Enzalutamide With Ribociclib for Metastatic, Castrate-Resistant, Chemotherapy-Naive Prostate Cancer That Retains RB Expression

Inclusion Criteria:

• Willing and able to provide written informed consent and HIPAA authorization for the release of personal health information. NOTE: HIPAA authorization may be either included in the informed consent or obtained separately.

Consent and HIPPA authorization must be obtained prior to any screening procedures.

Males 18 years of age and above
Histological or cytological proof of prostate cancer

Documented progressive mCRPC based on at least one of the following criteria:

PSA progression defined as 25% increase over baseline value with an increase in the absolute value of at least 2 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 2 ng/mL.
Soft-tissue progression defined as an increase ≥ 20% in the sum of the LD of all target lesions based on the smallest sum LD since treatment started or the appearance of one or more new lesions.
Progression of bone disease (evaluable disease) or (new bone lesion(s)) by bone scan.
Have testosterone < 50 ng/dL. Patients must continue primary androgen deprivation with an LHRH analogue (agonist or antagonist) if they have not undergone orchiectomy
ECOG performance status of 0-1
Patients on long term (>6 months) anti-androgen therapy (e.g., flutamide, bicalutamide, nilutamide) will need to be off anti-androgen for 4 weeks (wash out period) and show evidence of disease progression off the anti-androgen. Patients that have been on an anti- androgen 6 months or less will need to discontinue anti-androgen therapy prior to treatment start (no wash out period required).

Patient has adequate bone marrow and organ function as defined by the following laboratory values, obtained within 14 days prior to treatment start:

Absolute neutrophil count ≥ 1.5 × 109/L.
Platelets (UNVPLT) ≥ 100 × 109/L.
Hemoglobin (HGB) ≥ 9 g/dl.
Potassium (K), total calcium (CA)(corrected for serum albumin), magnesium, and phosphorus within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication.
INR ≤ 1.5.
Serum creatinine (CREAT) ≤ 1.5 mg/dL or creatine clearance > 50 mL/min.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN. If the patient has liver metastases, ALT and AST must still be ≤ 2.5 x ULN. Patients with liver metastases and AST/ALT above this limit will not be enrolled.
Total serum bilirubin ≤ 1.5 x ULN; or total bilirubin (TBILI) ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert's Syndrome.
The effects of ribociclib on the developing human fetus at the recommended therapeutic dose are unknown. Men must agree to use adequate contraception prior to treatment start, for the duration of study participation and for at least 3 months thereafter.
Must be able to take oral medication without crushing, dissolving or chewing tablets.

Exclusion Criteria:

Prior exposure to abiraterone acetate or other specific CYP-17 inhibitors. Abiraterone acetate given in the castration-sensitive setting is permissible if stopped at least 6 months prior to initial protocol treatment.
Prior exposure to enzalutamide, apalutamide, or other investigational AR directed therapy
Prior chemotherapy for castration resistant disease. Chemotherapy given in the castration-sensitive setting is permissible if stopped at least 4 weeks prior to treatment start.
Prior isotope therapy with strontium-89, samarium or radium-223 within 12 weeks of treatment start.
Administration of antifungal agents (itraconazole, fluconazole, etc) within 4 weeks of treatment start or unrecovered AEs due to agents administered more than 4 weeks of treatment start.
History of pituitary or adrenal dysfunction, active or symptomatic viral hepatitis or chronic liver disease.
Known symptomatic brain metastases.
Use of any prohibited concomitant medications: immunotherapy, 5 alpha reductase inhibitors, spironolactone, diethystilbestrol (DES), ketoconazole, newer medications targeting ARs.

NOTE: Because of the potential for drug-drug interaction, the concurrent use of all other drugs, over-the-counter medications, or alternative therapies must be documented. The principal investigator should be alerted if the patient is taking any agent that interacts with CYP450 system.

