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

Prior treatment

• Currently receiving active therapy for other neoplastic disorders will not be eligible

Other illness

• Patients with pain attributable to their prostate cancer and requiring the use of opioids
• Tumor causing urinary outlet obstruction that requires catheterization for voiding. Patients that require catheterization to void secondary to benign strictures or other non-cancer causes will be permitted to enroll.
• Presence of dementia, psychiatric illness, and/or social situations limiting compliance with study requirements or understanding and/or giving of informed consent
• 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

Lab values

• Active or symptomatic viral hepatitis or chronic liver disease AST or ALT \> 2.5 x ULN or total bilirubin \> ULN (unless Gilbert's syndrome is the etiology of hyperbilirubinemia)
• Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of \<35 % at baseline

Other

• Histologic evidence of small cell carcinoma (morphology alone - immunohistochemical evidence of neuroendrocrine differentiation without morphologic evidence is not exclusionary)
• Known parenchymal brain metastasis
• Liver metastases

• Signed informed consent form (ICF) providing agreement to adhere to the dosing schedule, report for all trial visits and authorization, use and release of health and research trial information
• 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 an orchiectomy must be maintained on effective GnRH analogue/antagonist therapy
• Castration resistant prostate cancer as defined by serum testosterone \< 50 ng/ml and one of the following:
  • PSA level of at least 2 ng/ml that has risen on at least 2 successive occasions at least 1 week apart.
  • Evaluable disease progression by modified RECIST 1.1 (Response Evaluation Criteria 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 CLIA level assay for DNA sequencing