Study of Abiraterone, Atezolizumab, Lupron, and Radiation Therapy for the Treatment of Men with Newly Diagnosed Metastatic Hormone-sensitive Prostate Cancer, SAABR Study

This phase II trial studies how well abiraterone acetate, atezolizumab, lupron, and stereotactic body radiotherapy works for the treatment of men with hormone-sensitive prostate cancer that has spread to different parts of the body (metastatic). Abiraterone acetate works by decreasing the production of the male sex hormone (testosterone) that causes prostate cancer to grow. The steroid drug prednisone is given with abiraterone acetate to reduce or prevent some of its side effects. Lupron (leuprolide) is a hormone treatment that reduces levels of testosterone, which slows the growth of prostate cancer. Atezolizumab is a type of drug called a PD-L1 blocker; it blocks a protein located on the surface of some tumor cells and immune cells that can act as a “brake” on the immune system. Blocking this protein releases the brakes, allowing the immune system to function more efficiently to identify and attack cancer cells. Stereotactic body radiotherapy delivers very precisely targeted high-dose radiation in less time than standard radiation therapy, which reduces potential damage to healthy tissues near the targeted treatment area. Adding atezolizumab and stereotactic body radiotherapy to treatment with abiraterone acetate, prednisone, and lupron may boost the immune system's ability to identify and destroy cancer cells, which may prevent the cancer from getting worse.

Inclusion Criteria

• Willing and able to provide or have a legally authorized representative to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for the release of personal health information. A signed informed consent must be obtained before screening procedures are performed * NOTE: HIPAA authorization may be either included in the informed consent or obtained separately
• Untreated metastatic (M1a/b/c) hormone-sensitive prostate cancer documented by positive bone scan or metastatic lesion on computed tomography (CT) or magnetic resonance imaging (MRI); untreated is defined as having never received surgical, radiotherapeutic, or systemic therapy for their prostate cancer. Note: 10 subjects who have had prior hormonal therapy (GnRH analog +/- first-generation anti-androgen such a bicalutamide) started up to 3 months prior to signing consent to the trial will be permitted to enroll onto the study if they have demonstrated a decline in prostate specific antigen (PSA). Anti-androgens must be stopped prior to Cycle 1
• Biopsy-proven adenocarcinoma of the prostate
• Eligible for SBRT per institutional guidelines
• Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
• Absolute neutrophil count (ANC) >= 1,500/uL (within 14 days of treatment start)
• Albumin >= 3.5 g/dL (within 14 days of treatment start)
• Hemoglobin >= 9 g/dL (within 14 days of treatment start)
• Platelet count >= 100,000 / ul (within 14 days of treatment start)
• Creatinine clearance > 30 mL/min (calculated using the Cockcroft-Gault formula) (within 14 days of treatment start)
• Potassium >= 3.5 mmol/L (within institutional normal range) (within 14 days of treatment start)
• Bilirubin < 1.5 x upper limit of normal (ULN) (unless documented Gilbert's disease) (within 14 days of treatment start)
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate transaminase [AST]) < 1.5 x ULN (within 14 days of treatment start)
• Serum glutamate pyruvate transaminase (SGPT) (alanine transferase [ALT]) < 1.5 x ULN (within 14 days of treatment start)
• International normalized ratio (INR) =< 1.5 x ULN (unless on anti-coagulation medication such as coumadin in which case elevated INR is permitted) (within 14 days of treatment start)
• Subjects must agree to use a medically acceptable method of birth control (e.g., spermicide in conjunction with a barrier such as a condom) or sexual abstinence for the duration of the study, including 150 days after the last dose of study drug. Sperm donation is prohibited during the study and for 30 days after the last dose of study drug. Female partners must use hormonal or barrier contraception unless postmenopausal or abstinent
• Subjects must have adequate tissue available for genomic profiling tests (refer to lab manual for required amount of each correlative test). If subject’s pathology is from an outside lab, verbal confirmation from the host lab that 20-35 unstained slides are available is acceptable (fewer slides may be accepted on a case-by-case basis). If cores are available, 5 cores are enough to create 20-35 slides

Exclusion Criteria

• History of malignancy within 3 years prior to initiation of study treatment, except for malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival [OS] rate > 90%), such as non-melanoma skin carcinoma and superficial urothelial cancer
• Pathological finding consistent with pure small cell carcinoma of the prostate (no adenocarcinoma in the biopsy specimen)
• Known or suspected brain metastasis or active leptomeningeal disease
• Asymptomatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g. clinically significant epidural disease, structurally unstable bone lesions)
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (one monthly or more frequently)
• Uncontrolled hypertension (systolic blood pressure >= 160 mmHg or diastolic blood pressure (BP) >= 95 mmHg). Subjects with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
• Positive human immunodeficiency virus (HIV) test at screening
• Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test and/or HBV polymerase chain reaction (PCR) at screening. Subjects with a past or resolved HBV infection, defined as having a negative HBsAg and HBV PCR test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study
• Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV RNA test at screening. The HCV ribonucleic acid (RNA) test will be performed only for subjects who have a positive HCV antibody test
• History of adrenal dysfunction
• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
• 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: * Subjects with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone * Subjects with controlled type 1 diabetes mellitus who are on an insulin regimen * Subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., subjects with psoriatic arthritis are excluded) are allowed provided all the 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 ** 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
• 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
• 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 6 months 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
• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
• 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
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
• 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
• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antiTNF-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: * Subjects 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 after Sponsor Principal Investigator approval has been obtained * Subjects 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
• 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 abiraterone or prednisone formulations
• Any other disease, metabolic dysfunction, physical examination finding, clinical laboratory finding or situation that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the subject at high risk from treatment complications

PRIMARY OBJECTIVE:

I. To determine if the addition of stereotactic body radiotherapy (SBRT) and atezolizumab to abiraterone and leuprolide acetate (lupron) improves freedom-from-failure (binary) at 2-years relative to the failure-free survival at 2 years in the STAMPEDE trial (70%) for the metastatic cohort.

SECONDARY OBJECTIVES:

I. To determine symptomatic skeletal events (SSEs) defined as symptomatic fracture, surgery or radiation to bone, or spinal cord compression.

II. To determine prostate cancer specific survival: defined as time from treatment start to death from prostate cancer; patients who die from other causes will be classified as a competing risk.

III. To determine overall survival: time from start of treatment to death due to any cause; surviving patients will be censored at time of last follow up.

IV. To assess safety and tolerability and measure proportion of adverse events by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).

CORRELATIVE/EXPLORATORY/TERTIARY OBJECTIVE:

I. To evaluate potential tissue and blood-based predictors of response to therapy.

OUTLINE:

Patients receive atezolizumab intravenously (IV) over 60 minutes on day 1. Beginning cycle 2, patients receive abiraterone acetate orally (PO) once daily (QD) and prednisone PO QD on days 10-15. Beginning cycle 3, patients receive leuprolide acetate intramuscularly (IM) on day 1 of cycle 3 and then every 3 months thereafter. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of cycle 5, patients also undergo stereotactic body radiotherapy (SBRT) twice per week for a total of 5 treatments.

After completion of study treatment, patients are followed up every 3 months.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Dana Rathkopf

• Primary ID 19-461
• Secondary IDs NCI-2020-01586
• Clinicaltrials.gov ID NCT04262154