A Phase II, Double-Blinded, Placebo-Controlled Randomized Trial of Salvage Radiotherapy With or Without Enhanced Anti-Androgen Therapy With Apalutamide in Recurrent Prostate Cancer (BALANCE*)
Overview
- Phase
- Phase 2
- Intervention
- External Beam Radiation Therapy
- Conditions
- Not specified
- Sponsor
- NRG Oncology
- Enrollment
- 324
- Locations
- 710
- Primary Endpoint
- Biochemical progression-free survival (bPFS)
- Status
- Active, Not Recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
This phase II trial studies how well radiation therapy with or without apalutamide works in treating patients with prostate cancer that has come back (recurrent). Radiation therapy uses high energy x-ray to kill tumor cells and shrink tumors. Androgen can cause the growth of prostate cancer cells. Drugs, such as apalutamide, may lessen the amount of androgen made by the body. Giving radiation therapy and apalutamide may work better at treating prostate cancer compared to radiation therapy alone.
Detailed Description
PRIMARY OBJECTIVE: I. To determine whether, in men with post-prostatectomy prostate-specific antigen (PSA) recurrences, salvage radiation (SRT) with enhanced anti-androgen therapy with apalutamide will improve biochemical progression-free survival (bPFS) compared to SRT alone. SECONDARY OBJECTIVES: I. To assess whether molecular stratification by the PAM50 gene expression clustering will identify subsets of prostate cancer (luminal A or basal, luminal B) which derive the greatest benefit from anti-androgen therapy. II. To assess overall survival. III. To assess cancer-specific mortality. IV. To assess metastasis-free survival. V. To assess distant metastasis. VI. To assess local-regional progression. VII. To assess PSA nadir during first year of treatment and prior to initiation of any hormonal salvage therapy. VIII. To assess initiation of salvage hormonal therapy. IX. To assess PSA with a non-castrate testosterone at 1 and 3 years post randomization: PSA \< 0.1 ng/ml and testosterone \>= 50 ng/dl. X. To assess acute and late physician-reported morbidity (per the Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0) after SRT +/- apalutamide. XI. To assess acute and late patient-reported symptomatic adverse events morbidity (per the patient reported outcomes \[PRO\]-CTCAE) after SRT +/- apalutamide. XII. To assess testosterone levels at 3, 6, 9, 12, and 36 months post randomization. EXPLORATORY OBJECTIVE: I. To assess the prognostic and predictive value of the genomic classifier Decipher. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive placebo orally (PO) once daily (QD) on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. ARM 2: Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive apalutamide PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years, and then yearly thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Pathologically (histologically) proven diagnosis of prostate adenocarcinoma; prostatectomy must have been performed within 10 years prior to Step 1 registration and any type of radical prostatectomy is permitted, including retropubic, perineal, laparoscopic or robotically assisted
- •Post-prostatectomy patients with a detectable serum PSA (\>= 0.1, but =\< 1.0 ng/mL) at study entry (within 90 days of Step 1 registration) and at least one of the following:
- •Gleason score 7-10 (International Society of Urological Pathology \[ISUP\] grade group 2 to 5)
- •ISUP grade group:
- •Grade group 1 = Gleason score =\< 6,
- •Grade group 2 = Gleason score 3 + 4 = 7,
- •Grade group 3 = Gleason score 4 + 3 = 7,
- •Grade group 4 = Gleason score 8,
- •Grade group 5 = Gleason scores 9 and 10
- •\>= T3a disease
Exclusion Criteria
- •PRIOR TO STEP 1 REGISTRATION:
- •Definitive clinical, radiologic, or pathologic evidence of metastatic disease (M1) or lymph node involvement (N1)
- •Prior invasive malignancy (except non-melanomatous skin cancer, carcinoma in situ of the male breast, penis, oral cavity, or stage Ta of the bladder, or stage I completely resected melanoma) unless disease free for a minimum of 2 years
- •Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable
- •Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
- •History of any of the following:
- •Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1 year prior to Step 1 registration)
- •History of documented inflammatory bowel disease
- •Transmural myocardial infarction within the last 4 months prior to Step 1 registration
- •Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months prior to Step 1 registration
Arms & Interventions
Arm 1 (radiation therapy, placebo)
Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive placebo PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: External Beam Radiation Therapy
Arm 1 (radiation therapy, placebo)
Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive placebo PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Placebo Administration
Arm 2 (radiation therapy, apalutamide)
Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive apalutamide PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Apalutamide
Arm 2 (radiation therapy, apalutamide)
Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive apalutamide PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: External Beam Radiation Therapy
Outcomes
Primary Outcomes
Biochemical progression-free survival (bPFS)
Time Frame: From randomization to the first occurrence of a rise in PSA, clinical or radiographic local, regional, or distant metastases, or death from any cause, assessed up to 5 years
bPFS curves will be estimated by the Kaplan-Meier (1958) method and compared between the two treatment arms using a one-sided logrank test at the alpha = 0.12 significance level. In addition, a multivariable Cox regression model will be fit incorporating the three stratification factors used in the randomization (surgical margins, pre-salvage radiation \[SRT\] PSA, and molecular subtype) as covariates to estimate the adjusted hazard ratio (HR) between the two treatment groups. Additional regression models will be fit including other pretreatment characteristics as covariates. The goodness-of-fit of the proportional hazards assumption will be evaluating using graphical methods (Kay, 1977), residual plots, and the global test proposed by Grambsch and Therneau (1994). Missing covariates will be handled using multiple imputation as described in White and Royston (1982).
Secondary Outcomes
- Distant metastasis(Up to 5 years)
- PSA nadir during first year of treatment and prior to initiation of any hormonal salvage therapy(During first year of treatment)
- Initiation of salvage hormonal therapy(Up to 5 years)
- Undetectable PSA with a non-castrate testosterone (PSA < 0.1 ng/ml and testosterone >= 50 ng/dl))(3 years)
- Acute patient-reported morbidity symptomatic adverse events (per the patient reported outcomes [PRO]-CTCAE)(Up to 5 years)
- Overall survival (OS)(From randomization until death from any cause, assessed up to 5 years)
- Cancer-specific mortality (CSM)(From the date of randomization to the date of death due to prostate cancer, assessed up to 5 years)
- Metastasis-free survival (MFS)(From randomization until distant metastasis (clinical and/or radiographic appearance of disseminated disease) or death from any cause, assessed up to 5 years)
- Local-regional progression(From randomization to local or regional recurrence ignoring biochemical failure and distant recurrence and censoring for death, assessed up to 5 years)
- Testosterone levels(Every 3 months until 6 months post treatment)
- Undetectable PSA with a non-castrate testosterone (PSA < 0.1 ng/ml and testosterone >= 50 ng/dl)(1 year)
- Acute physician-reported morbidity (per the Common Terminology Criteria for Adverse Events [CTCAE] version 5)(Up to 30 days after radiation therapy)
- Late physician-reported morbidity (per the CTCAE version 5) defined as grade 3+ adverse events occurring more than 30 days after the completion of radiation therapy(From the time protocol treatment started to the time of the first recorded late grade 3+ adverse event, assessed up to 5 years)
- Late patient-reported morbidity symptomatic adverse events (per the PRO-CTCAE)(Up to 5 years)