Apalutamide Plus Intermittent Hormone Therapy Versus Intermittent Hormone Therapy Alone in Prostate Cancer

Apalutamide Plus Intermittent Hormone Therapy (IHT) Versus IHT Alone in Prostate Cancer Patients With Biochemical Recurrence

This study is open to men who have biochemical recurrence (BCR, increased PSA) following local treatment of their prostate cancer. Androgen deprivation therapy (ADT) is a standard treatment option, but is only effective for 16-24 months and has a number of side effects that impact quality of life. These side effects may include fatigue, hot flushing, loss of sex drive, brain fog, decreased bone mineral density, loss of muscle mass, mild anemia (low levels of red blood cells that can make people feel tired and weak), diabetes (low blood sugar), heart disease, metabolic syndromes (sometimes called "pre-diabetes" and includes obesity, increased blood pressure, high levels of cholesterol and triglycerides in blood), and risk of fractures. An alternative to continuous ADT is intermittent administration, where patients are given "breaks" from ADT to let their testosterone levels return to baseline. There are a number of potential benefits to intermittent hormone therapy (IHT): (1) longer time to the development of resistance; (2) improved patient quality of life owing to recovery from adverse effects, particularly sexual function; and (3) substantial cost savings owing to less time spent receiving medication. Leuprolide is the name of the ADT / IHT drug.

Apalutamide is an investigational drug, which means it has not been approved by the Food and Drug Administration (FDA). It is an antitumor drug, taken by mouth. The purpose of this study is to determine the ability of Apalutamide to extend the time between the first two injections of leuprolide and improve quality of life. This study will also look at the safety of Apalutamide and the effects that Apalutamide has on prostate cancer.

Men will be randomized (like flipping a coin) to receive:

• Group A: Leuprolide + Apalutamide or
• Group B: Leuprolide only (until second leuprolide injection), then leuprolide + Apalutamide 45 men will be in Group A and 21 men will be in Group B. Leuprolide is given as an intramuscular shot that lasts for 3 months intermittently and Apalutamide is taken by mouth (4 tablets) daily. Each cycle is 4 weeks long.

Intermittent treatment with Apalutamide + leuprolide will continue until continuous leuprolide is needed to maintain undetectable PSA levels (i.e., PSA levels rise above undetectable level unless leuprolide is given without pause, every 3 months).

Study Overview

• Status: Withdrawn
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Apalutamide; Drug: IHT

Detailed Description

Prostate-specific antigen (PSA) is a sensitive and specific biomarker of prostate tissue. Monitoring of PSA after local treatment for prostate cancer can assist in identifying patients who have only increased PSA (biochemical recurrence [BCR]) despite no symptoms, signs, or evidence of radiographic metastatic disease. This subpopulation of patients are referred to as having "biochemical failure." Androgen deprivation therapy (ADT) is a standard treatment option, but is only effective for 16-24 months and has a number of side effects that impact quality of life. These side effects may include fatigue, hot flushing, loss of sex drive, brain fog, decreased bone mineral density, loss of muscle mass, mild anemia, diabetes, heart disease, metabolic syndromes and risk of fractures. An alternative to continuous ADT is intermittent administration, where patients are given "breaks" from ADT to let their testosterone levels return to baseline. There are a number of potential benefits to intermittent hormone therapy (IHT): (1) longer time to the development of resistance, owing to the removal of constant pressure causing faster mutation of resistant cells; (2) improved patient quality of life owing to recovery from adverse effects, particularly sexual function; and (3) substantial cost savings owing to less time spent receiving medication. Leuprolide is the name of the ADT / IHT drug.

Apalutamide is an investigational antitumor drug, taken by mouth. It is a synthetic compound rationally designed to bind the androgen receptor (with higher affinity than enzalutamide or bicalutamide), prevent both nuclear translocation and DNA binding, and induce apoptosis. It has greater antitumor activity at a lower dose, achieves steady-state levels at a lower dose, and accumulates more into tumor tissue without building up in the brain, which both increases effectiveness and decreases the risk of seizure.

Apalutamide's mechanism of action gives it the potential to extend the time to PSA increase during intermittent ADT, delaying the necessity for continuous ADT. Investigators will assess the potential applications of intermittent ADT plus Apalutamide for participants with BCR. This study will elucidate the potential of this regimen to reduce the burden of adverse events of continuous ADT and delay the development of hormone resistance.

This is a randomized crossover study intended to determine the interval of ADT administration achievable with supportive Apalutamide treatment. Investigators will assess the significance of time to PSA recurrence, time to next leuprolide injection, time to testosterone recovery, duration of testosterone recovery, time to biochemical recurrence, percentage of men developing biochemical recurrence, number of detectable CTCs, and quality of life measures.

Treatment will be 66 participants in 2:1 randomized crossover - 45 IHT + apalutamide:21 IHT only until second leuprolide injection, then IHT + apalutamide

Apalutamide + IHT Participants will be treated with 240 mg (4 60 mg tablets) oral Apalutamide daily plus 22.5 mg 3-month depot intramuscular leuprolide intermittently.

