Abemaciclib with or without Atezolizumab for the Treatment of Metastatic Castration Resistant Prostate Cancer

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 prostate specific antigen (PSA) values at a minimum of 1-week intervals * Radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST)1.1 for soft tissue and/or per Prostate Cancer Working Group 3 (PCWG3) for bone, with or without PSA progression
• Adult males 18 years of age or older
• Eastern Cooperative Oncology Group (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 at acceptable risk for research biopsy per institutional standards, 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 luteinizing hormone releasing hormones (LHRH) agonist or antagonist therapy for the duration of the study period
• Must have recovered from any treatment-related toxicities to =< Common Terminology Criteria for Adverse Events (CTCAE) grade 1 * Patients with =< CTCAE grade 2 anorexia, alopecia, neuropathy, and/or fatigue however, are also permitted to enroll
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Lymphocyte count >= 500/mcL
• Hemoglobin >= 9 g/dL (without transfusion or growth factor in prior 28 days, except for patients assigned to atezolizumab monotherapy in Arm C for whom transfusion to meet this eligibility criterion is permitted)
• Platelets >= 100,000/mcL (without transfusion or growth factor in prior 28 days)
• Serum albumin >= 25 g/L (2.5 g/dL)
• Total bilirubin =< 1.5 x institutional upper limit of normal, unless the subject has known or suspected Gilbert’s syndrome in which case total bilirubin must be =< 2 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal, except for patients assigned to atezolizumab monotherapy in Arm C for whom =< 2.5 x upper limit of normal is permitted
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x institutional upper limit of normal, unless the subject is receiving therapeutic anticoagulation, in which case they must be on a stable anticoagulant regimen
• Creatinine clearance >= 30 mL/min/1.73 m^2 (by Cockcroft-Gault formula or 24-hour urine collection)
• 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 Institutional Review Board (IRB)-approved informed consent
• Additional Inclusion Criteria (Arm C patients): Must have documentation (via Clinical Laboratory Improvement Act [CLIA] approved, College of American Pathologists [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

• History of leptomeningeal disease, or clinical evidence of, or known and untreated metastatic CNS disease
• Concurrent active malignancy with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival [OS] rate > 90%) * Patients with adequately treated 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
• Treatment with chemotherapy or radiotherapy within 4 weeks prior to planned cycle 1 day 1 of study treatment
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Treatment with oral anti-neoplastic intervention such as an oral hormonal agent, PARP inhibitor, or AR targeted therapy within 14 days prior to planned cycle 1 day 1 of study treatment
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
• Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
• Prior treatment with an inhibitor of CDK4 and/or 6
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti– CTLA-4, anti–PD-1, PD-L1, or PD-L2-therapeutic antibodies
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
• Known allergy or hypersensitivity to any component of the abemaciclib formulation
• 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
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions: * Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study * Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: ** Rash must cover < 10% of body surface area ** Disease is well controlled at baseline and requires only low-potency topical corticosteroids ** There has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• Prior allogeneic stem cell or solid organ transplantation
• Treatment with a live attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
• Active smoking (of tobacco, marijuana, or any other substance) or vaping at time of enrollment, or a history of smoking equivalent to greater than 20 pack-years of cigarettes (i.e. # packs of cigarettes [or equivalent per the below] smoked per day x # of years patient has smoked > 20) * Equivalents: ** Marijuana joints, 1 pack/day equivalent (20 cigarettes/pack): 10 / day ** Marijuana joints, 20 pack-year equivalent: 200 joint-years ** Cigars, 1 pack/day equivalent (20 cigarettes/pack): 5 / day ** Cigars, 20 pack-year equivalent: 200 joint-years ** Pipes, 1 pack/day equivalent (20 cigarettes/pack): 8 / day ** Pipes, 20 pack-year equivalent: 180 joint-years ** Water pipes (20 minute session), 1 pack/day equivalent (20 cigarettes/pack): 5 / day ** Water pipes (20 minute session), 20 pack-year equivalent: 200 joint-years
• 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. This exclusion criterion does not apply to patients assigned to atezolizumab monotherapy in Arm C, who may have received prior radiation to thorax
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Active tuberculosis
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) * Patients with indwelling catheters (e.g., PleurX) are allowed
• Any history of lung cancer, regardless of stage or treatment
• Any of the following abnormalities on pre-treatment pulmonary function testing: * Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio < lower limit of normal (LLN) and FEV1 < 75% predicted OR * FVC < 70% of predicted, regardless of FEV1/FVC ratio OR * Diffusion capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) < 70% of predicted
• The LLN of the FEV1/FVC ratio, which recognizes the change with age of this measurement, is determined by subtracting 10% or 0.10 from the age-specific FEV1/FVC predicted for any individual
• Uncontrolled tumor-related pain * Patients requiring pain medication must be on a stable regimen at study entry * Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period * Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment
• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
• Severe infection, or active known detectable viral infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis) within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact patient safety
• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: * Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study. * Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment * Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
• Current treatment with anti-viral therapy for hepatitis B virus (HBV)
• Arterial or venous thromboembolic event within the last 3 months
• Significant cardiovascular disease (such as New York Heart Association class II or greater cardiac disease, myocardial infarction, cerebrovascular accident, unstable arrhythmia, or unstable angina) within 3 months prior to initiation of study treatment
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
• 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