Randomized Phase II Study of Salvage XRT + ADT +/- Abiraterone and Apalutamide for Rising PSA After RP (FORMULA-509)

Randomized Phase II Study of Salvage XRT + ADT +/- Abiraterone Acetate and Apalutamide (ARN-509) for Rising PSA After Radical Prostatectomy With Adverse Features.(FORMULA-509 Trial)

This research study is comparing two different combinations of androgen deprivation therapy (ADT) used together with radiation as a treatment for rising PSA after radical prostatectomy (prostate cancer).

Study Overview

• Status: Active, not recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: GnRH; Drug: Bicalutamide; Radiation: Salvage radiation; Drug: Abiraterone; Drug: Prednisone; Drug: Apalutamide

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that an intervention is being studied. In this study, the investigational agents are apalutamide and abiraterone acetate.

Currently, the best standard treatment for men with this type of prostate cancer includes radiation therapy combined with androgen deprivation therapy (ADT). ADT blocks the function of hormones including testosterone which prostate cancer uses to grow and spread. All participants in this study will receive the main standard form of ADT called a luteinizing hormone-releasing hormone agonist (LHRHA). Physicians often also use another drug called bicalutamide to help the LHRHA block hormone function. The investigators are testing whether using two newer anti-hormonal drugs called abiraterone acetate and apalutamide with LHRHA can improve cure rates compared to using bicalutamide plus LHRHA. These two drugs work together to suppress both testosterone and the receptor where testosterone binds thereby providing more potent hormone suppression.

• Study Type: Interventional
• Enrollment (Actual): 345
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92093
      • University of California, San Diego
    • San Francisco, California, United States, 94158
      • University of California, San Francisco
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute/Brigham and Women's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed prostate cancer

• PSA ≥ 0.1 after radical prostatectomy (value w/in 3 months of registration) AND at least 1 unfavorable risk factor listed below.

  • Gleason 8-10
  • PSA > 0.5
  • Pathologically positive lymph nodes
  • pT3 or pT4
  • PSA doubling time (DT) < 10 months
  • Negative margins
  • Persistent PSA after RP (PSA never dropped below 0.1 after RP)
  • Local/regional recurrence on imaging
  • Decipher "High risk" (a Medicare-reimbursed test for risk of metastases after prostatectomy)
• Candidate for salvage radiation and ADT treatment
• Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Subject must have the ability to understand and willingness to sign the written informed consent document.
• 18 ≤ Age ≤ 95 at the time of consent
• ECOG Performance Status ≤ 2 (Appendix A)
• Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 3 months of registration.
• System Laboratory Value

• Hematological:

  • Platelet count (plt) ≥ 100,000/ µL
  • Hemoglobin (Hgb) ≥ 9 g/dL
  • Absolute neutrophil count (ANC) ≥ 1000 cells/µL

• Renal:

  --GFR1 ≥ 45 mL/min

• Hepatic and Other:

  • Bilirubin2 ≤ 1.5 × upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) ≤ 2.5 × ULN
  • Alanine aminotransferase (ALT) ≤ 2.5 × ULN
  • Serum Albumin > 3.0 g/dL
  • Serum potassium ≥ 3.5 mmol/L

• Coagulation:

  • International Normalized Ratio (INR)
  • or Prothrombin Time (PT)

• Activated Partial Thromboplastin Time

  • (aPTT) ≤ 1.5 × ULN (unless on prophylactic or therapeutic dosing with low molecular weight heparin)
  • Cockcroft-Gault formula will be used to calculate creatinine clearance (see study procedure manual SPM)
  • In subjects with Gilbert's syndrome, if total bilirubin is >1.5 × ULN, measure direct and indirect bilirubin; if direct bilirubin is ≤1.5 × ULN, subject may be eligible
• 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.
• Ability to understand and comply with study procedures for the entire length of the study as determined by the site investigator or protocol designee
• Medications known to lower the seizure threshold (see list under prohibited meds) must be discontinued or substituted at least 4 weeks prior to study entry (Section 5.5)
• Use of CYP3A4 inhibitors or inducers and CYP2D6 substrates must be discontinued prior to study entry
• Able to swallow pills

Exclusion Criteria:

• Use of post-prostatectomy ADT for > 30 continuous days prior to registration (ADT defined as use of GnRH agonist, with or without an anti-androgen). However, patients with testosterone recovery after post-prostatectomy ADT are eligible (testosterone recovery defined as total testosterone > 190 ng/dL) regardless of how long they have been on ADT.
• Prior pelvic radiation unless additional radiation can be safely delivered according to the treating physician
• PSA > 15 ng/mL in screening

• History of any of the following:

