safety profile for the combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or without enzalutamide in selected populations of men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining: a retrospective study. Lin, H., Liu, Q., Zeng, X., et al.[2023]

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]

The KEYNOTE-991 trial is a phase III study involving approximately 1232 patients with metastatic hormone-sensitive prostate cancer, testing the combination of pembrolizumab and enzalutamide with androgen deprivation therapy to see if it improves survival and delays disease progression.

This trial aims to explore the potential synergistic effects of combining a PD-1 inhibitor (pembrolizumab) with standard hormonal therapy (enzalutamide), which could lead to new treatment options for patients who typically develop resistance to current therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-991: pembrolizumab plus enzalutamide and androgen deprivation for metastatic hormone-sensitive prostate cancer. Gratzke, C., Kwiatkowski, M., De Giorgi, U., et al.[2023]

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 III trial involving patients with metastatic, castration-resistant prostate cancer (mCRPC) who had progressed after docetaxel treatment, enzalutamide significantly improved overall survival, with a median survival of 18.4 months compared to 13.6 months for placebo, indicating a 37% reduction in mortality risk.

Enzalutamide was generally well tolerated, with most side effects being mild to moderate, although there is a small, dose-dependent risk of seizures; it also improved quality of life and pain management for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide: a review of its use in metastatic, castration-resistant prostate cancer. Sanford, M.[2021]

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]

Combining atezolizumab, an anti-PD-L1 immunotherapy, with enzalutamide, an androgen receptor antagonist, did not improve survival rates in patients with metastatic prostate cancer.

Further research is needed to understand the mechanisms of resistance to immunotherapy in the prostate tumor microenvironment, which may help improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer. Siddiqui, BA., Subudhi, SK., Sharma, P.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3721441/

Evidence for the efficacy of enzalutamide in ... The phase III AFFIRM trial demonstrated that enzalutamide significantly improved OS in men with mCRPC who had progressed in their disease after prior treatment ...

2. pfizer.com pfizer.com/news/press-release/press-release-detail/astellas-and-pfizers-xtanditm-enzalutamide-shows-long-term

Astellas and Pfizer's XTANDI™ (enzalutamide) Shows ... OS at 96 months was 50% with XTANDI and 40% for NSAA; progression-free survival (PFS) also favored XTANDI over NSAA (HR: 0.49; 95% CI, 0.42-0.57) ...

3. xtandihcp.com xtandihcp.com/crpc/efficacy

Efficacy Results in CRPC EFFICACY RESULTS IN CRPC · XTANDI + GnRH therapy* significantly extended overall survival in mCRPC · For patients on GnRH therapy* who have progressed to mCRPC ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.10527

Efficacy and toxicity of low-doses versus standard- ... In the ENACT trial, enzalutamide monotherapy reduced the risk of PCa progression compared to active surveillance (AS) in patients with ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1903835

Enzalutamide in Metastatic Prostate Cancer Kaplan–Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care ...

6. 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 ...

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

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

8. withpower.com withpower.com/trial/zen-3694-enzalutamide-pembrolizumab-for-prostate-cancer-37e4f

ZEN-3694 + Enzalutamide + Pembrolizumab for Prostate ... The KEYNOTE-641 study is a Phase III clinical trial designed to evaluate the safety and efficacy of combining the PD-1 inhibitor pembrolizumab with enzalutamide ...

9. clin.larvol.com clin.larvol.com/trial-detail/NCT04471974

ZEN-3694, Enzalutamide, and Pembrolizumab for ... This clinical trial will evaluate the aforementioned triple combination therapy in mCRPC patients that have become resistant to a 1st line ARSI therapy.” ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6204864/

Enzalutamide-resistant castration-resistant prostate cancer The new-generation hormonal agent enzalutamide has been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC), in both post- and ...