Pembrolizumab Combination Therapies for Prostate Cancer

Recruiting in Palo Alto (17 mi)

+44 other locations

Age: 18+

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Merck Sharp & Dohme Corp.

Must be taking: Androgen deprivation therapy

Must not be taking: Immunosuppressive therapy, CYP3A4 inhibitors

Disqualifiers: Autoimmune disease, Pneumonitis, HIV, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests pembrolizumab combined with other drugs in patients with advanced prostate cancer that doesn't respond to usual treatments. The treatment works by boosting the immune system to better attack cancer cells. Pembrolizumab has been previously tested in combination with chemotherapy for other cancers, showing improved response rates and progression-free survival.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, certain medications like strong CYP3A4 inhibitors or inducers are restricted for some cohorts, and prior treatments with specific drugs may affect eligibility. It's best to discuss your current medications with the trial team to understand any potential conflicts.

What evidence supports the effectiveness of the drug pembrolizumab in combination with other therapies for prostate cancer?

Research shows that pembrolizumab, when combined with enzalutamide, has shown unexpected antitumor activity in some patients with metastatic castration-resistant prostate cancer, leading to significant reductions in prostate-specific antigen levels and partial responses in measurable disease. ^{1 2 3 4 5}

Is pembrolizumab safe for use in prostate cancer treatments?

Pembrolizumab has been studied in combination with other drugs like enzalutamide for prostate cancer, and while it shows some promise, there have been reports of immune-related side effects such as myositis (muscle inflammation) and hypothyroidism (underactive thyroid). These side effects were significant in some patients, indicating that while pembrolizumab can be used, it may cause notable side effects in certain individuals. ^{2 6 7 8 9}

What makes the pembrolizumab combination therapy unique for prostate cancer?

This treatment is unique because it combines pembrolizumab, an immune checkpoint inhibitor, with other drugs like enzalutamide and abiraterone acetate, which are typically used for prostate cancer. Pembrolizumab has shown unexpected antitumor activity in patients resistant to other treatments, offering a new option for those with advanced prostate cancer. ^{2 6 10 11 12}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

Men with advanced prostate cancer that's resistant to hormone therapy and has spread, who are still undergoing androgen deprivation (testosterone <50 ng/dL). They must be relatively healthy (ECOG 0-2), able to provide a recent tumor sample, and have had cancer progression within the last 6 months. Participants should agree to contraception if applicable. Those with certain prior treatments or medical conditions like HIV, hepatitis B/C, brain metastases, or intense bone scans aren't eligible.

Inclusion Criteria

My prostate cancer biopsy shows specific cell types and has been confirmed by a central review.

I can provide a recent biopsy of my cancer that hasn't been radiated.

My prostate cancer has worsened in the last 6 months, shown by tests or scans.

Exclusion Criteria

I have had lung inflammation that needed steroids or have it now.

Has known active Hepatitis B or Hepatitis C

I have not received a live vaccine in the last 30 days.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab combination therapies in various cohorts, with treatment continuing for a maximum of 35 cycles (up to 2 years) or until progression.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Second Course Treatment (optional)

Participants who discontinue pembrolizumab after 35 infusions for reasons other than disease progression or intolerability may receive a second course of treatment with up to 17 additional infusions.

Approximately 1 year

Treatment Details

Interventions

• Abiraterone acetate (Androgen Synthesis Inhibitor)
• Belzutifan (Hypoxia-Inducible Factor-2 Alpha Inhibitor)
• Carboplatin (Chemotherapy)
• Enzalutamide (Androgen Receptor Inhibitor)
• Etoposide (Chemotherapy)
• Lenvatinib (Tyrosine Kinase Inhibitor)
• Olaparib (PARP Inhibitor)
• Pembrolizumab (Checkpoint Inhibitor)
• Prednisone (Corticosteroid)

Trial Overview The trial is testing how safe and effective pembrolizumab is when combined with other drugs in different groups of patients with metastatic castration-resistant prostate cancer. There are ten cohorts each receiving various combinations including pembrolizumab plus olaparib, docetaxel/prednisone, enzalutamide, abiraterone/prednisone among others.

