Apalutamide, Abiraterone Acetate, Prednisone, and Radiation Therapy in Treating Patients with Prostate Adenocarcinoma

Status: Active

Description

This phase II trial studies how well apalutamide, abiraterone acetate, prednisone, and radiation therapy work in treating patiens with prostate adenocarcinoma. Drugs used in chemotherapy, such as apalutamide and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Abiraterone acetate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. It is not known which combination will work best in treating prostate adenocarcinoma.

Eligibility Criteria

Inclusion Criteria

  • Willing and able to provide written informed consent and authorization for use and release of health and research study information (Health Insurance Portability and Accountability Act [HIPAA] authorization) * NOTE: HIPAA authorization may be either included in the informed consent or obtained separately
  • Serum testosterone of >= 150 ng/dL (For cohorts A and B1, testosterone level requirement is exempted if they are already on ADT prior to treatment start. For cohort B2, patients will be considered eligible if their testosterone is currently >= 150 ng/dL
  • Cohort A * Clinically localized disease with histologically confirmed adenocarcinoma of the prostate with either >= 3 positive cores or 2 positive cores if > 1cm in length with at least 50% tumor content WITH ** Gleason score 8-10 or ** Gleason 4 + 3 or 3 + 4 with one of the following features: *** PSA >= 20 ng/mL within 2 months prior to diagnostic biopsy *** Magnetic resonance imaging (MRI) suspicious for radiographic >= T3 disease (as long as urologist deems tumor is resectable at baseline); defined as > 75% probability of extracapsular extension or seminal vesicle invasion in the opinion of the reading radiologist or ** Gleason 3 + 4 or 4 + 3 and Oncotype Dx Genomic Prostate score of > 40 WITH/WITHOUT *** Clinical N1 (size > 1.5 cm in the short axis) (Gleason score requirement can be omitted if node positive) OR
  • Cohort B1 * Newly diagnosed low-volume metastatic disease with either: ** Bone metastases as documented by computed tomography (CT), MRI or radionuclide bone scan amenable to treatment with a maximum of 3 radiation isocenters; these lesions must have a structural correlate on CT or MRI in order to allow for adequate radiation targeting (Note: patients with positron emission tomography [PET] scans that show osseous metastases that would not be amenable to 3-isocenter radiation treatment are still eligible as long as conventional imaging shows osseous disease that can be treated with 3 radiation isocenters) AND/OR ** Retroperitoneal nodes up to the level of the renal hilum with/without pelvic nodal metastasis > 1.5 cm in the short axis
  • Cohort B2 * Rising PSA after RP with: ** Osseous or retroperitoneal nodal metastases (up to the level of renal hila) as documented by fluciclovine F18 (FACBC) or prostate-specific membrane antigen (PSMA) PET which are: *** Amenable to treatment with a maximum of 3 radiation isocenters; these lesions should have structural correlates on CT or MRI. Lesions without structural correlates will be viewed as equivocal and not need to be irradiated but will be followed. *** With associated CT or MRI correlate ** No evidence of local recurrence within prior radiation field on MRI or other imaging studies i.e. local recurrence is acceptable in patients without prior salvage radiation ** Prior salvage radiotherapy is permitted * (Multiple lesions within one isocenter may be permitted upon review by the sponsor’s radiation oncologist)
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 1
  • Absolute neutrophil count (ANC) >= 1500/ul (within 28 days prior to treatment start)
  • Hemoglobin >= 9 g/dL (within 28 days prior to treatment start)
  • Platelet count >= 100,000/ul (within 28 days prior to treatment start)
  • Serum creatinine glomerular filtration rate (GFR) > 45 mL/min (within 28 days prior to treatment start)
  • Potassium within institutional normal range (within 28 days prior to treatment start)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 28 days prior to treatment start) (Note: In subjects with Gilbert’s syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is =< 1.5 x ULN, subject may be eligible)
  • Albumin >= 3.0 g/dL (within 28 days prior to treatment start)
  • Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x ULN (within 28 days prior to treatment start)
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x ULN (within 28 days prior to treatment start)
  • Patients must have a clinical T stage documented by the treating urologist/medical oncologist within 90 days prior to treatment start using the seventh (7th) edition American Joint Committee on Cancer (AJCC) staging system, recorded as the urologist’s/medical oncologist’s best clinical assessment of extent of local disease by digital rectal examination and/or available imaging studies such as transrectal ultrasound, CT scan, and/or MRI; Applicable to Cohort A and B1
  • The primary tumor must be considered resectable by RP based on initial imaging with gross negative margins as determined by a urologist and documented as such (Applicable to cohorts A and B1 only)
  • Recovery of reversible effects of prior surgery (i.e., incisional pain, wound drainage) to grade =< 1, and at least 4 weeks from prior surgery to treatment start (biopsy excluded)
  • Able to swallow the study drug(s) whole as a tablet
  • Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least one hour before and for at least two hours after the dose of abiraterone acetate is taken. (Note: apalutamide does not have to be taken on an empty stomach)
  • Agrees to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug. Must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug
  • For cohorts B1 and B2 only, biopsy confirmation of metastases (strongly encouraged; if safe and feasible at treating center)

