Phase II Randomized Study Of Neoadjuvant And Adjuvant Abiraterone Acetate + Apalutamide For Intermediate-High Risk Prostate Cancer Undergoing Prostatectomy
Overview
- Phase
- Phase 2
- Intervention
- Leuprolide
- Conditions
- Prostate Cancer
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 118
- Locations
- 4
- Primary Endpoint
- Combined pCR or MRD Rate [Part 1]
- Status
- Completed
- Last Updated
- 10 months ago
Overview
Brief Summary
This multicenter randomized phase II trial investigates the impact of intense androgen deprivation on radical prostatectomy (RP) pathologic response and radiographic and tissue biomarkers in localized prostate cancer (NCT02903368).
Detailed Description
This is a multicenter, phase II, prospective, randomized trial designed to investigate the efficacy of neoadjuvant and adjuvant abiraterone acetate + apalutamide for men with intermediate-high risk prostate cancer who are candidates for RP. The study includes two parts. In part 1, patients will be randomized in 1:1 ratio to receive 6 months of abiraterone acetate, apalutamide, leuprolide and prednisone (Arm 1A) versus 6 months of abiraterone acetate, leuprolide and prednisone (Arm 1B) followed by RP, stratified by risk factor (intermediate versus high-risk). High-risk factors will be defined as a Gleason score ≥ 8, PSA \> 20 ng/dL, or T3 disease on MRI. In part 2 (post-RP), patients will be randomized in 1:1 ratio to receive an additional 12 months of abiraterone acetate, apalutamide, leuprolide and prednisone (Arm 2A) or observation (Arm 2B) stratified by type of neoadjuvant therapy and pathological T-stage (\< pT3 versus ≥ pT3) after RP but before cycle 7 day 1 following neoadjuvant therapy. There will be an early stopping rule for Part 2 should a high rate of patients refuse to participate or drop out early while receiving adjuvant therapy (\<6 months).
Investigators
Mary-Ellen Taplin, MD
Mary-Ellen Taplin, MD
Dana-Farber Cancer Institute
Eligibility Criteria
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 (a minimum of 6 core biopsies must be obtained). Prostate biopsy must be within seven months from screening. Less than 3 core biopsies are 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/dL or T3 disease (as determined by MRI).
- •No evidence of metastatic disease as determined by radionuclide bone scans and 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 of 0 to
- •Participants must have normal organ and marrow function as defined below:
Exclusion Criteria
- •Prior hormone therapy for prostate cancer including orchiectomy, antiandrogens (including first-generation antiandrogens, enzalutamide, Apalutamide and others), CYP17 inhibitors (including abiraterone acetate, TAK-700, galeterone, ketoconazole, and others), estrogens, Luteinizing Hormone Releasing Hormone (LHRH) agonist/antagonists. Prior therapy with 5α-reductase inhibitors is allowed. LHRH therapy allowed if begun within 4 weeks of day
- •Prior chemotherapy, radiation therapy, 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.
- •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 disease;
- •Arterial or venous thromboembolic events (such as pulmonary embolism cerebrovascular accident including transient ischemic attacks);
Arms & Interventions
Arm 1B: APL Neoadjuvant Therapy [Part 1]
Eligible Participants will be randomized to receive: APL: Abiraterone acetate (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/day orally) for 6 months
Intervention: Leuprolide
Arm 1B: APL Neoadjuvant Therapy [Part 1]
Eligible Participants will be randomized to receive: APL: Abiraterone acetate (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/day orally) for 6 months
Intervention: Prednisone
Arm 1A: AAPL Neoadjuvant Therapy [Part 1]
Eligible Participants will be randomized to receive: AAPL: Abiraterone acetate (240 mg/day orally), Apalutamide (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/twice daily orally) for 6 months Pts x weeks to RP
Intervention: Apalutamide
Arm 1A: AAPL Neoadjuvant Therapy [Part 1]
Eligible Participants will be randomized to receive: AAPL: Abiraterone acetate (240 mg/day orally), Apalutamide (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/twice daily orally) for 6 months Pts x weeks to RP
Intervention: Leuprolide
Arm 1A: AAPL Neoadjuvant Therapy [Part 1]
Eligible Participants will be randomized to receive: AAPL: Abiraterone acetate (240 mg/day orally), Apalutamide (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/twice daily orally) for 6 months Pts x weeks to RP
Intervention: Prednisone
