Pembrolizumab + ADT for Prostate Cancer

Not currently recruiting at 303 trial locations

Age: 18+

Sex: Male

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must be taking: Androgen deprivation therapy

Must not be taking: Steroids, Anti-PD-1 agents

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: 3

Duration: Approximately 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a new combination of treatments can help men with metastatic prostate cancer. Researchers aim to determine if adding pembrolizumab (an immunotherapy drug) to standard treatments like enzalutamide and Androgen Deprivation Therapy (ADT) is more effective at stopping cancer growth and extending life compared to standard treatment alone. Men with prostate cancer that has spread and who are already undergoing ADT might be suitable for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking advancements in prostate cancer treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must continue Androgen Deprivation Therapy (ADT) during the study. 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 adding pembrolizumab to enzalutamide and hormone therapy can cause serious side effects. In studies, participants who took this combination experienced more severe side effects than those who did not take pembrolizumab. These side effects included skin rashes and other serious health issues. While some individuals may tolerate it well, the risk of serious side effects is higher with this treatment mix. It is crucial to discuss potential risks and benefits with a doctor before joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for prostate cancer?

Researchers are excited about combining pembrolizumab with androgen deprivation therapy (ADT) and enzalutamide for prostate cancer because pembrolizumab introduces a novel mechanism of action. Unlike standard treatments that primarily target hormones, pembrolizumab is an immunotherapy that works by blocking a protein called PD-1, helping the immune system recognize and attack cancer cells. This approach could potentially enhance the effectiveness of existing hormone therapies and offer new hope for patients with advanced prostate cancer.

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

This trial will compare the combination of pembrolizumab with enzalutamide and androgen deprivation therapy (ADT) against a placebo with enzalutamide and ADT for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Studies have shown that using pembrolizumab with enzalutamide and ADT may improve outcomes for these patients. Specifically, the KEYNOTE-991 study found that this combination might slow disease progression and improve survival rates. Pembrolizumab, a type of immunotherapy, helps the body's immune system fight cancer cells. When combined with enzalutamide, which blocks hormones that promote prostate cancer growth, and ADT, it might offer better control over cancer growth. Research suggests that this combination could be more effective than using just enzalutamide and ADT. ^{2 5 6 7 8}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

Men with advanced prostate cancer that has spread, who haven't had certain treatments like anti-PD-1 or anti-PD-L1 therapy. They must be able to perform daily activities with little help (ECOG status of 0 or 1), have good organ function, and agree to use contraception. Excluded are those with seizure history, vaccine within the last month, organ transplants, active autoimmune diseases needing recent treatment, significant heart issues or uncontrolled blood pressure.

Inclusion Criteria

I am willing to continue hormone therapy or have had both testicles removed.

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

My organs are functioning well.

Exclusion Criteria

I have an active HIV, HBV, or HCV infection.

I have been treated with advanced hormone therapy for cancer.

I have a history of seizures or conditions that could lead to seizures.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

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

Approximately 2 years

Every 3 weeks (Q3W) for up to 35 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 32 months

Standard of Care

Participants continue to receive standard of care treatment if deriving clinical benefit after stopping pembrolizumab/placebo

What Are the Treatments Tested in This Trial?

Interventions

• Androgen Deprivation Therapy (ADT)
• Enzalutamide
• Pembrolizumab
• Placebo

Trial Overview The trial is testing if adding pembrolizumab to enzalutamide and ADT improves survival without cancer growth compared to placebo plus enzalutamide and ADT in men with metastatic hormone-sensitive prostate cancer. The study was blinded but now all participants will receive standard care after stopping pembrolizumab/placebo.

How Is the Trial Designed?

Group I: Pembrolizumab + Enzalutamide + ADT Experimental Treatment 3 Interventions

Starting on Day 1 of each 21-day cycle, participants receive 200 mg pembrolizumab IV every 3 weeks (Q3W) for up to 35 cycles (approximately 2 years), plus 160 mg enzalutamide taken orally once daily, while maintaining continuous ADT with a luteinizing-hormone releasing hormone (LHRH) agonist or antagonist during study treatment. Participants will continue to receive enzalutamide and ADT until criteria for discontinuation are met.

