- Diagnosis of metastatic castration resistant prostate cancer (mCRPC), with histologic
confirmation of adenocarcinoma of the prostate, without evidence of small cell
- ECOG performance status of 0 or 1.
- Evaluable for response based on: baseline PSA ≥ 2 ng/mL OR measurable disease per
RECIST 1.1 criteria.
- Past progression or intolerance to at least one novel antiandrogen therapy
(abiraterone, enzalutamide, galeterone, apalutamide, darolutamide, orteronel,
seviteronel or equivalent) in either the hormone-sensitive or castration-resistant
- Not a candidate for docetaxel or cabazitaxel chemotherapy due to: progression within
12 months of completion or intolerance to prior taxane OR refusal of taxane OR
contraindication to, or lack of fitness for taxane OR Investigator assessment that
taxane is not clinically indicated or preferred.
- Maintenance of castration status, defined as serum testosterone level of less than 50
ng/dL. Patients must be surgically castrate or maintained on LHRH agonist or
antagonist therapy for the duration of the study period.
- Must have recovered from any treatment-related toxicities to ≤ CTCAE grade 1. Patients
with ≤ CTCAE grade 2 anorexia, alopecia, neuropathy, and/or fatigue however, are also
permitted to enroll.
- Adequate bone marrow, renal, and liver function with no lab abnormalities > CTCAE
grade 1. Platelet count of ≥100 x 109 /L.
- Life expectancy of at least 6 months, as determined by a study Investigator.
- Ability to swallow oral medications.
- Ability to understand and willingness to sign an IRB-approved informed consent.
For inclusion specifically in Arm C, documentation (via CLIA approved, CAP certified next
generation sequencing [NGS] assay report) of genomic aberration resulting in CDK12 loss of
function in metastatic tumor tissue.
- Clinical evidence of, or known and untreated metastatic CNS disease.
- Concurrent active malignancy. Patients with non-melanomatous skin cancer, cancer not
needing active therapy for at least 2 years, cancer for which the treating
investigator deems the subject to be in remission, or any prior malignancy that was
treated with curative intent (no evidence of disease for at least 3 years) are also
permitted to enroll.
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to planned cycle 1 day 1 of study treatment.
- Patients who have received oral anti-neoplastic intervention such as an oral hormonal
agent, PARP inhibitor, AR targeted therapy, or oral experimental agent within 14 days
prior to planned cycle 1 day 1 of study treatment.
- Prior treatment with an inhibitor of CDK4 and/or 6.
- Prior treatment with an inhibitor of PD-1, PD-L1, or PD-L2.
- Patients on concurrent therapy with a moderate or strong CYP3A4 inducer or inhibitor
which cannot be safely stopped at least five half-lives prior to initiation of therapy
- Evidence of an active autoimmune disease that has required systemic treatment within
the last 2 years (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Patients with conditions requiring replacement therapy
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for
adrenal or pituitary insufficiency, etc.) are permitted to enroll.
- Live vaccine within 30 days of registration.
- Evidence of active, non-infectious pneumonitis. Patients with a history of
asymptomatic radiation pneumonitis with no signs of active process are permitted to
- Active bacterial or fungal infection, or known detectable viral infection (e.g., Human
Immunodeficiency Virus [HIV] or viral hepatitis).
- Arterial or venous thromboembolic event within the last 3 months.
- Significant infection, medical condition, or social situation which, in the opinion of
the investigator, would preclude participation or limit the patient's ability to
comply with study requirements.