Arm 1A: AAPL Neoadjuvant Therapy [Part 1]
Eligible Participants will be randomized to receive: AAPL: Abiraterone acetate (240 mg/day orally), Apalutamide (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/twice daily orally) for 6 months Pts x weeks to RP
Intervention: Abiraterone Acetate
Arm 1B: APL Neoadjuvant Therapy [Part 1]
Eligible Participants will be randomized to receive: APL: Abiraterone acetate (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/day orally) for 6 months
Intervention: Abiraterone Acetate
Arm 2A: AAPL Adjuvant Therapy [Part 2]
Eligible Participants will be randomized to receive: AAPL: Abiraterone acetate (240 mg/day orally), Apalutamide (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/twice daily orally) for 12 months
Intervention: Apalutamide
Arm 2A: AAPL Adjuvant Therapy [Part 2]
Eligible Participants will be randomized to receive: AAPL: Abiraterone acetate (240 mg/day orally), Apalutamide (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/twice daily orally) for 12 months
Intervention: Leuprolide
Arm 2A: AAPL Adjuvant Therapy [Part 2]
Eligible Participants will be randomized to receive: AAPL: Abiraterone acetate (240 mg/day orally), Apalutamide (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/twice daily orally) for 12 months
Intervention: Prednisone
Arm 2A: AAPL Adjuvant Therapy [Part 2]
Eligible Participants will be randomized to receive: AAPL: Abiraterone acetate (240 mg/day orally), Apalutamide (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/twice daily orally) for 12 months
Intervention: Abiraterone Acetate
Outcomes
Primary Outcomes
Combined pCR or MRD Rate [Part 1]
Time Frame: Assessed from RP specimens, at 6 months from the initiation of neoadjuvant therapy.
Pathological response, defined as achieving either pCR or MRD at radical prostatectomy (RP). Pathological Complete Response (pCR) is defined as the absence of morphologically identifiable carcinoma in the RP specimen. MRD will be defined as residual tumor in the RP specimen measuring ≤ 5 mm.
Biochemical Progression Free Survival (bPFS) Rate at 3 Years Post RP [Part 2]
Time Frame: At 3 years post RP
3-year bPFS rate is defined as the probability of biochemical progression free and survival at 3 years from the date of Part 2 randomization, which is estimated using Kaplan Meier methods. The event is considered to be biochemical progression (defined as a confirmed PSA ≥ 0.2 ng/mL), local, regional, or distant metastatic disease on CT/MRI or bone scan, or receipt of post-operative systemic therapy or radiotherapy for rising PSA, or death from any cause. Participants who are lost to follow-up before the 3-year mark are censored at date last disease evaluation.
Secondary Outcomes
- Frequency of Presenting Cribriform at RP (Part 1)(Assessed from RP specimens, at 6 months from the initiation of neoadjuvant therapy.)
- Frequency of Presenting Intraductal Carcinoma at RP (Part 1)(Assessed from RP specimens, at 6 months from the initiation of neoadjuvant therapy.)
- Biochemical Progression Free Survival (bPFS) Rate at 4 Years Post RP [Part 2](At 4 years post RP)
- Mean Scores for Quality of Life (QOL) Questionnaires EPIC-26 at 12-months Post-RP (Part 2)(At 12-months post-RP)
- Rate of pCR at RP (Part 1)(Assessed from RP specimens, at 6 months from the initiation of neoadjuvant therapy.)
- Percent of Participants With Nadir PSA < 0.2 ng/mL Prior to RP (Part 1)(Assessed on day 1 of each cycle (1 cycle=28 +/- 2 days), up to 6 months from the initiation of neoadjuvant therapy.)
- Rate of Freedom From Further Anti-cancer Therapy at 3-years Post RP (Part 2)(At 3 years post RP)
- Median of Residual Cancer Burden (RCB) at RP (Part 1)(Assessed from RP specimens, at 6 months from the initiation of neoadjuvant therapy.)
- Frequency of Positive Surgical Margins at RP (Part 1)(Assessed from RP specimens, at 6 months from the initiation of neoadjuvant therapy.)
- Frequency of Presenting Intra-operative Complications Following RP (Part 1)(Assessed post-RP, at 6 months from the initiation of neoadjuvant therapy.)
- Biochemical Progression Free Survival (bPFS) Rate at 2 Years Post RP [Part 2](At 2 years post RP)
- Rate of Freedom From Further Anti-cancer Therapy at 4-years Post RP (Part 2)(At 4-years post RP)
- Mean Scores for Quality of Life (QOL) Questionnaires EPIC-26 at 6-months Post-RP (Part 2)(At 6-months post-RP)
- Rate of Freedom From Further Anti-cancer Therapy at 2-years Post RP (Part 2)(At 2-years post RP)
- Mean Scores for Quality of Life (QOL) Questionnaires EPIC-26 at 24-months Post-RP (Part 2)(At 24-months post-RP)