Treatment-related toxicity from prior therapy > Grade 2.
Peripheral neuropathy > 2
History of hypersensitivity to ribociclib or compounds of similar chemical or biologic composition to ribociclib including to peanut and soy or other drugs formulated with polysorbate 80; or enzalutamide.
Currently taking any herbal, alternative or food supplements (i.e., PC-Spes, Saw Palmetto, St John Wort, etc.). All herbal, alternative and food supplements must be discontinued prior to treatment start. Patients may continue on a daily Multi-Vitamin, calcium and Vitamin D.
Planned surgery or radiation therapy during protocol treatment,
Hormonal-acting agents (including DES, aldosterone, and spironolactone but not including GnRH agonists or antagonists) are forbidden during the trial and must be stopped prior to treatment start. No washout period will be required for any of these agents.
Initiation of bisphosphonate/denosumab therapy during protocol treatment. Patients on stable doses of bisphosphonates or denosumab which have been started no less than 4 weeks prior to treatment start may continue on this medication. NOTE: Initiation of bisphosphonate/denosumab therapy will be allowed for the treatment of osteoporosis or prevention of skeletal-related events (SRE) during protocol treatment.
Patient has a concurrent malignancy or malignancy within 3 years of treatment start, with the exception of adequately treated, basal or squamous cell carcinoma, non- melanomatous skin cancer or curatively resected cervical cancer.
Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
Patient has a known history of HIV infection (testing not mandatory).
Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.).

Patient has clinically significant, uncontrolled heart disease and/or recent events including any of the following:

History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to treatment start
History of documented congestive heart failure (New York Heart Association functional classification III-IV)
Documented cardiomyopathy
Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening
History of any cardiac arrhythmias, eg., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months prior to treatment start.
Family history of QTc prolongation or of unexplainable sudden death at <50 years of age.
On screening 12 lead ECG, any of the following cardiac parameters: bradycardia (heart rate < 50 at rest), tachycardia (heart rate > 90 at rest), PR interval > 220 msec, QRS interval >109 msec, or QTcF >450 msec. Congenital long QT syndrome or family history of long QT syndrome.
Systolic blood pressure (SBP) >160 mmHg or <90 mmHg.
Bradycardia (heart rate < 50 at rest), by ECG or pulse, at screening
On screening, inability to determine the QTcF interval on the ECG (i.e.: unreadable or not interpretable) or QTcF >450 msec (using Fridericia's correction). All as determined by screening ECG (mean of triplicate ECGs)

Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to treatment start:

Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges.
That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
That have a known risk to prolong the QT interval or induce Torsades de Pointes.
Herbal preparations/medications, dietary supplements

Patient is currently receiving or has received systemic corticosteroids within <2 weeks prior to treatment start, or who have not fully recovered from side effects of such treatment.

The following uses of corticosteroids are permitted: a short duration (<5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)
Patient is currently receiving warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed.
Participation in other studies involving investigational drug(s) within 30 days prior to randomization or within 5 half-lives of the investigational product (whichever is longer) or participation in any other type of medical research judged not to be scientifically or medically compatible with this study. If the patient is enrolled or planned to be enrolled in another study that does not involve an investigational drug, the agreement of the Novartis study medical lead is required to establish eligibility..

Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for palliation

≤ 2 weeks prior to treatment start, and who has not recovered to Grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom ≥ 30% of the bone marrow was irradiated.

Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:

At least 4 weeks from prior therapy completion (including radiation and/or surgery) to treatment start
Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases
Patient has had major surgery within 14 days prior to treatment start or has not recovered from major side effects (tumor biopsy is not considered as major surgery).
Patient has not recovered from all toxicities related to prior anticancer therapies to NCI- CTCAE version 4.03 Grade <1 (Exception to this criterion: patients with grade 1 taxane- induced neuropathy, any grade of alopecia, amenorrhea or other toxicities not considered a safety risk for the patient as per investigator's discretion, are allowed to enter the study).
Patient with a Child-Pugh score B or C.
Patient has a history of non-compliance to medical regimen or inability to grant consent
Sexually active males, unless they use a condom during intercourse while taking the study drug and for at least 3 months after stopping study treatment. Sexually active males should not father a child during this period. A condom is required to be used by vasectomized men in order to prevent delivery of the drug via seminal fluid.