Participant Groups

Group I: Pembrolizumab/Vibostolimab coformulation:t-NE Experimental Treatment 1 Intervention

Participants with t-NE mCRPC in Cohort H will receive a coformulation fixed dose combination of 200 mg pembrolizumab and 200 mg vibostolimab (MK-7684) Q3W IV from Day 1 of Cycle 1. Treatment will continue for a maximum of 35 cycles (up to 2 years) or until progression.

Group II: Pembrolizumab/Vibostolimab coformulation Experimental Treatment 1 Intervention

Participants with AC mCRPC in Cohort G will receive a coformulation fixed dose combination of 200 mg pembrolizumab and 200 mg vibostolimab (MK-7684) Q3W IV from Day 1 of Cycle 1. Treatment will continue for a maximum of 35 cycles (up to 2 years) or until progression.

Group III: Pembrolizumab+Olaparib Experimental Treatment 3 Interventions

Participants with adenocarcinoma (AC) mCRPC in Cohort A will receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week dosing cycle (Q3W) and olaparib 400 mg capsules or 300 mg tablets by mouth (PO) twice a day (BID) continuously from Day 1 of Cycle 1. Treatment with pembrolizumab will continue until progression or a maximum of 35 treatment cycles (up to 2 years). Treatment with olaparib will continue until progression. Participants who must discontinue 1 of the 2 drugs in the combination due to adverse events may continue the study with the other combination drug.

Group IV: Pembrolizumab+Lenvatinib:t-NE Experimental Treatment 2 Interventions

Participants with neuroendocrine (t-NE) mCRPC in Cohort F will receive pembrolizumab 200 mg IV on Day 1 Q3W, and lenvatinib 20 mg PO QD continuously from Day 1 of Cycle 1. Treatment with pembrolizumab will continue for a maximum of 35 cycles (up to 2 years) or until progression. Participants who must discontinue 1 of the 2 drugs due to adverse events in the combination may continue the study with the other combination drug.

Group V: Pembrolizumab+Lenvatinib: AC Experimental Treatment 2 Interventions

Participants with AC mCRPC in Cohort E will receive pembrolizumab 200 mg IV on Day 1 Q3W, and lenvatinib 20 mg PO QD continuously from Day 1 of Cycle 1. Treatment with pembrolizumab will continue for a maximum of 35 cycles (up to 2 years) or until progression. Participants who must discontinue 1 of the 2 drugs due to adverse events in the combination may continue the study with the other combination drug.

Group VI: Pembrolizumab+Enzalutamide Experimental Treatment 2 Interventions

Participants with AC mCRPC in Cohort C will receive pembrolizumab 200 mg IV on Day 1 Q3W and enzalutamide 160 mg PO every day (QD) continuously from Day 1 of Cycle 1. Treatment with pembrolizumab will continue until progression or a maximum of 35 treatment cycles (up to 2 years). Treatment with enzalutamide will continue until progression. Participants who must discontinue 1 of the 2 drugs in the combination due to adverse events may continue the study with the other combination drug.

Group VII: Pembrolizumab+Docetaxel+Prednisone Experimental Treatment 4 Interventions

Participants with AC mCRPC in Cohort B will receive pembrolizumab 200 mg IV on Day 1 Q3W, docetaxel 75 mg/m\^2 IV on Day 1 Q3W, and prednisone 5 mg tablet PO BID continuously from Day 1 of Cycle 1. Participants will only be permitted to receive a maximum of 10 cycles of docetaxel and prednisone. Treatment with pembrolizumab will continue for a maximum of 35 cycles (up to 2 years) or until progression. Participants who must discontinue 1 of the 2 drugs due to adverse events in the combination may continue the study with the other combination drug.

