Immunotherapy + Radiation ± PARP Inhibitor for Prostate Cancer

Recruiting at 1 trial location

Overseen By Bryan Courtney

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Zin W Myint

Must not be taking: LHRH agonists, LHRH antagonists

Disqualifiers: PSA > 150ng/ml, Prior radiation, Metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

64 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new ways to treat high-risk prostate cancer using a combination of therapies. Researchers aim to determine if adding a PARP inhibitor (a drug that helps repair DNA damage) to immunotherapy (Pembrolizumab) and radiation therapy enhances treatment effectiveness. Men with prostate cancer that hasn't spread beyond regional lymph nodes and who haven't undergone hormone therapy for more than 90 days might be suitable candidates. The trial includes two groups: one receiving both Pembrolizumab and Olaparib, and the other receiving only Pembrolizumab. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on a 5-alpha reductase inhibitor, it must be stopped at least 60 days before joining the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using pembrolizumab and olaparib together can help fight tumors, with side effects similar to those seen when each drug is used alone. These side effects align with existing knowledge about each drug and are manageable.

For pembrolizumab alone, studies have found that its side effects are generally tolerable for patients.

Pembrolizumab is already used for other conditions, providing doctors with extensive information about its safety in people. The current trial is in phase 2, so researchers are still studying the treatment's safety and effectiveness, but they already have some safety data from earlier studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for high-risk prostate cancer because they combine immunotherapy with new mechanisms of action. Pembrolizumab, an immunotherapy drug, works by boosting the body's immune system to attack cancer cells. When combined with Olaparib, a PARP inhibitor, it may enhance the effectiveness by targeting cancer cells' DNA repair processes. This dual approach could potentially offer a more robust response compared to traditional treatments like hormone therapy or chemotherapy. By leveraging these unique mechanisms, these treatments could provide new hope for patients with aggressive forms of prostate cancer.

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

Research has shown that Pembrolizumab, one of the treatments in this trial, can effectively treat prostate cancer, particularly in patients with genetic traits like MSI-H, a type of DNA repair issue. It has helped patients live longer without cancer progression and can lower PSA levels by more than 50% in some cases. In this trial, some participants will receive Pembrolizumab alone, while others will receive a combination of Pembrolizumab and Olaparib. This combination has shown early signs of reducing tumors, although it hasn't consistently led to longer survival in all studies. Initial results suggest promise, but outcomes have varied. Overall, both treatments have shown potential benefits for prostate cancer, especially in patients with specific genetic profiles. ^{1 5 6 7 8}

Who Is on the Research Team?

Zin W. Myint

Principal Investigator

University of Kentucky

Are You a Good Fit for This Trial?

Men with high-risk localized prostate cancer who meet specific health criteria can join this trial. They must have a certain level of physical fitness, no large pelvic nodes as per CT scans, and agree to use contraception post-treatment. Those with PSA levels over 150ng/ml, extensive prior hormone therapy or radiation to the prostate, other cancers within 2 years, or recent anti-cancer treatments cannot participate.

Inclusion Criteria

My pelvic nodes are not larger than 2 cm as shown by a CT scan.

I am fully active or can carry out light work.

My organs and bone marrow are working well.

Exclusion Criteria

PSA > 150ng/ml

I have had radiation treatment on my prostate before.

I have been on hormone therapy for prostate cancer for over 90 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Pembrolizumab with or without Olaparib in combination with radiation therapy

6 months

Regular visits during treatment

Adjuvant Immunotherapy

Participants receive adjuvant immunotherapy for one year after completion of radiation treatment

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib
• Pembrolizumab
• Radiation Therapy

Trial Overview The study is testing if combining Pembrolizumab (an immunotherapy drug) and radiation therapy improves treatment outcomes in these patients. Some will also receive Olaparib (a PARP-inhibitor) to see if it boosts the immune system's response when added to the mix.

How Is the Trial Designed?

Group I: Arm 2 - Pembrolizumab Experimental Treatment 3 Interventions

Patients with high-risk prostate cancer receiving combination therapy with Pembrolizumab.

Group II: Arm 1 - Pembrolizumab and Olaparib Experimental Treatment 4 Interventions

Patients with high-risk prostate cancer receiving combination therapy with Pembrolizumab and Olaparib.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Zin W Myint

Lead Sponsor

Trials

3

Recruited

120+

Merck Sharp & Dohme LLC

Industry 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

PARP inhibitors, specifically olaparib and rucaparib, have demonstrated effective antitumor activity and are FDA-approved for treating metastatic castrate-resistant prostate cancer with specific DNA repair defects.

Ongoing clinical trials for other PARP inhibitors like talazoparib, veliparib, and niraparib suggest that more treatment options may soon be available for patients with similar conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DNA Repair and Prostate Cancer: A Field Ripe for Harvest. Bryce, AH., Sartor, O., de Bono, J.[2021]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

The combination of the PARP inhibitor veliparib and ionizing radiation (IR) significantly enhances the presentation of immune markers (MHC-1 and PD-L1) on colorectal cancer cells, which may improve their recognition by the immune system.