Group II: Placebo + Enzalutamide + ADT Placebo Group 3 Interventions

Starting on Day 1 of each 21-day cycle, participants receive placebo IV Q3W for up to 35 cycles (approximately 2 years), plus 160 mg enzalutamide taken orally once daily, while maintaining continuous ADT with a LHRH agonist or antagonist during study treatment. Participants will continue to receive enzalutamide and ADT until criteria for discontinuation are met.

Androgen Deprivation Therapy (ADT) is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Androgen Deprivation Therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Non-metastatic high-risk prostate cancer

Approved in United States as Androgen Deprivation Therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Non-metastatic high-risk prostate cancer

Approved in Canada as Androgen Deprivation Therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Non-metastatic high-risk prostate cancer

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

Published Research Related to This Trial

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]

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]

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]

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]

In a study of 54 men with advanced prostate cancer treated with pembrolizumab, about 55% experienced stabilization or a decline in PSA levels, indicating modest efficacy of the treatment.

Men who started pembrolizumab with lower PSA levels and fewer bone metastases had a higher likelihood of responding to the treatment, suggesting that earlier intervention may improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real World Experience With Pembrolizumab in Recurrent or Advanced Prostate Cancer. Higa, J., Wilenius, K., Savino, S., 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]

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]

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]

In men with metastatic hormone-sensitive prostate cancer, enzalutamide, when combined with androgen-deprivation therapy, significantly prolonged radiographic progression-free survival compared to a placebo.

This finding highlights the efficacy of enzalutamide as an androgen-receptor inhibitor in improving outcomes for patients undergoing treatment for advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eyeing Enzalutamide for Hormone-Sensitive Prostate Cancer. [2020]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40383194/

the randomized, double-blind, phase III KEYNOTE-991 study The placebo-controlled, double-blind, phase III KEYNOTE-991 study evaluated the efficacy and safety of adding pembrolizumab to enzalutamide and androgen ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04934722?id=%22NCT02325557%22OR%22NCT02787005%22OR%22NCT02861573%22OR%22NCT03093428%22OR%22NCT03506997%22OR%22NCT03658447%22OR%22NCT03753243%22OR%22NCT03792841%22OR%22NCT04009967%22OR%22NCT04090528%22OR%22NCT04104893%22OR%22NCT04116775%22OR%22NCT04191096%22OR%22NCT04565496%22OR%22NCT04569461%22OR%22NCT04931979%22OR%22NCT04934722%22OR%22NCT04946370%22&rank=2

NCT04934722 | Efficacy and Safety of Pembrolizumab (MK ... This study will assess the efficacy and safety of pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT in Chinese participants ...

3. tandfonline.com tandfonline.com/doi/full/10.2217/fon-2022-0776

KEYNOTE-991: Pembrolizumab Plus Enzalutamide and ... For patients who develop metastatic disease, treatment options have evolved considerably; overall survival rate has improved; however, 5-year survival rates are ...

4. merck.com merck.com/news/merck-announces-keynote-991-trial-evaluating-keytruda-pembrolizumab-plus-enzalutamide-and-androgen-deprivation-therapy-in-patients-with-metastatic-hormone-sensitive-prostate-cancer-to-stop-for/

Merck Announces KEYNOTE-991 Trial Evaluating ... Despite high initial response rates with ADT alone, the majority of patients progress to castration-resistant prostate cancer within three years ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S266700542500047X

Emerging therapies to overcome antiandrogen resistance ... This review integrates current standard-of-care practices with emerging research on resistance mechanisms and novel treatment strategies.

6. annalsofoncology.org annalsofoncology.org/article/S0923-7534(25)00200-5/fulltext

the randomized, double-blind, phase III KEYNOTE-991 study The placebo-controlled, double-blind, phase III KEYNOTE-991 study evaluated the efficacy and safety of adding pembrolizumab to enzalutamide and ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04191096

NCT04191096 | Efficacy and Safety of Pembrolizumab (MK ... This study will assess the efficacy and safety of pembrolizumab plus enzalutamide plus Androgen Deprivation Therapy (ADT) versus placebo plus enzalutamide ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0923753425002005

Pembrolizumab plus enzalutamide and androgen ... The placebo-controlled, double-blind, phase III KEYNOTE-991 study evaluated the efficacy and safety of adding pembrolizumab to enzalutamide and androgen ...