Abiraterone Acetate and Apalutamide before and after Surgery in Treating Patients with Intermediate-High Risk Prostate Cancer
This phase II trial studies how well abiraterone acetate and apalutamide work in treating patients with intermediate-high risk prostate cancer before and after surgery. Androgens can cause the growth of prostate cancer cells. Drugs, such as abiraterone acetate and apalutamide, may lessen the amount of androgens made by the body.
Inclusion Criteria
- Male ≥ 18 years of age
- Histologically confirmed adenocarcinoma of the prostate without histological variants comprising > 50% of the sample as determined by academic center central review (including neuroendocrine differentiation, small cell, sarcomatoid, ductal adenocarcinoma, squamous or transitional cell carcinoma)
- Must have 3 core biopsies involved with cancer; prostate biopsy must be within seven months from screening; less than 3 core biopsies is allowed if the patient has > 1 cm or T3 disease on MRI
- Patients must have the following features: * Gleason >= 4+3 = 7 OR * Gleason 3+4 = 7 AND at least one of the following: PSA > 20 ng/mL, or T3 disease (as determined by MRI)
- No evidence of metastatic disease as determined by radionuclide bone scans and computed tomography (CT)/MRI; lymph nodes must be less than 20 mm in the short (transverse) axis
- Participants must be candidates for RP and considered surgically resectable by urologic evaluation
- Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
- Hemoglobin >= 9.0 g/dL
- Absolute neutrophil count (ANC) >= 1,500/mcL
- Platelets >= 100,000/mcL, independent of transfusions/growth factors within 3 months of treatment start
- Serum potassium >= 3.5 mmol/L
- Serum total bilirubin =< 1.5 x upper limit of normal (ULN) (except in subjects with Gilbert’s syndrome who have a total bilirubin > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is =< 2 x ULN, subject may be eligible)
- Aspartate aminotransferase (AST) =< 2.5 x ULN
- Alanine aminotransferase (ALT) =< 2.5 x ULN
- Serum albumin >= 3.0 g/dL
- Serum creatinine < 2.0 x ULN
- International normalized ratio (INR) =< 1.5 ULN unless on warfarin therapy (investigator would need to determine if safe for participant to stop warfarin prior to surgery and warfarin therapy)
- Partial thromboplastin time (PTT) =< 60
- 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
- Medications known to lower the seizure threshold must be discontinued or substituted prior to study treatment
- Have signed an informed consent document indicating that the subjects understand the purpose of and procedures required for the study and are willing to participate in the study
- Be willing/able to adhere to the prohibitions and restrictions specified in this protocol
- Able to swallow the study drug whole as a tablet
- Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least two hours before and or at least one hour after the dose abiraterone acetate is taken
Exclusion Criteria
- Prior hormone therapy for prostate cancer including orchiectomy, antiandrogens (including first-generation antiandrogens, enzalutamide, apalutamide and others), CYP17 inhibitors (including abiraterone, TAK-700, galeterone, ketoconazole, and others), estrogens, luteinizing hormone releasing hormone (LHRH) agonist/antagonists; prior therapy with 5-alpha-reductase inhibitors is allowed; LHRH therapy allowed if begun within 4-5 weeks of day 1; up to 30 days of bicalutamide is allowed if it is stopped two weeks prior to day 1
- Prior chemotherapy, radiation therapy for the treatment of prostate cancer, or immunotherapy for prostate cancer
- Prior systemic treatment with an azole drug within two weeks of start of treatment
- Hypogonadism or severe androgen deficiency as defined by screening serum testosterone < 200 ng/dL; patients who have a low screening testosterone due to prior antiandrogen therapy (ADT) will still be allowed to enroll on study if they do not have a known history of hypogonadism or severe androgen deficiency
- Clinically significant cardiovascular disease within 6 months of study treatment including: * Severe or unstable angina * Myocardial infarction * Symptomatic congestive heart failure * New York Heart Association (NYHA) (class II-IV heart failure) * Arterial or venous thromboembolic events (such as pulmonary embolism cerebrovascular accident including transient ischemic attacks) * History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes) * Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on screening electrocardiogram (EKG) > 470 msec * History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place * Uncontrolled hypertension (systolic blood pressure >= 140 mmHg or diastolic blood pressure >= 90 mmHg); participants with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive therapy
- History of seizure or any condition or concurrent medication that may predispose to seizure (including but not limited to prior stroke, transient ischemic attack, loss of consciousness within one year prior to randomization, brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect)
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to apalutamide, abiraterone acetate, or other study drugs
- Severe hepatic impairment (Child-Pugh class C)
- Active infection (such as human immunodeficiency virus [HIV] or viral hepatitis) or other medical condition that would make corticosteroid use contraindicated
- History of pituitary or adrenal dysfunction
- Gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug
- Pre-existing condition that warrants long-term corticosteroid use greater than the equivalent of 10 mg prednisone daily; physiologic replacement is permitted; topical, intra-articular steroids or inhaled corticosteroids are permitted
- Concomitant use of medications that may alter pharmacokinetics of abiraterone or apalutamide
- Individuals with a history of another malignancy are not eligible if the cancer is under active treatment or the cancer can be seen on radiology scans or if they are off cancer treatment but in the opinion of their oncologist have a high risk of relapse within 5 years
- Major surgery or radiation therapy within 4 weeks from start of treatment
- Any condition that in the opinion of the investigator would preclude participation in this study
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02903368.