IHT Participants will receive 22.5 mg 3-month depot intramuscular leuprolide until PSA progression, when they will receive 240 mg oral Apalutamide daily plus 22.5 mg 3-month depot intramuscular leuprolide intermittently.

Participants remain on study until continuous ADT is required to maintain castrate PSA levels (i.e., leuprolide is needed every 3 months to maintain PSA <1 ng/dL).

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • UTHealth Memorial Hermann Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Age ≥ 18 years
• Patients with a diagnosis of adenocarcinoma of the prostate
• Patients with BCR (PSA becomes detectable, with absolute value ≥1) following prostatectomy who have no evidence of metastatic disease based on radiographic assessment.
• Patients with BCR following radiation therapy who have no radiographic involvement per mpMRI and CT (RTOG-ASTRO Phoenix criteria), size of pelvic nodes ≤1 cm, and whose MRI-directed prostate biopsies are negative.
• Patients must be free of serious comorbidity as determined by investigator.
• Clinical laboratory values at screening:
• Serum testosterone level ≥150 ng/dL
• Hemoglobin ≥9.0 g/dL, independent of transfusion and/or growth factors within 3 months prior to randomization
• Platelet count ≥100,000 /µL independent of transfusion and/or growth factors within 3 months prior to randomization
• Serum albumin ≥3.0 g/dL
• GFR >45 mL/min
• Serum potassium ≥3.5 mmol/L
• Serum total bilirubin ≤1.5 × ULN (Note: In subjects with Gilbert's syndrome, if total bilirubin is >1.5 × ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤1.5 × ULN, subject may be eligible)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <2.5 × ULN
• Medications known to lower the seizure threshold (see list under prohibited meds, Appendix 3) must be discontinued or substituted at least 4 weeks prior to study entry.
• 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.
• Written, informed consent to participate in this study.

Exclusion Criteria:

• PSA doubling time >12 months
• Positive for HIV or chronic hepatitis B or hepatitis C infection
• Another primary malignancy that has not been in remission for at least 2 years. Non-melanoma skin cancer allowed.
• Use of herbal products that may decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of 10 mg of prednisone per day within 4 weeks of screening laboratory studies.
• Any other condition, including concurrent medical condition, social circumstance or drug dependency, which in the opinion of the investigator could compromise patient safety and/or compliance with study requirements

• History of any of the following:

  • Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1year to 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 (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomization Any condition that in the opinion of the investigator, would preclude participation in this study

• Current evidence of any of the following:

  • Uncontrolled hypertension
  • Gastrointestinal disorder affecting absorption
  • Active infection (eg, human immunodeficiency virus [HIV] or viral hepatitis) Any condition that in the opinion of the investigator, would preclude participation in this study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Apalutamide + IHT; Participants will be treated with 240 mg (4-60 mg tablets) oral Apalutamide daily plus 22.5 mg 3-month depot intramuscular leuprolide intermittently.	Drug: Apalutamide; Apalutamide 240 mg (4 60mg tablets) daily; Other Names: ARN-509; JNJ-56021927; Drug: IHT; Leuprolide 3-month depot 22.5 intramuscular dose; Other Names: Lupron Depot; Leuprolide
Active Comparator: IHT only; Participants will receive 22.5 mg 3-month depot intramuscular leuprolide until PSA progression, then they will crossover to Apalutamide + IHT	Drug: IHT; Leuprolide 3-month depot 22.5 intramuscular dose; Other Names: Lupron Depot; Leuprolide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to second injection	Time to second injection	48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to prostate-specific antigen (PSA) nadir	Time to prostate-specific antigen (PSA) nadir	48 months
Duration of PSA nadir	Duration of PSA nadir	48 months
Time to testosterone recovery to >50 ng/dl	Time to testosterone recovery to >50 ng/dl	48 months
Duration of testosterone recovery	Duration of testosterone recovery	48 months
Circulating tumor cell (CTC) enumeration	Circulating tumor cell (CTC) enumeration	48 months
Time until BCR after discontinuation of Apalutamide and ADT	Time until BCR after discontinuation of Apalutamide and ADT	48 months
Quality of life as determined by FACT-P survey	Quality of life as determined by FACT-P survey	48 months
Number of Adverse Events	Number of Adverse Events	48 months

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center, Houston
• Collaborators: Janssen Scientific Affairs, LLC
• Investigators: Principal Investigator: Robert J Amato, DO, The University of Texas Health Science Center, Houston

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2020
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: June 21, 2016
• First Submitted That Met QC Criteria: June 21, 2016
• First Posted (Estimate): June 23, 2016

Study Record Updates

• Last Update Posted (Actual): February 27, 2020
• Last Update Submitted That Met QC Criteria: February 25, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Prostate cancer; Apalutamide; IHT; BCR; Biochemical recurrence; intermittent hormone therapy
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Leuprolide
• Other Study ID Numbers: GU-15-105; HSC-MS-16-0477 (Other Identifier: CPHS)

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