Abemaciclib With or Without Atezolizumab for mCRPC

Inclusion Criteria:

* Diagnosis of metastatic castration resistant prostate cancer (mCRPC), with histologic confirmation of adenocarcinoma of the prostate (without evidence of small cell carcinoma), with progressive disease at the time of study entry by either

  * Sequence of at least 2 rising PSA values at a minimum of 1-week intervals
  * Radiographic progression per RECIST1.1 for soft tissue and/or per PCWG3 for bone, with or without PSA progression
* Adult males 18 years of age or older.
* ECOG performance status of 0 or 1
* Patients must have metastatic disease by bone scintigraphy or other nodal or visceral lesions on CT or MRI with a bone or soft tissue lesion amenable to image-guided percutaneous biopsy, and the patient must be evaluable for disease response by either

  * Baseline PSA ≥ 2.0 ng/mL OR
  * Measurable disease per RECIST 1.1
* 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 disease setting.
* 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.
* Participants must have adequate organ and marrow function as defined below:

  * leukocytes ≥3,000/mcL
  * absolute neutrophil count ≥1,500/mcL
  * hemoglobin ≥9 g/dL (without transfusion or growth factor in prior 28 days)
  * platelets ≥100,000/mcL (without transfusion or growth factor in prior 28 days)
  * total bilirubin ≤1.5 × institutional upper limit of normal, unless the subject has known or suspected Gilbert's syndrome
  * AST(SGOT)/ALT(SGPT) ≤1.5 × institutional upper limit of normal
  * creatinine clearance ≥30 mL/min/1.73 m2
* 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.
* Additional Inclusion Criteria (Arm C patients)

  * Must have 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.

    * Patients whose tumors have not previously undergone NGS are not eligible for Arm C but are eligible for the randomized unselected cohorts.

Exclusion Criteria:

* 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 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 with abemaciclib.
* 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.
* Active smoking or a history of smoking greater than 20 pack-years (i.e. # packs of cigarettes smoked per day × # of years patient has smoked \> 20).
* Prior history of radiation therapy to thorax (including to lungs/pleura, esophagus, intrathoracic lymph nodes, C7-L2 vertebrae, or ribs) for any reason and any duration/dose.
* Any history of interstitial lung disease, pneumonitis or idiopathic pulmonary fibrosis, regardless of remission or immunosuppression status.
* Any history of lung cancer, regardless of stage or treatment
* Any of the following abnormalities on pre-treatment pulmonary function testing:

  * FEV1/FVC \< lower limit of normal (LLN) and FEV1 \< 75% predicted OR
  * FVC \< 70% of predicted, regardless of FEV1/FVC ratio OR
  * DLCO (corrected for hemoglobin) \< 70% of predicted
* 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.