In preclinical models, this combination therapy not only prolonged the effectiveness of anti-PD-1 antibodies in slowing tumor growth but also improved survival rates, particularly in tumors with microsatellite instability, suggesting a promising new approach to treating resistant colorectal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Therapy with Radiation and PARP Inhibition Enhances Responsiveness to Anti-PD-1 Therapy in Colorectal Tumor Models. Seyedin, SN., Hasibuzzaman, MM., Pham, V., et al.[2021]

The PARP inhibitor AZD-2281 effectively enhances the effectiveness of radiotherapy in prostate cancer by causing significant growth delay and clonogenic kill in both oxic and hypoxic conditions, as demonstrated in preclinical studies using the 22Rv1 cell line.

Importantly, combining AZD-2281 with radiotherapy did not increase gut toxicity, suggesting a potentially safer treatment option that warrants further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo studies of the PARP inhibitor, AZD-2281, in combination with fractionated radiotherapy: An exploration of the therapeutic ratio. Gani, C., Coackley, C., Kumareswaran, R., et al.[2022]

Up to 90% of metastatic prostate cancer patients have actionable mutations, with over 20% showing defects in DNA repair genes, making them potential candidates for treatment with PARP inhibitors (PARPi) that exploit these vulnerabilities.

Clinical trials have demonstrated response rates of up to 88% for patients with specific DNA repair defects like BRCA1/2 or ATM mutations, leading to the FDA granting 'breakthrough designation' for the PARPi olaparib in this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARP Inhibitors in Prostate Cancer. Ramakrishnan Geethakumari, P., Schiewer, MJ., Knudsen, KE., et al.[2018]

PARP inhibitors like Olaparib and Rucaparib have shown effectiveness in treating advanced castration-resistant prostate cancer, particularly in patients with homologous recombination deficiency.

These inhibitors may enhance the effects of radiotherapy, allowing for a cytotoxic effect with lower radiation doses, which could reduce recurrence risk and treatment-related side effects in high-risk prostate cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARP inhibitors as a radiosensitizer: a future promising approach in prostate cancer? Angel, M., Zarba, M., Sade, JP.[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]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

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 1346 prostate cancer patients, only 3.1% were found to have microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, indicating that this molecular phenotype is rare but significant for treatment options.

Among 11 patients with MSI-H/dMMR castration-resistant prostate cancer who received anti-PD-1/PD-L1 therapy, 54.5% experienced a significant decline in prostate-specific antigen levels, suggesting that this therapy can be effective for some patients with this specific tumor type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. Abida, W., Cheng, ML., Armenia, J., et al.[2022]

In a study of 48 men with metastatic castrate-resistant prostate cancer (mCRPC) treated with pembrolizumab, 17% experienced a significant PSA decline of 50% or more, and 8% had an impressive decline of 90% or more, indicating potential efficacy of this treatment in a heavily pretreated population.

The presence of LRP1b mutations in some patients suggests that these genetic alterations may enhance the effectiveness of pembrolizumab, highlighting a possible mechanism for improved response to PD-1 inhibitors in prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer. Tucker, MD., Zhu, J., Marin, D., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02861573

NCT02861573 | Study of Pembrolizumab (MK-3475) ... The purpose of this study is to assess the safety and efficacy of pembrolizumab (MK-3475) combination therapy in participants with metastatic castration ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1558767325000849

Clinical Outcomes of Patients With Metastatic Prostate ... Treatment with pembrolizumab led to a significant rate of biochemical and radiographic response in a heavily pre-treated cohort of MSI-H metastatic prostate ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11408038/

Utility of pembrolizumab for metastatic castrate resistant ... The PD-1 inhibitor pembrolizumab has been found to improve progression-free survival and results in a PSA decline of over 50 % in patients with MMR deficiency ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02787005

NCT02787005 | Study of Pembrolizumab (MK-3475) in ... This is a study of pembrolizumab (MK-3475) in participants with metastatic castration-resistant prostate cancer (mCRPC).

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.6_suppl.165

Updated results of a phase Ib single-center study ... This study evaluated the safety and efficacy signals of pembrolizumab and chemotherapy in patients with small cell/neuroendocrine cancer of the prostate and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7186583/

Pembrolizumab for Treatment-Refractory Metastatic Castration ... Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-01283

The Randomized, Double-Blind, Phase III KEYNOTE-921 ... The addition of pembrolizumab to docetaxel did not significantly improve efficacy outcomes for participants with previously treated mCRPC.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11892552/

Response to pembrolizumab in advanced prostate cancer ... We found that 38.9% of patients showed a 50% or greater decline in PSA, all of whom had high microsatellite instability (MSI-H). One patient ...