Group VIII: Pembrolizumab+Carboplatin+Etoposide Experimental Treatment 3 Interventions

Participants with neuroendocrine mCRPC in Cohort I Arm 1 will receive pembrolizumab 200 mg IV on Day 1 Q3W + carboplatin titrated to an area under the plasma drug concentration-time curve \[AUC\] 5 IV on Day 1 Q3W + etoposide 100 mg/m\^2 IV on Days 1, 2, and 3 Q3W. Treatment with pembrolizumab will continue for a maximum of 35 cycles (up to 2 years) or until progression. Treatment with carboplatin+etoposide will continue for a maximum of 4 cycles (up to 2.8 months). Participants who must discontinue 1 or 2 of the 3 drugs due to adverse events in the combination may continue the study with the other combination drug/drugs.

Group IX: Pembrolizumab+Belzutifan Experimental Treatment 2 Interventions

Participants with AC mCRPC in Cohort J will receive belzutifan 120mg QD in the initial cohort. If an efficacy signal is detected in this arm based on a totality of evidence, Cohort J may be expanded further where participants will be randomized 1:1 to receive either belzutifan 120 mg QD or belzutifan 120 mg QD and pembrolizumab 200 mg Q3W. Treatment will continue for a maximum of 35 cycles (up to 2 years) or until progression.

Group X: Pembrolizumab+Abiraterone+Prednisone Experimental Treatment 3 Interventions

Participants with AC mCRPC in Cohort D will receive pembrolizumab 200 mg IV on Day 1 Q3W, abiraterone acetate 1000 mg PO QD and prednisone 5 mg tablet PO BID continuously from Day 1 of Cycle 1. Treatment with pembrolizumab will continue for a maximum of 35 cycles (up to 2 years) or until progression. Participants who must discontinue 1 of the 2 drugs due to adverse events in the combination may continue the study with the other combination drug.

Group XI: Carboplatin+Etoposide Experimental Treatment 2 Interventions

Participants with neuroendocrine mCRPC in Cohort I Arm 2 will receive carboplatin titrated to an area under the plasma drug concentration-time curve \[AUC\] 5 IV on Day 1 Q3W + etoposide 100 mg/m\^2 IV on Days 1, 2, and 3 Q3W. Treatment will continue for a maximum of 35 cycles (up to 2 years) or until progression. Treatment with carboplatin+etoposide will continue for a maximum of 4 cycles (up to 2.8 months). Participants who must discontinue 1 of the 2 drugs due to adverse events in the combination may continue the study with the other combination drug.

Group XII: Belzutifan Experimental Treatment 1 Intervention

Participants with AC mCRPC in Cohort J will receive belzutifan 120mg QD in the initial cohort. If an efficacy signal is detected in this arm based on a totality of evidence, Cohort J may be expanded further where participants will be randomized 1:1 to receive either belzutifan 120 mg QD or belzutifan 120 mg QD and pembrolizumab 200 mg Q3W. Treatment will continue for a maximum of 35 cycles (up to 2 years) or until progression.

Abiraterone acetate is already approved in Canada, Japan for the following indications:

Approved in Canada as Zytiga for:

• Metastatic castration-resistant prostate cancer

Approved in Japan as Zytiga for:

• Metastatic castration-resistant 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

In a network meta-analysis of four trials involving treatments for castration-resistant, docetaxel-resistant metastatic prostate cancer, no significant differences in overall survival were found among abiraterone acetate, enzalutamide, cabazitaxel, and Radium-223.

However, enzalutamide showed a significant advantage over the other treatments in delaying PSA progression, suggesting it may be more effective in managing disease progression despite similar overall survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Metastatic, Castration-resistant, Docetaxel-resistant Prostate Cancer: A Systematic Review of Literature With a Network Meta-analysis of Randomized Clinical Trials. Tassinari, D., Cherubini, C., Roudnas, B., et al.[2021]

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]

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 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]

In a study of 71,606 men with castration-resistant prostate cancer, 7% received emerging therapies like abiraterone and enzalutamide, indicating these treatments are becoming common in clinical practice.

