A Multi-Center Trial of Androgen Suppression With Abiraterone Acetate, Leuprolide, PARP Inhibition and Stereotactic Body Radiotherapy in Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to establish the maximum tolerable dose of niraparib when combined with prostate stereotactic body radiotherapy (SBRT), abiraterone, leuprolide, and prednisone (the phase 1 portion of the study) and determine 3-year biochemical PSA recurrence free-survival with this treatment approach (the phase 2 portion of the study).

Official Title
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A Multi-Center Trial of Androgen Suppression With Abiraterone aCetate, LEuprolide, PARP Inhibition and Stereotactic Body Radiotherapy (ASCLEPIuS): A Phase I/2 Trial in High Risk and Node Positive Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Niraparib
* Drug: Leuprolide
* Drug: Abiraterone Acetate
* Radiation: Stereotactic body radiotherapy (SBRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Pathologic biopsy proven adenocarcinoma of the prostate At least one of the following criteria: cN1 on conventional or PET imaging Grade group 5 Grade group 4 Grade group 3 and PSA ≥20 ng/mL High probability of Radiographic T3 on MRI AND Grade group ≥2 Grade Group 3 AND PSA ≥10 ng/mL AND ≥50% positive biopsy cores Age ≥ 18 ECOG < 1 Adequate organ and marrow function as defined per protocol. Use of highly effective contraception (e.g. condoms) for the duration of treatment and a minimum of 90 days thereafter. Men must also agree not to donate sperm for the duration of the study participation, and for at least 90 days thereafter. International Prostate Symptoms Score (IPSS) ≤ 20 Medically fit for treatment and agreeable to follow-up Ability to understand and the willingness to sign a written informed consent Tissue available for MiOncoSeq testing to assign DNA repair deficiency status Exclusion Criteria Clinical or radiographic evidence of distant metastatic disease by CT/bone scan Clinical or radiographic evidence of high probability of clinical T4 disease Prostate gland size >80 cc measured by ultrasound or MRI Prominent median lobe assessed by treating physician Lack of tissue from biopsy to be sent for correlative studies Any prior treatment for prostate cancer (incudes history of TURP within 5 years of enrollment, chemotherapy, radiation therapy, or anti-androgen therapy) Prohibited within 30 days prior to administration to study treatment: spironolactone and other investigational drug therapies. Prohibited 3 months before participant registration and during administration of study treatment: non-steroidal anti-androgens (e.g., bicalutamide, flutamide, nilutamide), steroidal antiandrogens (megestrol acetate, cyproterone acetate), oral ketoconazole, chemotherapy, immunotherapy, estrogens, radiopharmaceuticals. History of prior pelvic radiation therapy Concurrent treatment with strong CYP3A4 inducers such as phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital Enrollment concurrently in another investigational drug study within 1 month of registration History of another active malignancy within the previous 3 years except for adequately treated skin cancer or superficial bladder cancer History of or active Crohn's disease or ulcerative colitis Contraindication to or inability to tolerate MRIs Patients with severe depression Uncontrolled diabetes or known HbA1c>10 Any gastrointestinal disorder affecting absorption Active pituitary or adrenal dysfunction Patients with significant cardiovascular disease potentially including severe / unstable angina, recent history of myocardial infarction, clinically significant heart failure, cerebrovascular disease, venous thromboembolic events, clinically significant arrhythmias) Uncontrolled hypertension with persistently elevated systolic blood pressure >160 mmgHg or diastolic blood pressure >100 mmHg despite anti-hypertensive agents. Prolonged QTc >450 ms or any ECG changes that interfere with QT interval interpretation Major surgery within 1 month of registration History of myelodysplastic syndrome or leukemia A known hypersensitivity to niraparib, abiraterone acetate, leuprolide, and/or prednisone Active infection or other medical condition that would be a contraindication to prednisone use Patients with known active hepatitis or chronic liver disease including cirrhosis Any condition that in the opinion of the investigator would preclude participation in this study

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
Intervention Model: Single Group Assignment
Interventional Model Description: Time to Event Continual Reassessment Method (TITE-CRM) dose-finding clinical trial design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Niraparid Dose Escalation<br>Dose Level 1: 100 mg PO daily of Niraparib but held for 5 days (+/- 2 days) prior to RT, during SBRT, and 5 days (+/- 2 days) after last fraction of SBRT Dose Level 2: 200 mg PO daily of Niraparib but held for 5 days (+/- 2 days) prior to RT, during SBRT, and 5 days (+/- 2 days) after last fraction of SBRT Dose Level 3: 200 mg PO daily of Niraparib without breaks during SBRT until completion of 6 cycles. | Drug: Niraparib<br>* given PO per dose escalation schedule<br>Drug: Leuprolide<br>* 22.5 mg q3 month<br>Drug: Abiraterone Acetate<br>* 1000 mg daily<br>Radiation: Stereotactic body radiotherapy (SBRT)<br>* 5-6 fraction SBRT (total dose: 37.5-40 Gy)<br>* Other names: Ultra-hypofractionated radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities (Phase 1) | The proportion of patients at each dose level with dose-limiting toxicity (DLT), defined as any treatment related grade 3-5 adverse event experienced within the first 4 treatment cycles (112 days), assessed per NCI's CTCAE version 5.0. | Up to 112 days after initial dose of niraparib | 
| Proportion of patients experiencing biochemical failure | Change in PSA level from the beginning of study treatment for up to 3 years later will determine the biochemical failure rate. Biochemical failure will be defined using the Phoenix definition of the PSA nadir + 2 ng/mL. | Up to 3 years after first dose of niraparib | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in health related quality of life | Assessed via EPIC-26 questionnaire | From baseline up to 3 years after last dose of niraparib | 
| Proportion of patients with undetectable post-treatment PSA | Undetectable PSA will be defined as a PSA ≤0.1 ng/mL. | Measured during the end of the 6th cycle of therapy (during week 24 +/- 7 days) | 
| Proportion of patients with distant metastases | Distant metastases will be defined as any clinical or radiographic evidence of lymph node, bone, or visceral involvement of prostate cancer. | Up to 5 years after first dose of niraparib | 
| Prostate cancer specific survival | Prostate cancer specific survival will be defined as the duration of time from the start of treatment to death attributable to prostate cancer. Patients who have not died or die of non-prostate cancer related causes will be censored at the last known follow-up or date of death, respectively. Summarized using cumulative incidence or Kaplan-Meier curves as appropriate. | Up to 5 years after first dose of niraparib | 
| Overall survival | Overall survival (OS) will be defined as the duration of time from the start of treatment to death from any cause. Patients who have not died will be censored at the last known follow-up.Summarized using cumulative incidence or Kaplan-Meier curves as appropriate. | Up to 5 years after first dose of niraparib |