Darolutamide and Androgen Deprivation Therapy with or without Abemaciclib for the Treatment of Patients with Prostate Cancer

Inclusion Criteria

• PHASE I: Provision of signed informed consent prior to any study specific procedures, or have a legally authorized representative sign on the participant’s behalf
• PHASE I: Ability to swallow oral medications and comply with study procedures and requirements
• PHASE I: Males ≥ 18 years
• PHASE I: Histologically or cytologically confirmed adenocarcinoma of the prostate without histologic variants (including neuroendocrine differentiation, small cell, sarcomatoid, ductal adenocarcinoma, squamous or transitional cell carcinoma) comprising >50% of the sample as determined by academic medical center pathology review; men without histologic confirmation are eligible provided there is unequivocal evidence of prostate cancer (eg. very high PSA) in the view of the treating physician
• PHASE I: M0 or M1 (by CT/MRI and bone scans) CRPC with evidence of progression at study entry demonstrated during continuous androgen deprivation therapy (luteinizing hormone-releasing hormone [LHRH]/GnRH agonists/antagonists/post orchiectomy) and castrate level of serum testosterone (≤ 50ng/dl). Progression is defined as one or more of the following: * Sequence of at least 2 rising PSA values at a minimum of 1-week intervals with the last result being at least 1.0 ng/mL if confirmed PSA rise is the only indication of progression. Patients who received an anti-androgen (flutamide, bicalutamide or nilutamide) must have PSA progression ≥ 4 weeks after the last dose * Radiographic progression per RECIST 1.1 for soft tissue and/or per PCWG3 for bone (i.e., appearance of ≥ 2 new bone lesions), with or without PSA progression
• PHASE I: Serum testosterone level must be ≤50 ng/dL (1.73 nmol/L) at the screening visit. Participants who have not undergone bilateral orchiectomy are required to continue LHRH/GnRH agonists/antagonists) throughout the study. Use of relugolix is permitted
• PHASE I: Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
• PHASE I: Absolute neutrophil count (ANC) ≥ 1.5 ×10^9/L
• PHASE I: Platelets ≥ 100×10^9/L
• PHASE I: Hemoglobin ≥ 9g/dL (≥ 90g/L) independent of transfusions
• PHASE I: Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR < 2 × ULN if known or suspected Gilbert’s syndrome
• PHASE I: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN OR ≤ 5 × ULN if liver metastases present
• PHASE I: Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m^2 (based on Cockcroft-Gault formula OR 24 hour urine collection
• PHASE I: The effects of darolutamide and abemaciclib on the developing human fetus are unknown. Participants and their partners must agree to use an effective contraception method (hormonal or barrier method of birth control, or abstinence) during the study and for 3 weeks after the last dose of study treatment (darolutamide and/or abemaciclib) if engaged in sex with a woman of childbearing potential, and participants must not donate sperm during this period. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately
• PHASE II: Provision of signed informed consent prior to any study specific procedures, or have a legally authorized representative sign on the participant’s behalf
• PHASE II: Ability to swallow oral medications and comply with study procedures and requirements
• PHASE II: Males ≥18 years
• PHASE II: Histologically confirmed adenocarcinoma of the prostate without histologic variants (including neuroendocrine differentiation, small cell, sarcomatoid, ductal adenocarcinoma, squamous or transitional cell carcinoma) comprising > 50% of the sample as determined by academic medical center pathology review
• PHASE II: ≥ 3 biopsy cores (either systematic or targeted, or a combination) involved with prostate cancer. Prostate biopsy must have been performed within 6 months of screening. < 3 biopsy cores with cancer are allowed if the patient has > 1cm of tumor or ≥ cT3 disease on MRI prostate
• PHASE II: Participants must have at least 1 biopsy core with either: * Gleason ≥ 8 OR * Gleason 4+3=7 AND at least one of the following: ** PSA > 20ng/dL ** ≥ cT3 disease by MRI ** Evidence of extraprostatic extension (EPE) on biopsy
• PHASE II: No evidence of distant metastatic disease as determined by radionuclide bone scan and CT/MRI, and/or PSMA-PET. cN1 disease (with pelvic nodes ≤ 2cm) on CT or PSMA-PET is permitted. If PSMA-PET does not show evidence of distant metastatic disease, CT/MRI and bone scan is not required. Either PSMA-PET or CT/MRI abdomen and bone scan (along with MRI prostate) is required before cycle 1 day 1 (C1D1) NOTE: participants with evidence of M1 disease on PSMA-PET imaging at baseline are eligible (and their participation is encouraged), provided that all avid non-regional nodes are < 1.5cm in short axis, all visceral lesions are < 1cm and all soft tissue component to bone lesions are < 1cm (i.e. considered non-measurable by conventional imaging). All participants treated at Dana Farber Cancer Institute (DFCI) must undergo PSMA-PET at baseline or within 21 days of C1D1 (per institutional practice) and will also undergo a research-only PSMA-PET after completion of therapy and prior to RP
• PHASE II: Participants must be candidates for RP and be considered surgically resectable by a urologist
• PHASE II: ECOG performance status ≤ 1 (Karnofsky ≥ 70%)
• PHASE II: ANC ≥ 1.5 ×10^9/L
• PHASE II: Platelets ≥ 100×10^9/L
• PHASE II: Hemoglobin ≥ 9g/dL (≥ 90g/L) independent of transfusions
• PHASE II: Total bilirubin ≤ 1.5 × ULN < 2 × ULN if known or suspected Gilbert’s syndrome
• PHASE II: ALT and AST ≤ 3 × ULN
• PHASE II: eGFR ≥ 30 mL/min/1.73 m^2 (based on Cockcroft-Gault formula OR 24 hour urine collection
• PHASE II: The effects of darolutamide and abemaciclib on the developing human fetus are unknown. Participants and their partners must agree to use an effective contraception method (hormonal or barrier method of birth control, or abstinence) during the study and for 3 weeks after the last dose of study treatment (darolutamide and/or abemaciclib) if engaged in sex with a woman of childbearing potential, and participants must not donate sperm during this period. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately

Exclusion Criteria

• PHASE I: Participants who have had chemotherapy or radiotherapy within 4 weeks prior to planned cycle 1 day 1 of study treatment
• PHASE I: Participants who have received anti-neoplastic intervention or experimental antineoplastic therapy within 14 days of planned cycle 1 day 1 of study therapy
• PHASE I: Participants who are receiving any other investigational agents
• PHASE I: Participants who have previously received darolutamide, abemaciclib or another CDK4/6 inhibitor
• PHASE I: Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e. have residual toxicities ≥ grade 2) with the exception of alopecia
• PHASE I: Any of the following within 6 months before planned cycle 1 day 1 of study therapy: * Stroke * Myocardial infarction * Severe/unstable angina pectoris * Coronary/peripheral artery bypass graft * Congestive heart failure New York Heart Association (NYHA) class III or IV
• PHASE I: Known or suspected contraindications, hypersensitivity or allergy to darolutamide or abemaciclib or to any of their excipients
• PHASE I: Participants with hepatitis C, hepatitis B or human immunodeficiency (HIV) who are on anti-viral therapy that has the potential to interact with darolutamide or abemaciclib
• PHASE I: Participants with untreated brain metastases. Participants with treated brain metastases are eligible if follow-up brain imaging at least 4 weeks after central nervous system (CNS)-directed therapy shows no evidence of progression and ongoing corticosteroids are not required. Participants with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
• PHASE I: Participants treated with drugs known to be strong inhibitors and/or inducers of cytochrome P450 3A4 (CYP3A4) and the treatment cannot be discontinued or switched to a different medication at least 5 half-lives prior to starting study drug NOTE: precaution is warranted with concomitant use of agents with a narrow therapeutic index that are substrates of P-gp, BCRP and OCT1 Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product
• PHASE I: The participant has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance < 30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea)
• PHASE I: Concurrent active malignancy whose natural history or treatment has the potential to interfere with safety or efficacy assessment of the investigational regimen. Patients with non-melanomatous skin cancer, superficial bladder 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 permitted to enroll
• PHASE II: Prior radiotherapy, bilateral orchiectomy, investigational therapy or systemic therapy (including LHRH/GnRH agonists/antagonists, anti-androgens, CYP17 inhibitors, androgen receptor [AR] antagonists) for prostate cancer. LHRH/GnRH agonists/antagonists are permitted if begun within 4 weeks of day 1; up to 4 weeks of bicalutamide is permitted if it is stopped 2 weeks prior to day 1. Prior therapy with 5-⍺-reductase inhibitors is allowed but must be stopped 2 weeks prior to day 1
• PHASE II: Hypogonadism or severe androgen deficiency as defined by screening serum testosterone < 200ng/dL. Patients who have a low screening testosterone due to prior ADT will still be allowed to enroll on study if they do not have a known history of hypogonadism or severe androgen deficiency
• PHASE II: Major surgery or radiotherapy within 4 weeks of start of treatment
• PHASE II: Any of the following within 6 months before randomization: * Stroke * Myocardial infarction * Severe/unstable angina pectoris * Coronary/peripheral artery bypass graft * Congestive heart failure New York Heart Association (NYHA) class III or IV
• PHASE II: Known or suspected contraindications, hypersensitivity or allergy to darolutamide or abemaciclib or to any of their excipients
• PHASE II: Participants with hepatitis C, hepatitis B or human immunodeficiency (HIV) who are on anti-viral therapy that has the potential to interact with darolutamide or abemaciclib
• PHASE II: Patient treated with drugs known to be moderate or strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) and the treatment cannot be discontinued or switched to a different medication at least 5 half-lives prior to starting study drug NOTE: precaution is warranted with concomitant use of agents with a narrow therapeutic index that are substrates of CYP3A4, P-gp, BCRP and OCT1. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product
• PHASE II: The participant has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance < 30ml/min] or history of renal transplant, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea)
• PHASE II: Concurrent active malignancy whose natural history or treatment has the potential to interfere with safety or efficacy assessment of the investigational regimen. Patients with non-melanomatous skin cancer, superficial bladder 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 permitted to enroll