Immunotherapy + Radiation ± PARP Inhibitor for Prostate Cancer

Recruiting at 1 trial location

Overseen By Cary Osborne, RN,CCRC

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

Trial Summary

What is the purpose of this trial?

This trial will evaluate whether the immune-sensitizing effects of immunotherapy (Pembrolizumab) and radiation with or without a PARP-inhibitor (Olaparib) will increase the effects of immunotherapy in men with high-risk localized prostate cancer.

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.

What data supports the effectiveness of the treatment Immunotherapy + Radiation ± PARP Inhibitor for Prostate Cancer?

Pembrolizumab, an immune therapy drug, has shown antitumor activity in certain prostate cancer patients, especially those with specific genetic markers like microsatellite instability. Additionally, PARP inhibitors like Olaparib have shown promise in enhancing the effects of radiation therapy in prostate cancer, suggesting a potential benefit when combined with other treatments. ^{1 2 3 4 5}

Is the combination of immunotherapy and radiation with or without a PARP inhibitor generally safe for humans?

Pembrolizumab, an immunotherapy drug, has been studied in various cancers and is generally considered less toxic than traditional chemotherapy, but it can cause side effects like pneumonitis (lung inflammation) in 1%-5% of patients. In prostate cancer studies, some patients experienced immune-related side effects such as myositis (muscle inflammation) and hypothyroidism (underactive thyroid). ^{2 4 5 6 7}

How is the treatment with Pembrolizumab, radiation, and PARP inhibitors unique for prostate cancer?

This treatment is unique because it combines immunotherapy (Pembrolizumab), radiation, and PARP inhibitors, which may enhance the effectiveness of each component. PARP inhibitors can make cancer cells more sensitive to radiation, potentially allowing for lower doses of radiation, and may also improve the response to immunotherapy by making cancer cells more recognizable to the immune system. ^{1 8 9 10 11}

Research Team

Zin W. Myint

Principal Investigator

University of Kentucky

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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]

References

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

PARP inhibitors as a radiosensitizer: a future promising approach in prostate cancer? [2022]

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

Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. [2022]

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

Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer. [2023]

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

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

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

7. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

DNA Repair and Prostate Cancer: A Field Ripe for Harvest. [2021]

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

PARP Inhibitors in Prostate Cancer. [2018]

10. Ireland 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. [2022]

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

Combination Therapy with Radiation and PARP Inhibition Enhances Responsiveness to Anti-PD-1 Therapy in Colorectal Tumor Models. [2021]