Pembrolizumab + ADT for Prostate Cancer

Recruiting at 212 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

1251 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will assess the efficacy and safety of pembrolizumab plus enzalutamide plus Androgen Deprivation Therapy (ADT) versus placebo plus enzalutamide plus ADT in participants with mHSPC. The primary hypothesis is that in participants with mHSPC, the combination of pembrolizumab plus enzalutamide plus ADT is superior to placebo plus enzalutamide plus ADT with respect to 1) radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR) and 2) overall survival (OS). As of 19-JAN-2023, the study was unblinded and all study participants stopped ongoing treatment with pembrolizumab/placebo and will continue to receive Standard of Care treatment until meeting protocol-specified discontinuation criteria if deriving clinical benefit. Safety analysis will be performed at the end of the study; there will be no further analyses for efficacy and electronic patient-reported outcome (ePRO) endpoints collected from participants beyond the IA1 cutoff date. All study participants will stop ongoing treatment with pembrolizumab/placebo. Exceptions may be requested for study participants who, in the assessment of their study physician, are benefitting from the combination of enzalutamide and pembrolizumab, after consulting with the Sponsor. All other study participants should be discontinued from study and be offered standard of care (SOC) treatment as deemed necessary by the Investigator. If enzalutamide as SOC is not accessible off study to the participant, central sourcing may continue. As of Amendment 04, disease progression will no longer be centrally verified, participants will only be assessed locally. As of Amendment 4, Second Course treatment is not an option for participants. There are currently no participants in the Second Course Phase.

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.

What data supports the effectiveness of the drug pembrolizumab combined with enzalutamide and ADT for prostate cancer?

Research suggests that combining pembrolizumab with enzalutamide and ADT may have potential benefits for prostate cancer patients. In a study, some patients who were resistant to enzalutamide showed significant reductions in prostate-specific antigen levels when pembrolizumab was added, indicating a possible synergistic effect. ^{1 2 3 4 5}

Is the combination of pembrolizumab and enzalutamide safe for prostate cancer patients?

In studies involving prostate cancer patients, pembrolizumab combined with enzalutamide has shown some immune-related side effects, such as muscle inflammation and thyroid issues, but these were not experienced by all patients. The safety of this combination is still being evaluated in ongoing trials. ^{1 3 6 7 8}

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

This drug combination is unique because it combines pembrolizumab, an immune system booster, with enzalutamide and ADT, which are hormone therapies, to potentially enhance the treatment effect in prostate cancer. The combination aims to delay disease progression and improve survival by leveraging the potential synergistic effects of these drugs, which is not typically seen in standard treatments. ^{1 3 4 7 9}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

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

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

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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 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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

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

4. 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]

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

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

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

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

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

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

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

Real World Experience With Pembrolizumab in Recurrent or Advanced Prostate Cancer. [2021]