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}

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 European Union, United States, Canada, Japan for the following indications:

🇪🇺 Approved in European Union as Zytiga for:

• Metastatic castration-resistant prostate cancer

🇺🇸 Approved in United States as Zytiga for:

• Metastatic castration-resistant prostate cancer
• High-risk metastatic hormone-sensitive prostate cancer

🇨🇦 Approved in Canada as Zytiga for:

• Metastatic castration-resistant prostate cancer

🇯🇵 Approved in Japan as Zytiga for:

• Metastatic castration-resistant prostate cancer

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Call for Information (Investigational Site 2038) Louisville, KY

Call for Information (Investigational Site 0007) Orange, CA

Call for Information (Investigational Site 0004) Cary, NC

Merck Canada Kirkland, Canada

More Trial Locations

Who Is Running the Clinical Trial?

Merck Sharp & Dohme Corp. Lead Sponsor

Merck Sharp & Dohme LLC Lead Sponsor

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] To compare the efficacy of abiraterone acetate, enzalutamide, cabazitaxel and Radium-223 in the treatment of castration-resistant, docetaxel-resistant metastatic prostate cancer.

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

Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. [2022] While programmed cell death 1 (PD-1) inhibitors have shown clear anti-tumor efficacy in several solid tumors, prior results in men with metastatic castration resistant prostate cancer (mCRPC) showed no evidence of activity. Here we report unexpected antitumor activity seen in mCRPC patients treated with the anti-PD-1 antibody pembrolizumab. Patients with evidence of progression on enzalutamide were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses; pembrolizumab was added to standard dose enzalutamide. Three of the first ten patients enrolled in this ongoing phase II trial experienced rapid prostate specific antigen (PSA) reductions to ≤ 0.2 ng/ml. Two of these three patients had measurable disease upon study entry; both achieved a partial response. There were three patients with significant immune-related adverse events. One had grade 2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism. None of these patients had a response. Two of the three responders had a baseline tumor biopsy. Immunohistochemistry from those biopsies showed the presence of CD3+, CD8+, and CD163+ leukocyte infiltrates and PD-L1 expression. Genetic analysis of the two responders revealed markers of microsatellite instability in one. The surprising and robust responses seen in this study should lead to re-examination of PD-1 inhibition in prostate cancer.

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

KEYNOTE-991: pembrolizumab plus enzalutamide and androgen deprivation for metastatic hormone-sensitive prostate cancer. [2023] Current treatment for patients with metastatic hormone-sensitive prostate cancer (mHSPC) delays disease progression and improves survival, but resistance is inevitable. Additional therapies that prolong survival are needed. Androgen deprivation therapy (ADT) combined with next-generation hormonal agents, such as enzalutamide, is standard-of-care for men with mHSPC. Emerging evidence suggests potential synergism between enzalutamide and the PD-1 inhibitor pembrolizumab in prostate cancer. The phase III randomized, placebo-controlled, double-blind KEYNOTE-991 trial will investigate the efficacy and safety of pembrolizumab versus placebo in combination with enzalutamide when initiating ADT in participants with mHSPC naive to next-generation hormonal agents. Approximately 1232 patients will be randomly assigned 1:1 to receive pembrolizumab 200&#160;mg every 3&#160;weeks&#160;or placebo every 3 weeks, both with enzalutamide 160&#160;mg once daily and ADT. Dual primary end points are overall survival&#160;and radiographic progression-free survival. Secondary end points include time to first subsequent therapy, time to symptomatic skeletal&#160;related event, objective response rate&#160;and safety and tolerability. Clinical Trial Registration: NCT04191096 (ClinicalTrials.gov).

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] The purpose of this retrospective study was to evaluate the survival outcomes of pembrolizumab (PEM) plus enzalutamide (ENZ) versus PEM alone in selected populations of men with previously untreated metastatic castration-resistant prostate cancer (mCRPC) harbouring programmed cell death ligand-1 (PD-L1) staining.

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] This observational study of oncologic clinical practices was designed to describe real-world patterns of use of emerging therapies (abiraterone acetate, cabazitaxel, enzalutamide, radium-223, sipuleucel-T) in patients with castration-resistant prostate cancer and to characterize their concomitant use with denosumab or zoledronic acid.

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] Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population.

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] Limited responses have been observed in patients treated with enzalutamide after disease progression on abiraterone for metastatic castration-resistant prostate cancer (mCRPC), but androgen receptor signaling impacts T-cell function.

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] In the past 4 years, five new agents have been approved for metastatic, castration-resistant prostate cancer. Four of them are non-chemotherapeutic and generally well tolerated. However, each has toxicities that can negatively impact patients, particularly the elderly. This review covers the epidemiology of prostate cancer in elderly men. It discusses the efficacy data for sipuleucel-T, abiraterone in chemotherapy-naïve patients, enzalutamide in chemotherapy-naïve patients and radium-223 and presents any additional studies done for those over 75 years of age. Disease burden, such as the presence or absence of visceral disease, and comorbid conditions weigh into the selection of therapy and are discussed here. Drug-drug interactions between these agents and other drugs commonly used in the elderly population are also considered. The emerging therapies tasquinimod and ipilimumab are reviewed. With the arrival of so many agents for prostate cancer, selection of the most appropriate agent can be perplexing, particularly because these agents were tested against placebo, not one another. Furthermore, the study population differs significantly from those seen in clinical practice. This review addresses these issues.

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

KEYNOTE-641: a Phase III study of pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer. [2021] Current treatment options for men with metastatic castration-resistant prostate cancer (mCRPC) are noncurative, and median survival upon development of mCRPC is approximately 3&#160;years. The novel hormonal agent enzalutamide has an established role in the mCRPC treatment paradigm, and emerging evidence suggests potential synergism with enzalutamide and the PD-1 inhibitor pembrolizumab in men with mCRPC. Here, we describe the design and rationale for the multicenter, randomized, double-blind, Phase III KEYNOTE-641 study, which will be conducted to compare the efficacy and safety of pembrolizumab plus enzalutamide with that of enzalutamide plus placebo in mCRPC. Clinical trial registration: NCT03834493 (ClinicalTrials.gov).

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

Real World Experience With Pembrolizumab in Recurrent or Advanced Prostate Cancer. [2021] Phase II trials have shown activity with pembrolizumab against prostate cancer. However, the clinical factors predictive of a response to pembrolizumab in men with prostate cancer are unknown.

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

Pembrolizumab in mCRPC - Combination therapies as breakthrough to success? [2023] Immune checkpoint inhibitors (ICIs) have shown promising antitumor activity in various malignant diseases. This narrative review provides an update on ongoing clinical studies investigating the only FDA-approved ICI programmed death receptor 1 (PD-1) inhibitor pembrolizumab in mono- and combination therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).

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

Pembrolizumab for a patient with metastatic castration-resistant prostate cancer with microsatellite instability-high. [2022] We report the case of a patient with metastatic castration-resistant prostate cancer with microsatellite instability-high who was treated with pembrolizumab after cabazitaxel administration.