This is a phase I-II trial to find the safety and activity of adding a new drug (neraparib) to the usual treatment (radiation combined with male hormone deprivation therapy) in lowering the chance of prostate cancer growing or returning. Niraparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Adding niraparib to the usual care may lower the chance of prostate cancer growing or returning.
PRIMARY OBJECTIVES: I. To establish the preferred dose of niraparib in combination with radiation and antiandrogen therapy (ADT). (Phase I) II. To compare the disease-free state, defined as prostate specific antigen (PSA) remaining \< 0.1 ng/ml at the end of ADT therapy in men with high risk prostate cancer treated with standard therapy with or without the addition of niraparib. (Phase IIR) SECONDARY OBJECTIVES: I. To further establish the safety and toxicity profile of standard treatment with radiation and androgen deprivation therapy specifically, two years from initiation of ADT, plus niraparib at the phase II dose. II. To compare the overall survival, prostate cancer-specific survival, local/regional or distant progression, and distant metastatic disease rates of standard therapy with or without the addition of niraparib. EXPLORATORY OBJECTIVE: I. To identify genomic biomarkers of response to combination therapy with radiation, ADT and PARP inhibition. OUTLINE: This is a phase I, dose-escalation study of niraparib, followed by a randomized phase II study. PHASE I: Patients receive niraparib orally (PO) once daily (QD) and receive standard of care gonadotrophin releasing hormone (GnRH) agonist androgen suppression therapy. Treatment with niraparib continues for 12 months, and GnRH agonist therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib and GnRH agonist, patients undergo standard of care intensity-modulated radiation therapy (IMRT) 5 days per week for about 6-9 weeks, depending on type of radiation therapy given, in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) on study. PHASE II: Patients are randomized to 1 of 2 arms: ARM I: Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8-28 weeks after starting GnRH agonist, patients undergo IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy given in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study. ARM II: Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months, and niraparib PO QD for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy given in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study. After completion of study treatment, patients are followed up every 6 months for 3 years, then annually for 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
22
Receive standard of care GnRH agonist androgen suppression therapy
Undergo standard of care IMRT
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Banner MD Anderson Cancer Center
Gilbert, Arizona, United States
University of Arizona Cancer Center-Orange Grove Campus
Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
City of Hope Comprehensive Cancer Center
Duarte, California, United States
Cedars Sinai Medical Center
Los Angeles, California, United States
Number of Participants Disease-free Until Completion of Treatment (2 Years From Start of ADT)
Participants will be considered disease-free if their PSA values remain below 0.1 ng/ml until the completion of treatment. The proportion of patients disease-free at 24 months were to be compared in the two treatment arms using a non-continuity-corrected chi-square test. PSA levels will be assessed prior to the start of RT, at the end of RT, and every three months for 24 months. all PSA values obtained up to and including the two-year landmark must be \< 0.1 ng/ml. Patients who die prior to two years from prostate cancer will be counted as failures. Patients who die from causes other than prostate cancer will be considered non-evaluable for the primary endpoint. Patients still under follow-up but who have a missing PSA value at two years or more than two missing values prior to two years will also be counted as failures.
Time frame: Baseline to completion of treatment (two years from start of ADT)
Percent of Participants Alive (Overall Survival)
Survival rates were to be estimated using the Kaplan-Meier method and the treatment arms were to be compared using a log-rank test.
Time frame: From baseline to death or last follow-up, analyzed after phase II participants have been followed for two years, which was expected to occur 3.5 years from start of phase II component.
Percentage of Participants With Prostate Cancer Deaths (Prostate Cancer-specific Survival)
Prostate cancer death rates were to be estimated using the cumulative incidence method, treating deaths due to other causes as competing risks. The treatment arms were to be compared using the Fine-Gray test
Time frame: From baseline to death or last follow-up, analyzed after all phase II participants have been followed for two years, which was expected to occur 3.5 years from start of phase II component.
Percentage of Participants With Pathologic Complete Response (pCR) at Two Years
Complete response was to be determined by a12-core biopsy. Treatment arms were to be compared using a chi-square test.
Time frame: At two years
Percentage of Participants With Local/Regional or Distant Progression
Progression rates were to be estimated using the cumulative incidence method, treating deaths as competing risks. The treatment arms were to be compared using the Fine-Gray test
Time frame: From baseline to local/regional or distant progression, death, or last follow-up, whichever occurs first, analyzed after all phase II participants have been followed for two years, which was expected to occur 3.5 years from start of phase II component.
Percentage of Participants With Distant Metastases
Distant metastases rates were to be estimated using the cumulative incidence method, treating death as a competing risk. The treatment arms were to be compared using the Fine-Gray test
Time frame: From baseline to distant metastasis, death, or last follow-up, analyzed after all phase II participants have been followed for two years, which was expected to occur 3.5 years from start of phase II component.
Percentage of Participants Alive Without Biochemical Progression (Biochemical Progression-free Survival)
Biochemical progression is defined as PSA ≥ 2 ng/ml over the nadir PSA, the presence of local, regional, or distant recurrence, or death from prostate cancer. Biochemical progression-free survival rates were to be estimated using the Kaplan-Meier method and the treatment arms were to be compared using a log-rank test.
Time frame: From baseline to biochemical progression or last follow-up, analyzed after all phase II participants have been followed for two years, which was expected to occur 3.5 years from start of phase II component.
Number of Participants by Highest Grade Adverse Event Reported
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. Adverse events were to be categorized as early (within 90 days of completion of radiotherapy) or late (more than 90 days after the completion of radiotherapy).The number of participants per grade was to be compared between the arms for early, late, and all adverse events using chi-square or Fisher exact tests
Time frame: From baseline to last follow-up, analyzed after all phase II participants have been followed for two years, which was expected to occur 3.5 years from start of phase II component.
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