Prostate Cancer
Conditions
Keywords
immunotherapy, PARP, radiation, androgen deprivation therapy, ADT, PD-1
Brief summary
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.
Detailed description
Immunotherapy and PARP-inhibitor are known to have radio-sensitizing effects when combined with radiation therapy. In addition, the combination with PARP-inhibitor and radiation can increase neoantigen expression, cytotoxic lymphocyte infiltration within the tumor microenvironment and increased immune stimulating cytokine concentration. Thus, there is a potential synergy of combining immunotherapy and PARP-inhibitor. This is a phase 2 randomized 1:1 study. Subjects will be randomized to one arm (pembro + PARPi + standard of care therapy which is definitive radiation therapy combined with hormonal therapy) vs. another arm (pembro + standard of care therapy). All subjects will receive adjuvant immunotherapy for one year once they are done with definitive radiation treatment. Due to slow accrual and feasibility concerns, the protocol was modified to single arm phase II study. All patients will receive definitive radiation therapy combined with ADT per institutional standards. In addition to concurrent ADT and radiation therapy, patients on this trial will also receive as follow: Pembrolizumab (17 cycles) combined with olaparib (the first three cycles). The remaining patients will be enrolled to Arm 1 only (i.e., Arm 2 usual care is closed to accrual upon Amendment 5 protocol).
Interventions
BIOLOGICALPembrolizumab
Pembrolizumab will be delivered via IV at 200mg on day 1 of each 3-week cycle for approximately 12 months. Cycle 1 begins 21 days prior to radiation therapy and cycles 2-17 are administered during and after radiation therapy.
DRUGOlaparib
200mg Olaparib will be given twice daily for a total of 3 cycles. Cycle 1 begins 21-days prior to radiation therapy.
DRUGAndrogen Deprivation Therapy
Androgen Deprivation Therapy (either LHRH agonist or LHRH antagonist) as per treating physician choice will be allowed within 3 months prior to randomization. Duration is per institutional standards.
RADIATIONRadiation Therapy
Definitive radiation (total dose and fractions) will be dosed per institutional standards. Definitive radiation may include external beam radiation therapy with or without brachytherapy, based on NCCN risk score and as per treating physicians.
Sponsors
Zin W Myint
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
1:1
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male participants with histologically confirmed adenocarcinoma of the prostate * High-risk / very high-risk status per NCCN guidelines * ECOG performance status 0 to 1 * Regional lymph nodes are allowed. * Agree to use contraception during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period. * Ability to understand and the willingness to sign a written informed consent document. * Adequate organ and marrow function * Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation is ≤90 days prior to the date of registration * Known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.
Exclusion criteria
* Prior hormonal therapy with LHRH agonists (e.g., Lupron) and LHRH antagonists (e.g., Degarelix)for prostate cancer continuously for more than 90-days prior to study enrollment. * Prior radiation to the prostate or pelvic nodes radiation. * Previous or major surgery (colorectal anastomosis, total cystectomy, etc.). * History of Ulcerative proctitis. * Concurrent active, additional malignancy in the last 2 years. * Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization. * Patients with M1 disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response Rate | 6 months | The proportion of patients who achieve a PSA nadir level of ≤ 0.06ng/mL six months after completion of radiation therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biochemical-Free Survival | 3 years | Biochemical-free survival rate at 3 years as defined by Phoenix Criteria. |
| Metastasis-Free Survival | 3 years | Metastasis-free survival rate at 3 years as defined by RECIST v1.1 criteria. |
| Time to Normalization of Serum Testosterone | 3 years | Time from normalization is the date of first return to normal serum testosterone 270 ng/ml or greater after withdrawal of androgen deprivation therapy. |
| Molecular Alterations in Homologous Recombination Repair Genes | 3 years | Molecular alterations in the homologous recombination repair (HHR) genes. |
Countries
United States
Contacts
CONTACTBryan Courtney
PRINCIPAL_INVESTIGATORZin W Myint, MD
University of Kentucky
Outcome results
None listed