Niraparib With Standard Combination Radiation Therapy and Androgen Deprivation Therapy in Treating Patients With High Risk Prostate Cancer

Study Overview
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Brief Summary
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This phase II trial studies the side effects and best dose of niraparib, and to see how well it works in combination with standard of care radiation therapy and hormonal therapy (androgen deprivation therapy) in treating patients with prostate cancer that has a high chance of coming back (high risk). Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Adding niraparib to the usual treatments of radiation therapy and hormonal therapy may lower the chance of prostate cancer growing or returning.

Detailed Description
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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 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 OBJECTIVES: 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 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. 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. 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. After completion of study treatment, patients are followed up every 6 months for 3 years, then annually for 3 years.

Official Title
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Randomized Phase II Trial of Niraparib With Standard Combination Radiotherapy and Androgen Deprivation Therapy (ADT) in High Risk Prostate Cancer (With Initial Phase I)

Conditions
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Prostate Adenocarcinoma, Stage IIC Prostate Cancer AJCC v8, Stage III Prostate Cancer AJCC v8, Stage IIIA Prostate Cancer AJCC v8, Stage IIIB Prostate Cancer AJCC v8, Stage IIIC Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8

Intervention / Treatment
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* Biological: Gonadotrophin Releasing Hormone
* Radiation: Intensity-Modulated Radiation Therapy
* Drug: Niraparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed (within 180 days prior to registration) adenocarcinoma of the prostate at high risk for recurrence as determined by the following criteria, according to American Joint Committee on Cancer (AJCC) 8th edition: Phase I enrollment Gleason ≥ 9, PSA ≤ 150 ng/mL, any T-stage Phase II enrollment Gleason ≥ 9, PSA ≤ 150 ng/mL, any T-stage Gleason 8, PSA < 20 ng/mL, and ≥ T2 Gleason 8, PSA ≥ 20-150 ng/mL, any T-stage Gleason 7, PSA ≥ 20-150 ng/mL, any T-stage No distant metastases as evaluated by: Bone scan 90 days prior to registration Lymph node assessment by computed tomography (CT) or magnetic resonance (MR) of pelvis or nodal sampling within 90 days prior to registration (Please note: Lymph nodes will be considered negative (N0) if they are < 1.5 cm short axis) History/physical examination within 90 days prior to registration Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 180 days prior to registration Pretreatment serum PSA, obtained prior to any androgen suppression therapy and within 180 days of registration Phase I patients: Prior androgen suppression for prostate cancer is not allowed prior to registration Phase II patients: Prior androgen suppression for prostate cancer is allowed ≤ 45 days prior to registration Hemoglobin ≥ 9.0 g/dL (within 90 days prior to registration) Platelets ≥ 100,000 cells/mm^3 (within 90 days prior to registration) Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (within 90 days prior to registration) Serum creatinine ≤1.5 x upper limit of normal (ULN) OR a calculated creatinine clearance >= 30 mL/min estimated using Cockcroft-Gault equation (within 90 days prior to registration) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN (within 90 days prior to registration) Serum albumin ≥ 3 g/dL (within 90 days prior to registration) Serum potassium ≥ 3.5 mmol/L (within 90 days prior to registration) Serum total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ 1 x ULN (Note: in subjects with Gilberts syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin, and if direct bilirubin is ≤ 1.5 x ULN, subject may be eligible) (within 90 days prior to registration) Men of child-producing potential must be willing to consent to use effective contraception while on treatment and for at least 3 months afterwards The patient or a legally authorized representative must provide study-specific informed consent prior to study entry Exclusion Criteria: PSA > 150 ng/mL Definitive clinical or radiologic evidence of metastatic disease Pathologically positive lymph nodes or nodes > 1.5 cm short axis on CT or MR imaging Prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy for any reason Any active malignancy within 2 years of study registration that may alter the course of prostate cancer treatment. Prior systemic therapy for prostate cancer; note that prior therapy for a different cancer is allowable Prior radiotherapy, including brachytherapy, to the region of the prostate that would result in overlap of radiation therapy fields Current treatment with first generation anti-androgens (bicalutamide, nilutamide, flutamide). For patients enrolled to phase II, if prior anti-androgens were administered, a washout period of >= 30 days is required prior to enrollment Severe, active co-morbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months Transmural myocardial infarction within the last 6 months Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration Uncontrolled acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] >=160 mmHg or diastolic BP >= 100 mmHg). Subjects with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment Prior allergic reaction to the drugs involved in this protocol (including known allergies, hypersensitivity or intolerance to the excipients of niraparib. Please see Niraparib IB for details.) Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter Note that patients who are HIV positive are eligible, provided they have a CD4 count >= 200 cells/microliter within 90 days prior to registration. Patients receiving treatment with highly active antiretroviral therapy (HAART) will not be eligible due to concern for radiosensitization Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be affected by these drugs. Any history or current diagnosis of Myelodysplasitc Syndromes (MDS)/ Acute Myeloid Leukemia (AML). Prior or current treatment with PARP inhibitor