Exclusion Criteria

  • Prior treatment for prostate cancer including prior surgery (excluding transurethral resection of the prostate [TURP] and patients with rising PSA after RP), pelvic lymph node dissection, radiation therapy unless the patient is eligible for cohort B2
  • Prior cytotoxic chemotherapy or biologic therapy for prostate cancer
  • More than 2 months of prior ADT with gonadotrophin releasing hormone (GnRH) antagonist/agonist at time of treatment start. Bicalutamide given for =< 2 months at the time of registration as flare prevention is allowed; For Cohort B2, prior ADT and/or first generation anti-androgen treatment in the (neo)adjuvant and/or salvage setting in conjunction with radiation or surgery is allowed provided last effective dose of ADT and/or first generation anti-androgen is > 12 months prior to the date of randomization and total duration of prior therapy is 12 months or lesser, and their testosterone is currently > 150 ng/dL
  • Prior exposure to ketoconazole (systemic), abiraterone acetate, enzalutamide or other agents targeting the androgen receptor (AR) signaling pathway
  • Concomitant therapy with any other experimental drug
  • Known brain, liver, lung or other visceral metastasis (with the exception of retroperitoneal and/or pelvic nodal metastases as per inclusion criteria
  • Prior prostate cancer metastasis-directed therapies
  • Currently active second malignancy or past history of malignancies diagnosed within the last 5 years that require active therapy and/or in remission with life expectancy of < 5 years, with the exception of resected non-melanoma skin cancers, non-muscle invasive bladder cancer, stage I head and neck cancer, or stage I colorectal cancer
  • Significant medical condition other than cancer, that would prevent consistent and compliant participation in the study that would, in the opinion of the investigator, make this protocol unreasonably hazardous including but not limited to: * Any medical condition requiring a higher dose of corticosteroid than 10mg prednisone/prednisolone once daily * History of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agents * Uncontrolled hypertension (systolic blood pressure [BP] >= 160 mmHg or diastolic BP >= 95 mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment (systolic BP <160 mmHg or diastolic BP <95 mmHg) * Active or symptomatic viral hepatitis or chronic liver disease * Known active human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection. (HIV testing is not mandatory) * History of pituitary or adrenal dysfunction * History of hypogonadism * Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class III or IV heart disease or cardiac ejection fraction measurement of < 50% at baseline, or clinically significant ventricular arrhythmias within 6 months prior to treatment start. * History of seizure or any condition that may predispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness =< 1 year prior to treatment start; brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect) * Uncontrolled diabetes mellitus * History of inflammatory bowel disease * Baseline moderate and severe hepatic impairment (Child Pugh class B & C)
  • Use of any prohibited concomitant medications within 14 days prior to treatment start, or use of prohibited concomitant medications within the outlined windows * Note: Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to treatment start
  • Pre-existing condition that warrants long-term corticosteroid use in excess of 10 mg prednisone/prednisolone daily. (Note: If a subject has been receiving glucocorticoids other than prednisone or prednisolone, it will be necessary to switch the glucocorticoids to prednisone or prednisolone 5 mg twice daily prior to day 1)
  • Known allergies, hypersensitivity or intolerance to apalutamide, abiraterone acetate, prednisone, or GNRH agonist or GNRH antagonist
  • Administration of an investigational therapeutic within 30 days of treatment start
  • Patients that cannot tolerate MRI
  • Any condition which, in the opinion of the investigator, would preclude participation in this trial

Locations & Contacts

Massachusetts

Boston
Beth Israel Deaconess Medical Center
Status: Active
Contact: Glenn J. Bubley
Email: gbubley@bidmc.harvard.edu
Dana-Farber Cancer Institute
Status: Active
Contact: Mary-Ellen Taplin
Phone: 617-582-7221
Email: mary_taplin@dfci.harvard.edu

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Howard I. Scher
Phone: 646-422-4323
Email: scherh@mskcc.org

New York

Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Howard I. Scher
Phone: 646-422-4323
Email: scherh@mskcc.org
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Howard I. Scher
Phone: 646-422-4323
Email: scherh@mskcc.org
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Howard I. Scher
Phone: 646-422-4323
Email: scherh@mskcc.org

Ohio

Cleveland
Cleveland Clinic Foundation
Status: Active
Contact: Jorge A. Garcia
Phone: 216-444-6833

Trial Objectives and Outline

PRIMARY OBJECTIVE:

I. The proportion of patients with a pathologic complete response (pCR) + minimal residual disease (MRD) (=< 5 mm tumor) in the prostate in patients undergoing radical prostatectomy (RP) (cohorts A and B1).

