S2210, "Targeted Neoadjuvant Treatment for Patients with Localized Prostate Cancer and Germline DNA Repair Deficiency"

1. Disease Related Criteria

Participant must have histologic diagnosis of prostate adenocarcinoma.

Participant must have high or very high-risk disease defined by at least one of the following:
cT3a to cT4x
Grade Group 4 or 5 (Gleason sum 8-10)
PSA > 20 ng/mL prior to registration

Participant must have documented evidence of germline mutation (pathogenic/likely pathogenic variant) in BRCA2 or BRCA1 through testing in a CLIA-certified lab.

NOTE: Local lab report is sufficient for eligibility.

Participant must not have evidence of distant metastatic disease by conventional imaging within 90 days prior to registration.

NOTE: cN1 detected only by PSMA-PET is permitted if urologist deems sites of disease to be potentially completely resectable.

2. Prior/Concurrent Therapy Criteria

Participant may have initiated gnRH agonist, gnRH antagonist, oral anti-androgen (e.g. bicalutamide, nilutamide, flutamide), or other agent intended to treat prostate cancer prior to registration. The effectiveness of the current depot of such treatment must not extend beyond 1 month after study registration. Agents listed above cannot be started after participant registration.

Participant must not have received prior RT to the pelvic region.

3. Clinical/Laboratory Criteria

Participant must be greater than or equal to 18 years old.

Participant must have Zubrod Performance Status of 0-2.

Participant must have a complete medical history and physical exam within 28 days prior to registration.

Participant must have adequate organ and marrow function as defined below within 28 days prior to registration:
absolute neutrophil count: greater than or equal to1.5 x 10^3/uL
platelets: greater than or equal to100 x 10^3/uL
AST/ALT: greater than or equal to 3 x institutional ULN

Participant must have a serum creatinine less than or equal to the IULN OR measured OR calculated creatinine clearance greater than or equal to 50 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to registration:

Calculated Creatinine Clearance = (140 - age) X (weight in kg)
72 x serum creatinine *

The kilogram weight is the participant weight with an upper limit of 140% of the IBW.
* Actual lab serum creatinine value with a minimum of 0.7 mg/dL.

Participant must have adequate cardiac function. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification (see Section 18.1) within 28 days prior to registration. To be eligible for this trial, participants must be class 2B or better.

Participant with known human immunodeficiency virus (HIV)-infection must be receiving anti-retroviral therapy and have an undetectable viral load test within 6 months prior to registration.

Participant with history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within in 28 days prior to registration.

Participant with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment must have an undetectable HCV viral load within in 28 days prior to registration.

Participants who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including vasectomy with testing showing no sperm in the semen.

Participant must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of protocol treatment.

4. Additional Criteria

Prior to registration, participant must have had a urologic consult and be deemed a surgical candidate with known sites of disease deemed by the urologist to be potentially resectable.

Participants must be offered the opportunity to participate in specimen banking. With participant consent, specimens must be collected and submitted via the SWOG Specimen Tracking System.