A Phase 2 Study of Neoadjuvant PARP Inhibition Followed by Radical Prostatectomy in Patients With Unfavorable Intermediate-Risk or High-Risk Prostate Cancer With Select HRR Gene Alterations (NePtune)
Phase 2 open-label, single-arm clinical trial evaluating the efficacy and safety of neoadjuvant olaparib + LHRH agonist administered for 6 months prior to radical prostatectomy (RP) in men with unfavorable intermediate-risk or high-risk localized prostate cancer. All patients must have confirmed germline or somatic select HRR alterations. Germline and somatic mutation testing will be performed as part of commercially available CLIA assays and will be validated on a uniform platform centrally all patients retrospectively. Eligible patients will receive treatment with olaparib + LHRH agonist. Following 6 months of therapy, patients will undergo RP with mandatory lymph node dissection. The lymph node dissection template will be at the discretion of the treating urologist. RP specimens will undergo pathology blinded independent central review. Following RP, patients will be followed for testosterone recovery and PSA progression.
∙ Subject must meet all of the following applicable inclusion criteria to participate in this study:
• Written informed consent and HIPAA authorization for release of personal health information prior to registration.
• Age ≥ 18 years at the time of consent.
• T stage 1-3 prostatic adenocarcinoma per AJCC staging manual Ed8.
• Histologically confirmed adenocarcinoma of the prostate without histological variants comprising \>50% of the sample. Patients with intraductal carcinoma are eligible.
• Must have 3 core biopsies involved with cancer (a minimum of 6 core biopsies must be obtained). Prostate biopsy must be within 7 months from registration. Less than 3 core biopsies are allowed if the patient has \>1 cm or T3 disease on magnetic resonance imaging (MRI).
• Localized unfavorable intermediate or high-risk prostate cancer patients. Patients must have at least one of the following features:
‣ Gleason ≥ 4+3 (grade group 3, 4, 5) OR
⁃ PSA \> 20 ng/dL OR
⁃ T3 disease NOTE: Patients with intraductal carcinoma are eligible independent of Gleason score, PSA and T stage.
• Must have evidence of germline or somatic BRCA1/2, PALB2, RAD51B, RAD51C, RAD51D, RAD54L2, BARD1, FANCA, BRIP1, CHEK2, ATM, and CDK12 gene alteration via standard of care CLIA based assay detection. Testing will be confirmed centrally but results of central testing not required for enrollment.
• No evidence of metastatic disease as determined by radionuclide bone scan and CT/MRI. Lymph nodes must be less than 20 mm in the short (transverse) axis.
• Participants must be candidates for RP and considered surgically resectable by urologic evaluation.
• ECOG Performance Status of 0-1 within 28 days prior to registration.
• Demonstrate adequate organ function as defined below. All screening labs to be obtained within 28 days prior to registration.
‣ White blood cell count ≥ 3,000/mcL
⁃ Absolute neutrophil count ≥ 1,500/mcL
⁃ Hemoglobin ≥ 10 g/dL with no transfusion support in the past 28 days
⁃ Platelets ≥ 100,000/mcL
⁃ Aspartate aminotransferase, alanine aminotransferase ≤ 2.5×ULN, and total bilirubin ≤ 1.5 x Institutional upper limit of normal
⁃ Calculated creatinine clearance ≥ 51 mL/min based on Cockcroft-Gault formula or 24 hour urine. NOTE: See the protocol for Cockcroft-Gault formula or 24 hour urine.
• Life expectancy≥ 16 weeks.
• Subjects must use a condom plus spermicide beginning prior to treatment Cycle 1 Day 1, during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential. See protocol for additional details.
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.