Among those receiving emerging therapies, 61% also used denosumab or zoledronic acid, particularly in patients with bone metastases, highlighting a trend towards combined treatment approaches for better management of prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Observational Study of Concomitant Use of Emerging Therapies and Denosumab or Zoledronic Acid in Prostate Cancer. Liede, A., Wade, S., Lethen, J., et al.[2019]

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 102 patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously failed abiraterone treatment, the combination of pembrolizumab and enzalutamide showed a confirmed prostate-specific antigen (PSA) response rate of only 24%, indicating limited antitumor activity.

The treatment was associated with a high incidence of treatment-related adverse events (92%), including severe reactions in 43% of patients, but the safety profile was consistent with the known effects of each drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab and Enzalutamide in Patients with Abiraterone Acetate-Pretreated Metastatic Castration-Resistant Prostate Cancer: Cohort C of the Phase 1b/2 KEYNOTE-365 Study. Yu, EY., Berry, WR., Gurney, H., et al.[2023]

Five new agents have been approved for treating metastatic, castration-resistant prostate cancer, with four being non-chemotherapeutic and generally well tolerated, although they can still cause toxicities that may affect elderly patients.

The review highlights the importance of considering disease burden, comorbid conditions, and potential drug-drug interactions when selecting therapies for elderly patients, as the clinical trial populations often differ from real-world patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapeutic management of metastatic, castration-resistant prostate cancer in the elderly: focus on non-chemotherapy agents. Graff, JN., Beer, TM.[2022]

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]

Pembrolizumab, an FDA-approved immune checkpoint inhibitor, has shown promising responses in specific subgroups of patients with metastatic castration-resistant prostate cancer (mCRPC), despite most trials not meeting their primary endpoints.

Innovative combination therapies involving pembrolizumab with other treatments, such as radioligands and DNA vaccines, are currently being explored and show potential for improving patient survival in mCRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in mCRPC - Combination therapies as breakthrough to success? Plas, S., Pircher, A., Heidegger, I.[2023]

A 58-year-old patient with metastatic castration-resistant prostate cancer and microsatellite instability-high showed significant clinical improvement after treatment with pembrolizumab, including decreased prostate-specific antigen levels and reduced lymph node size.

This case suggests that pembrolizumab could be an effective treatment option for patients with microsatellite instability-high in castration-resistant prostate cancer, despite its rarity, marking a potential new avenue for therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for a patient with metastatic castration-resistant prostate cancer with microsatellite instability-high. Fujiwara, M., Komai, Y., Yuasa, T., et al.[2022]

References

1. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Treatment of Metastatic, Castration-resistant, Docetaxel-resistant Prostate Cancer: A Systematic Review of Literature With a Network Meta-analysis of Randomized Clinical Trials. [2021]

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

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

3. England pubmed.ncbi.nlm.nih.gov

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

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

An Observational Study of Concomitant Use of Emerging Therapies and Denosumab or Zoledronic Acid in Prostate Cancer. [2019]

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. Netherlands pubmed.ncbi.nlm.nih.gov

Pembrolizumab and Enzalutamide in Patients with Abiraterone Acetate-Pretreated Metastatic Castration-Resistant Prostate Cancer: Cohort C of the Phase 1b/2 KEYNOTE-365 Study. [2023]

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

Pharmacotherapeutic management of metastatic, castration-resistant prostate cancer in the elderly: focus on non-chemotherapy agents. [2022]

9. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

Pembrolizumab in mCRPC - Combination therapies as breakthrough to success? [2023]

12. Australia pubmed.ncbi.nlm.nih.gov

Pembrolizumab for a patient with metastatic castration-resistant prostate cancer with microsatellite instability-high. [2022]