PRIMARY OBJECTIVES:
I. To determine whether combination of abiraterone acetate + apalutamide improves frequency of achieving a pathologic complete response (pCR) or minimal residual disease (MRD) (defined as residual tumor in radical prostatectomy [RP] specimen measuring =< 5 mm) at RP as compared with abiraterone acetate alone, in men treated with neoadjuvant leuprolide and prednisone prior to RP. (Part 1)
II. To determine whether the use of adjuvant abiraterone acetate + apalutamide + prednisone following RP improves biochemical progression free survival (bPFS) at 3 years post-RP as compared with no adjuvant treatment. (Part 2)
SECONDARY OBJECTIVES:
I. To evaluate the frequency of achieving a pCR at RP following therapy with Arm 1A compared to Arm 1B. (Part 1)
II. To evaluate the frequency of achieving favorable residual cancer burden (RCB) (defined as the 33rd percentile of the RCB index which is calculated as the tumor volume x cellularity) at RP following therapy with Arm 1A compared to Arm 1B. (Part 1)
III. To evaluate the frequency of presenting cribriform or intraductal carcinoma at RP following therapy with Arm 1A compared to Arm 1B. (Part 1)
IV. To evaluate the frequency of positive surgical margins, extracapsular extension, positive seminal vesicles, and positive lymph nodes at time of RP following treatment with Arm 1A compared to Arm 1B. (Part 1)
V. To determine changes in prostate specific antigen (PSA) (median nadir value, percentage of participants with PSA < 0.2 ng/mL, proportion of participants with achieving 50% and 90% decrease in PSA, time to PSA nadir) from baseline to prior to RP with Arm 1A compared to Arm 1B. (Part 1)
VI. To assess intra-operative and post-operative complications following RP between treatment arms (1A and 1B). (Part 1)
VII. To determine the effect of treatment on freedom from biochemical failure at 2-, 3-, and 5-years post-RP between Arms 2A and 2B among patients who achieve testosterone recovery (defined as a testosterone > 200 ng/dL). (Part 2)
VIII. To determine the effect of treatment on (or freedom from) further prostate cancer therapy (to include adjuvant or salvage radiation therapy, androgen deprivation therapy [ADT], or other therapies) at 2-, 3-, and 5-years post-RP between Arms 2A and 2B. (Part 2)
IX. To assess the safety and tolerability of each treatment arm. (Part 2)
X. To assess quality of life parameters over time between treatment arm 2A and observation arm 2B. (Part 2)
CORRELATIVE OBJECTIVES:
I. To assess time to testosterone recovery, body-mass index, lipids, and cardiovascular events for treatment Arms 2A and 2B.
II. To assess changes in serum hormone levels (dehydroepiandrosterone [DHEA], androstenedione, testosterone, dihydrotestosterone [DHT], androsterone, progesterone, pregnenolone, deoxycorticosterone, cortisol, dehydroepiandrosterone-sulfate [DHEA-S]) by mass spectroscopy from pretreatment to during treatment to prior to RP and to post-RP between treatment Arms 1A and 1B and Arms 2A and 2B.
III. To correlate serum hormone levels from pretreatment to during treatment and to prior to RP with pathologic response at RP.
IV. To compare serum abiraterone acetate and apalutamide levels to tissue abiraterone acetate (abiraterone) and apalutamide levels and serum and hormone levels with pCR + minimum residual disease.
V. To compare prostate androgen levels by mass spectroscopy in the RP specimens between treatment Arms 1A and 1B.
VI. To compare the expression of the androgen receptor (AR) and proteins involved in the androgen synthesis, apoptosis, WNT signaling, and PTEN-PI3K-AKT pathways by immunohistochemistry (IHC) and expression analysis in the RP specimens between treatment Arms 1A and 1B and between patients with MRD compared to those without MRD.
VII. To assess changes in circulating tumor DNA from pretreatment to during treatment to prior to RP and to post-RP between Arms 2A and 2B.
VIII. To assess changes in the whole exome and whole transcriptome by high throughput parallel sequencing technologies in evaluable samples from RP between treatment Arms 1A and 1B.
IX. To assess proportion of patients with downstaging on second multi-parametric prostate magnetic resonance imaging (MRI) compared to baseline MRI between Arms 1A and 1B.
X. To correlate imaging T stage at second multi-parametric prostate MRI with pathologic T stage in all patients and by treatment arm.
XI. To determine if multi-parametric prostate MRI can be used to predict pathologic response (defined as pCR, MRD, and RCB) following neoadjuvant hormone therapy.
XII. To assess the prevalence of germline mutations in homologous recombination genes in all enrolled patients.
XIII. To correlate homologous recombination gene germline mutation status with pathologic response (defined as pCR, MRD, and RCB).
XIV. To evaluate family history of cancers in the study population and correlate family cancer history with germline mutation status.
OUTLINE:
PART 1: Patients are randomized to 1 of 2 arms.
ARM 1A: Patients receive abiraterone acetate orally (PO) once daily (QD), prednisone PO QD, and apalutamide PO QD on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive leuprolide acetate intramuscularly (IM) every 3 months for 6 months. Patients also undergo radical prostatectomy on day 180.
ARM 1B: Patients receive abiraterone acetate PO QD and prednisone PO QD on days 1-28. Treatment repeats for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive leuprolide acetate IM every three months for 6 months. Patients also undergo radical prostatectomy on day 180.
PART 2: Patients are randomized to 1 of 2 arms.
ARM 2A: Patients receive abiraterone acetate PO QD, prednisone PO QD, and apalutamide PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive leuprolide acetate IM every three months for 12 months.
ARM 2B: Patients undergo standard of care observation only.
After completion of study treatment, patients in Arm 2A are followed up every 3 months for years 2-3, and then every 6 months for up to 5 years post-RP. Patients in Arm 2B are followed up every 3 months during years 1-3 post RP, and then every 6 months for up to 5 years post-RP.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorMary-Ellen Taplin
- Primary ID16-223
- Secondary IDsNCI-2016-01764
- ClinicalTrials.gov IDNCT02903368