  • Seizure or known condition that may predispose to seizure (e.g., prior stroke within 1 year of randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign CNS or meningeal disease which may require treatment with surgery or radiation therapy)
  • Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomization

• Current evidence of any of the following:

  • Uncontrolled hypertension
  • Gastrointestinal disorder affecting absorption
  • Active infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis)
  • Any chronic medical condition requiring a dose of corticosteroid higher than 10 mg prednisone/prednisolone once daily
  • Any condition that, in the opinion of the site investigator, would preclude participation in this study
  • Moderate or severe hepatic impairment (Child Pugh Class B or C)
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, psychiatric illness or social situations that would limit compliance with study requirements

• 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
• Confirmed bone metastases on imaging

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GnRH + Bicalutamide; GnRH agonist injection monthly or every 3 months for 6 months; Bicalutamide by mouth once/day for 6 months; Salvage radiation (starting 4-10 weeks after initiation of ADT)	Drug: GnRH; -blocks the function of hormones including testosterone which prostate cancer uses to grow and spread; Other Names: LHRHA; Drug: Bicalutamide; -blocks the function of hormones including testosterone which prostate cancer uses to grow and spread; Other Names: Casodex; Radiation: Salvage radiation; Radiation
Experimental: GnRH+Abiraterone+Apalutamide+Prednisone; GnRH agonist injection monthly or every 3 months for 6 months; Abiraterone acetate by mouth once/day for 6 months; Prednisone by mouth once/day for 6 months; Apalutamide by mouth once/day for 6 months; Salvage radiation (starting 4-10 weeks after initiation of ADT)	Drug: GnRH; -blocks the function of hormones including testosterone which prostate cancer uses to grow and spread; Other Names: LHRHA; Radiation: Salvage radiation; Radiation; Drug: Abiraterone; -blocks the function of hormones including testosterone which prostate cancer uses to grow and spread; Other Names: Zytiga; Drug: Prednisone; Prednisone is a corticosteroid. It prevents the release of substances in the body that cause inflammation. It also suppresses the immune system.; Other Names: Deltasone; Drug: Apalutamide; -blocks the function of hormones including testosterone which prostate cancer uses to grow and spread; Other Names: ARN-509

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PSA Progression Free Survival	Time from randomization to PSA failure or death due to any cause	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metastasis Free Survival on conventional imaging or pathologically (MFS)	Time from randomization to distant metastasis, identified on conventional imaging (CT, bone scan, or MRI) or pathologically, or death due to any cause or censored at date last known alive.	Up to 5 years
Metastasis Free Survival only visible by PET Imaging (MFS-PET)	Time from randomization to distant metastasis, visible only by PET portion of a PET-CT, or death due to any cause or censored at date last known alive.	Up to 5 years
Cause Specific Survival	The interval from randomization to the date of last known follow-up alive or date of death from each of the following causes: prostate cancer, cardiovascular disease, other causes.	Up to 5 years
Overall Survival	Time from randomization to death due to any cause or censored at date last known alive	Up to 5 years
Time to Testosterone Recovery	Time from randomization to date at which testosterone level returns to a normal level, or censored at the date of last disease evaluation for those whose testosterone has not reached a normal level	Up to 5 years
Toxicity as measured by CTCAE v.4.0	Measure Grade 1-5 toxicities at study visits and follow-up using the CTCAE v.4.0 forms and determine attribution	Up to 5 years
Time to reinitiation of ADT	Time from randomization to date at which ADT is restarted for disease progression. Censoring occurs at date of last disease evaluation for those who are not restarted on ADT.	Up to 5 years
Patient reported QOL	Patient-reported Quality of Life will be measured by a fatigue questionnaire	Up to 5 years
Patient reported QOL	Patient-reported Quality of Life will be measured by a questionnaire assessing symptoms related to prostate cancer	Up to 5 years
Patient reported QOL	Patient-reported Quality of Life will be measured by a memory survey	Up to 5 years
Cardiovascular events consisting of myocardial infarction	Time from randomization to date at which first cardiovascular event (myocardial infarction, stroke, deep venous thrombosis, or pulmonary embolism) occurs. Censoring occurs at date of last disease evaluation for those who did not have a cardiovascular event.	Up to 5 years

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: Janssen Pharmaceutica
• Investigators: Principal Investigator: Paul Nguyen, MD, Brigham and Women's Hospital/Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2017
• Primary Completion (Estimated): April 5, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: May 3, 2017
• First Submitted That Met QC Criteria: May 4, 2017
• First Posted (Actual): May 5, 2017

Study Record Updates

• Last Update Posted (Actual): May 14, 2024
• Last Update Submitted That Met QC Criteria: May 13, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Prostate Cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Androgen Antagonists; Prednisone; Bicalutamide
• Other Study ID Numbers: 16-623

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No