Immunotherapy + Radiation ± PARP Inhibitor for Prostate Cancer
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Male
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Zin W Myint
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Approved in 3 jurisdictions
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.
12345Is 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).
24567How 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.
1891011Eligibility 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.Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Arm 2 - PembrolizumabExperimental Treatment3 Interventions
Patients with high-risk prostate cancer receiving combination therapy with Pembrolizumab.
Group II: Arm 1 - Pembrolizumab and OlaparibExperimental Treatment4 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
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
University of KentuckyLexington, KY
Huntsman Cancer InstituteSalt Lake City, UT
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Who is running the clinical trial?
Zin W MyintLead Sponsor
Merck Sharp & Dohme LLCIndustry Sponsor
References
PARP inhibitors as a radiosensitizer: a future promising approach in prostate cancer? [2022]Poly (ADP-ribose) polymerase (PARP) inhibitors (iPARPs) have shown efficacy in homologous recombination (HR) deficiency patients with advanced castration resistant prostate cancer and have shown a radiosensitizing effect in preclinical and early clinical trials. Preclinical data in prostate cancer cells suggest a similar cytotoxic effect with half the radiation dose under the effect of Olaparib or Rucaparib irrespective of HR status. Due to the biologic synergy of radiotherapy (RT) and iPARPs, the risk of recurrence of high-risk prostate cancer and the morbidity associated with prostate cancer local treatment, this interesting strategy seems promising, and a better understanding of the clinical implications remains to be elucidated.
Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. [2022]The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown.
Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer. [2023]Pembrolizumab is approved for patients with metastatic, microsatellite instability (MSI)-high or mismatch repair-deficient (dMMR) solid tumors. However, very few men with prostate cancer were included in these initial studies.
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.
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.
Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.
Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP).
DNA Repair and Prostate Cancer: A Field Ripe for Harvest. [2021]Recent data have revealed antitumor activity for four PARP inhibitors, two of which (olaparib and rucaparib) are approved by the US Food and Drug Administration for metastatic castrate-resistant prostate cancer with selected DNA repair defects. Additional clinical trials are in progress for talazoparib, veliparib, and niraparib. More progress can be anticipated in the near future.
PARP Inhibitors in Prostate Cancer. [2018]The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve "synthetic lethality" in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded "breakthrough designation" to develop the PARPi olaparib in treating this subset of metastatic PCa patients. The search for predictive biomarkers has expanded the realm of DNA repair genetic defects and combination genetic platforms are being evaluated as tools to assess potential "BRCAness" of tumors. Ongoing clinical trials seek to determine the optimal timing and sequence of using these agents in current PCa treatment algorithms. Combination strategies of PARPi with chemo-, radiation, and hormonal therapies, targeted agents, and immunotherapy are promising avenues of current research. Multi-center international collaborations in well-designed biomarker-driven clinical trials will be key to harness the potential of PARPi in managing a heterogeneous disease like prostate cancer.
In vivo studies of the PARP inhibitor, AZD-2281, in combination with fractionated radiotherapy: An exploration of the therapeutic ratio. [2022]Pre-clinical data have shown that PARP inhibitors (PARPi) may increase the efficacy of radiotherapy in prostate cancer. However, it is uncertain as to whether PARPi lead to clonogenic kill when combined with radiotherapy (RT).
Combination Therapy with Radiation and PARP Inhibition Enhances Responsiveness to Anti-PD-1 Therapy in Colorectal Tumor Models. [2021]The majority of colorectal cancers are resistant to cancer immune checkpoint inhibitors. Ionizing radiation (IR) and several radiosensitizers, including PARP inhibitors, can enhance responsiveness to immune checkpoint inhibitors by potentially complementary mechanisms of action. We assessed the ability of radiation and PARP inhibition to induce proimmunogenic changes in tumor cells and enhance their in vivo responsiveness to anti-PD-1 antibodies.