High Dose Testosterone for ATM, CDK12 or CHEK2 Altered Prostate Cancers

Inclusion Criteria:

• Signed informed consent form (ICF) providing agreement to adhere to the dosingschedule, report for all trial visits and authorization, use and release of healthand research trial information

• Male age > 18 years

• Histologically or cytologically confirmed adenocarcinoma of the prostate

• Ongoing gonadal androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) analogues, antagonists or orchiectomy. Patients who have not had anorchiectomy must be maintained on effective GnRH analogue/antagonist therapy

• Castration resistant prostate cancer as defined by serum testosterone < 50 ng/ml andone of the following:

• PSA level of at least 2 ng/ml that has risen on at least 2 successive occasionsat least 1 week apart.

• Evaluable disease progression by modified RECIST 1.1 (Response EvaluationCriteria in Solid Tumors)

• Progression of metastatic bone disease on bone scan with > 2 new lesions

• Presence of metastatic disease on bone or CT scan

• Patients must have progressed on 1 next-generation AR-signaling inhibitor (e.g.abiraterone, enzalutamide, apalutamide, darolutamide, etc.).

• Asymptomatic or minimal cancer related symptoms

• Eastern Cooperative Oncology Group (ECOG) Performance Status of < 2

• Presence of inactivating mutations in ATM, CDK12 or CHEK2 as determined by a CLIAlevel assay for DNA sequencing.

Exclusion Criteria:

• Currently receiving active therapy for other neoplastic disorders will not beeligible.

• Histologic evidence of small cell carcinoma (morphology alone - immunohistochemicalevidence of neuroendrocrine differentiation without morphologic evidence is notexclusionary)

• Known parenchymal brain metastasis

• Liver metastases

• Active or symptomatic viral hepatitis or chronic liver disease AST or ALT > 2.5 xULN or total bilirubin > ULN (unless Gilbert's syndrome is the etiology ofhyperbilirubinemia).

• Clinically significant heart disease as evidenced by myocardial infarction, orarterial thrombotic events in the past 6 months, severe or unstable angina, or NewYork Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fractionmeasurement of <35 % at baseline

• Patients with pain attributable to their prostate cancer and requiring the use ofopioids.

• Tumor causing urinary outlet obstruction that requires catheterization for voiding.Patients that require catheterization to void secondary to benign strictures orother non-cancer causes will be permitted to enroll.

• Presence of dementia, psychiatric illness, and/or social situations limitingcompliance with study requirements or understanding and/or giving of informedconsent.

• Any condition(s), medical or otherwise, which, in the opinion of the investigators,would jeopardize either the patient or the integrity of the data obtained.