SECONDARY OBJECTIVES:

I. Elimination of metastatic disease evidenced by an undetectable prostate specific antigen (PSA) (< 0.1 ng/mL) following testosterone recovery (PSA0) at 24 months from the start of androgen deprivation therapy (ADT) stratified by the presence of metastasis at enrollment (i.e., M0 versus [vs] M1) for cohorts A + B1 + B2.

II. Proportion of patients with pCR in the prostate.

III. PSA response rate defined as percentage of patients with an undetectable PSA at 10 months from treatment start (after the completion of therapy with castrate levels of testosterone).

IV. Time to PSA progression defined as the time from the start of treatment to the date of first evidence of disease progression (serum PSA >= 0.2 ng/mL, which is confirmed by a second determination with a PSA >= 0.2 ng/mL, according to the 2007 American Urological Association Prostate Guidelines).

V. Quality of life.

VI. Time to and frequency of testosterone recovery.

VII. Systemic therapy-related toxicity rates.

EXPLORATORY OBJECTIVES:

I. Proportion of patients with pCR in primary tumor and resected lymph nodes.

II. Proportion of patients with pCR + MRD in primary tumor and resected lymph nodes.

CORRELATIVE OBJECTIVES:

I. Molecular characterization of disease prior to therapy. (Pre-treatment)

II. Molecular characterization of foci of resistant tumors in the primary and metastatic lesions following systemic therapy. (Post-treatment)

III. In-depth molecular analysis of exceptional responders (e.g., pT0 pN0 and PSA0 at 24 months, subjected to different definitions based on knowledge gained during the study or other emerging data) and/or primary refractory disease.

IV. Utility of cell-free deoxyribonucleic acid (DNA) (cfDNA) to characterize molecular profile of disease at recurrence.

V. Incidence of germline mutations in cancer-predisposition genes including DNA damage repair genes, and their correlation with treatment sensitivity/resistance.

OUTLINE: Participants are randomized to 1 of 6 arms.

COHORT A: Participants with very high risk localized prostate cancer with/without regional lymphadenopathy are randomized to 1 of 2 arms.

ARM I: Patients receive apalutamide orally (PO) once daily (QD) on days 1-28.

ARM II: Patients receive apalutamide PO QD, abiraterone acetate PO QD and prednisone PO twice daily (BID) on days 1-28.

In both arms, patients also receive ADT via injection every month or every 3 months at the discretion of the treating physician. Patients undergo radical prostatectomy in cycle 7 and may undergo adjuvant radiation therapy in cycles 9-10. Treatment repeats every 28 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity.

COHORT B1: Patients with newly diagnosed low-volume metastatic disease with either bone metastases and/or retroperitoneal with/without pelvic nodal metastasis are randomized to 1 of 2 arms.

ARM I: Patients receive apalutamide PO QD on days 1-28.

ARM II: Patients receive apalutamide PO QD, abiraterone acetate PO QD and prednisone PO BID on days 1-28.

In both arms, patients also receive ADT via injection every month or every 3 months at the discretion of the treating physician. Patients undergo stereotactic body radiation therapy (SBRT) in cycle 4, then radical prostatectomy in cycle 7. Patients may also undergo adjuvant radiation therapy in cycles 9-10. Treatment repeats every 28 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity.

COHORT B2: Patients with rapidly rising PSA after radical prostatectomy with metastases are randomized to 1 of 2 arms.

ARM I: Patients receive apalutamide PO QD on days 1-28.

ARM II: Patients receive apalutamide PO QD, abiraterone acetate PO QD and prednisone PO BID on days 1-28.

In both arms, patients also receive ADT via injection every month or every 3 months at the discretion of the treating physician. Patients undergo SBRT in cycle 4, then salvage radiation therapy in cycles 7-8. Treatment repeats every 28 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 12, 15, 18, 21, 24, 30, 30 and 36 months.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Howard I. Scher

Trial IDs

Primary ID 17-646
Secondary IDs NCI-2018-01392
Clinicaltrials.gov ID NCT03436654