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I (niraparib, GnRH, IMRT)<br>Patients receive niraparib PO QD and receive standard of care 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 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. | Biological: Gonadotrophin Releasing Hormone<br>* Receive standard of care GnRH agonist androgen suppression therapy<br>* Other names: luteinizing hormone-releasing hormone;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo standard of care IMRT<br>* Other names: Intensity-Modulated Radiotherapy;Drug: Niraparib<br>* Given PO<br>* Other names: MK4827;|
| Active Comparator: Phase II, Arm I (GnRH, IMRT)<br>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. | Biological: Gonadotrophin Releasing Hormone<br>* Receive standard of care GnRH agonist androgen suppression therapy<br>* Other names: luteinizing hormone-releasing hormone;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo standard of care IMRT<br>* Other names: Intensity-Modulated Radiotherapy;|
| Experimental: Phase II, Arm II (niraparib, GnRH, IMRT)<br>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. | Biological: Gonadotrophin Releasing Hormone<br>* Receive standard of care GnRH agonist androgen suppression therapy<br>* Other names: luteinizing hormone-releasing hormone;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo standard of care IMRT<br>* Other names: Intensity-Modulated Radiotherapy;Drug: Niraparib<br>* Given PO<br>* Other names: MK4827;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maintenance of disease-free state | Will be characterized by PSA values sustained below 0.1 ng/ml. A modified intent-to-treat analysis will be conducted. The proportion of patients disease-free at 24 months will be compared in the two treatment arms using a non continuity-corrected chi-square test. As a secondary analysis, a logistic regression model will be fit to adjust for the stratification factors (risk group and type of radiation therapy). | Up to 2 years following the start of antiandrogen therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test. | From randomization until death from any cause, assessed up to 3 years | 
| Prostate cancer-specific survival | Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test. | From randomization until death from prostate cancer, assessed up to 3 years | 
| Pathologic Complete Response (pCR) | Will be assessed among patients undergoing 12-core biopsy. Will be compared using a chi-square test. | At 24 months | 
| Time to local/regional or distant progression | Cumulative incidence curves will be compared using the Fine-Gray test (Dignam 2008). | Up to 3 years | 
| Time to distant metastases | Cumulative incidence curves will be compared using the Fine-Gray test (Dignam 2008). | From randomization until detection of distant metastatic disease, assessed up to 3 years | 
| Biochemical Progression-Free Survival | Will be defined as PSA >= 2 ng/ml over the nadir PSA, the presence of local, regional, or distant recurrence, or death from prostate cancer. Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test. | Up to 3 years | 
| Incidence of Adverse Events (Phase II) | Adverse event (AE) rates in the two treatment arms will be summarized by time of occurrence (early versus late), type, grade, and attribution to treatment. For each type of AE, the worst grade occurring during the early treatment period, late treatment period, or entire treatment period will be determined. For each time period, treatment group comparisons will be conducted using chi-square or Fisher exact tests. | Up to 3 years |