Pembrolizumab + Enzalutamide for Prostate Cancer

Recruiting at 265 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Male

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must be taking: Androgen deprivation

Must not be taking: Steroids, Chemotherapy, Herbal products, others

Disqualifiers: Active malignancy, Autoimmune disease, Immunodeficiency, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 1

Duration: 104 weeks

1244 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to assess the efficacy and safety of the combination of pembrolizumab (MK-3475) and enzalutamide in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy for mCRPC, are abiraterone-naïve, or are intolerant to or progressed on abiraterone acetate. There are two primary study hypotheses. Hypothesis 1: The combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to Overall Survival (OS). Hypothesis 2: The combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to Radiographic Progression-free Survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded independent central review.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it does mention that participants must not have used certain treatments like enzalutamide, apalutamide, or certain herbal products before joining. It's best to discuss your specific medications with the trial team.

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

Research shows that Pembrolizumab, when combined with Enzalutamide, has shown unexpected antitumor activity in some patients with prostate cancer that is resistant to Enzalutamide alone, with some patients experiencing significant reductions in prostate-specific antigen (PSA) levels. ^{1 2 3 4 5}

Is the combination of pembrolizumab and enzalutamide safe for humans?

The combination of pembrolizumab (KEYTRUDA) and enzalutamide (XTANDI) has been studied for safety in men with metastatic castration-resistant prostate cancer. These studies suggest that while the combination is generally safe, it may have side effects, and its safety profile is being compared to enzalutamide with a placebo in ongoing research. ^{1 2 5 6 7}

What makes the drug combination of pembrolizumab and enzalutamide unique for prostate cancer?

The combination of pembrolizumab and enzalutamide is unique because it explores the potential synergistic effect of combining an immune checkpoint inhibitor (pembrolizumab) with a next-generation hormonal agent (enzalutamide) to enhance treatment efficacy in prostate cancer, particularly in cases resistant to standard hormone therapies. ^{1 2 3 5 8}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

Men with metastatic castration-resistant prostate cancer who haven't had chemotherapy for it, are either naive to or have not progressed on abiraterone acetate, and whose cancer has worsened despite hormone therapy. Participants must have a low testosterone level, be willing to avoid fathering children during the study, and cannot have had certain prior treatments including specific anti-cancer drugs.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

I have a recent biopsy from a non-irradiated area or from a tumor in a previously radiated area.

I have been on a stable dose of medication for bone health before joining the study.

Exclusion Criteria

I am currently being treated for an active infection.

I have a condition that affects how my body absorbs food or I can't swallow pills.

I have or had lung inflammation that needed steroids.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab plus enzalutamide or placebo plus enzalutamide for up to 35 cycles (approximately 2 years)

104 weeks

1 visit every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 40 months

Treatment Details

Interventions

• Enzalutamide
• Pembrolizumab
• Placebo

Trial Overview The trial is testing if pembrolizumab combined with enzalutamide improves survival compared to placebo plus enzalutamide in men with advanced prostate cancer. It looks at overall survival and time without disease progression using scans reviewed by experts blinded to treatment assignment.

Participant Groups

Group I: Pembrolizumab + Enzalutamide Experimental Treatment 2 Interventions

Participants receive 200 mg pembrolizumab by intravenous (IV) infusion administered on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 2 years) PLUS enzalutamide 160 mg administered orally (PO) once a day (QD) continuously until progression.

Group II: Placebo + Enzalutamide Placebo Group 2 Interventions

Participants receive placebo by IV infusion administered on Day 1 Q3W for up to 35 cycles (approximately 2 years) PLUS enzalutamide 160 mg administered PO QD continuously until progression.

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?

Merck Sharp & Dohme Corp.

Lead Sponsor

Trials

2,287

Recruited

4,582,000+

Chirfi Guindo

Merck Sharp & Dohme Corp.

Chief Medical Officer

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

Robert M. Davis

Merck Sharp & Dohme Corp.

Chief Executive Officer since 2021

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

Merck Sharp & Dohme LLC

Lead 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

Findings from Research

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]

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]

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]

In a phase II trial involving men with metastatic castration-resistant prostate cancer (mCRPC) who were progressing on enzalutamide, the anti-PD-1 antibody pembrolizumab showed unexpected antitumor activity, with three out of ten patients achieving significant reductions in prostate-specific antigen (PSA) levels.

The presence of immune cell infiltrates and PD-L1 expression in tumor biopsies from responders suggests that certain biological markers may predict the effectiveness of PD-1 inhibitors in prostate cancer, warranting further investigation into this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Graff, JN., Alumkal, JJ., Drake, CG., et al.[2022]

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]

In the phase II KEYNOTE-199 study involving 258 patients with metastatic castration-resistant prostate cancer (mCRPC), pembrolizumab demonstrated modest antitumor activity, with objective response rates of 5% in PD-L1-positive patients and 3% in PD-L1-negative patients, indicating some effectiveness in this challenging population.

The treatment was generally well-tolerated, with 60% of patients experiencing treatment-related adverse events, but only 5% discontinuing due to these events, suggesting that pembrolizumab has an acceptable safety profile while providing encouraging overall survival estimates, particularly in patients with bone-predominant disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. Antonarakis, ES., Piulats, JM., Gross-Goupil, M., et al.[2021]

In a study involving 249 men with metastatic castrate-resistant prostate cancer, patient preference between darolutamide and enzalutamide was balanced, with no significant preference for either treatment (p = 0.92).

Darolutamide was associated with less fatigue and a moderate improvement in episodic memory compared to enzalutamide, suggesting it may offer a better quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized, Open-label, Cross-over Phase 2 Trial of Darolutamide and Enzalutamide in Men with Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer: Patient Preference and Cognitive Function in ODENZA. Colomba, E., Jonas, SF., Eymard, JC., et al.[2023]

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]

References

1. England 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. [2023]

2. England pubmed.ncbi.nlm.nih.gov

KEYNOTE-641: a Phase III study of pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer. [2021]

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

Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer. [2023]

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

Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. [2022]

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

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

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

Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

A Randomized, Open-label, Cross-over Phase 2 Trial of Darolutamide and Enzalutamide in Men with Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer: Patient Preference and Cognitive Function in ODENZA. [2023]

8. England pubmed.ncbi.nlm.nih.gov

KEYNOTE-991: pembrolizumab plus enzalutamide and androgen deprivation for metastatic hormone-sensitive prostate cancer. [2023]