Clinical trial NCT04025372: INTREPId (INTermediate Risk Erection PreservatIon Trial)
Official title: INTREPId (INTermediate Risk Erection PreservatIon Trial): A Randomized Trial of Radiation Therapy and Darolutamide for Prostate Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Prostate Cancer
Keywords: Prostate Cancer
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Bayer
name: Decipher Biosciences
First posted: 2019-07-18
Enrollment: 234
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This research study is comparing the use of a new form of hormonal therapy used with radiation as a possible treatment for intermediate risk prostate cancer. More specifically, this research would help determine whether this new form of hormonal therapy is as effective as the standard hormone therapy while also preserving erectile function.

Detailed description: This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

In this research study, the investigators are looking at whether the novel form of hormonal therapy, called Darolutamide, when paired with radiation therapy will provide the same quality of care as the current standard treatments available for men with this type of cancer. Darolutamide prevents testosterone from signaling throughout the body. Although studies have shown that Darolutamide has activity in more advanced forms of prostate cancer, the activity of Darolutamide is unknown in intermediate risk prostate cancer treated with radiation therapy. The U.S. Food and Drug Administration (FDA) has not approved Darolutamide as a treatment for any disease.

The current standard of care treatments available to men with this type of cancer are radiation therapy with or without androgen deprivation therapy (ADT) involving a gonadotropin releasing hormone agonist plus bicalutamide (both FDA-approved) or surgery. ADT works by depriving the body of testosterone which "feeds" prostate cancer cells and weakens prostate cancer cells from repairing damage caused by radiation therapy.

In addition, the investigator will be assessing erectile function at baseline, during and after treatment to determine if short-term erectile function can be preserved without sacrificing long-term disease control.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed prostate adenocarcinoma by biopsy within 1 year (365 days) from registration. The most recent biopsy will determine eligibility
* National Cancer Center Network (NCCN) intermediate risk prostate cancer, defined as clinical T2b-T2c, Gleason 7, or PSA 10-20 ng/mL. Patients who only have radiographic evidence of T3 disease (i.e. extracapsular extension, or seminal vesical invasion radiographically) will not be excluded.
* Able to characterize the number of unfavorable intermediate risk factors below:

  * 2-3 intermediate risk factors

    * T2b-T2c
    * Gleason 7
    * PSA 10-20 ng/mL
  * Gleason 4+3 disease
  * Percent positive cores ≥ 50%
* Tissue available for submission for Decipher genomic score from archived tissue. Patients who had tissue sent to Decipher but did not have sufficient tissue for processing will not be excluded. Patients who already have a Decipher score must present official report documentation.
* Able to undergo radiation therapy with curative intent
* Age ≥ 18 at the time of consent.
* Demonstrate adequate organ function (hematologic, renal, hepatic) 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:

  * Glomerular filtration rate (GFR) ≥ 45 mL/min

    * CKD-EPI equation will be used to calculate GFR
* Hepatic and Other:

  * Bilirubin ≤ 1.5 × upper limit of normal (ULN)

    * 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
  * Aspartate aminotransferase (AST) ≤ 2.5 × ULN
  * Alanine aminotransferase (ALT) ≤ 2.5 × ULN
  * Serum Albumin \> 3.0 g/dL
  * Serum potassium ≥ 3.5 mmol/L
* Endocrine:

  * Testosterone ≥ 150 ng/dL
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
* Good erectile function, as assessed by 'firm enough for masturbation or foreplay' or 'firm enough for intercourse' response to the question "How would you describe the usual quality of your erections during the past 4 weeks" on the EPIC-26 questionnaire
* Agrees to use a condom and another effective method of birth control if he is having sex with a woman of childbearing potential (defined as a premenopausal female capable of becoming pregnant) 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. It is recommended that men who have had a vasectomy more than a year prior to trial registration use a condom. Must also agree not to donate sperm.
* Ability to understand and comply with study procedures for the entire length of the study as determined by the site investigator or protocol designee
* 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.
* Ability to swallow pills.
* For patients in whom SBRT/combination RT stratification is pre-specified, prostate volume as determined by MRI, CT, or ultrasound to be less than 90 cc.

Exclusion Criteria:

* Prior surgical, cryotherapy, or high-intensity focused ultrasound for prostate cancer
* Prior orchiectomy or hormonal therapy (gonadotropin releasing hormone (GnRH) agonists, non-steroidal anti-androgens)
* Prior treatment with a first generation AR inhibitor (e.g. bicalutamide, flutamide, nilutamide, cyproterone acetate) or second generation AR inhibitor (e.g.Enzalutamide, Apalutamide, or Darolutamide)
* Prior treatment with other investigational AR inhibitors, CYP17 enzyme inhibitor such as abiraterone acetate, TAK-700, or oral ketoconazole longer than 28 days
* Prior use of estrogens; patients who have used testosterone injections must have ceased utilization within 90 days prior to screening testosterone. Patients who have used any other type of testosterone supplementation (e.g. patches) must have ceased utilization within 45 days prior to screening testosterone.
* Use of 5-α reductase inhibitors (finasteride, dutasteride) within 28 days of randomization.
* Prior radiation therapy that would result in overlap of current radiation therapy fields
* Prior chemotherapy for prostate cancer
* Clinically positive lymph nodes by imaging, sampling, or dissection. Patients with lymph nodes greater than 1.5 cm on short axis will require a negative biopsy for eligibility.
* Metastatic disease, as assessed by abdominal or pelvic computed tomography (CT) or other imaging modality. Patients with 3 intermediate risk factors will require a CT abdomen/pelvis and a bone scan or PET imaging (PSMA PET/CT, fluciclovine PET/CT, etc.).
* Erectile aids other than oral phosphodiesterase (PDE)-5 inhibitors
* History of any of the following: Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure New York Heart Association (NYHA) class III or IV, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), clinically significant ventricular arrhythmias, moderate or severe hepatic impairment (Child Pugh Class B or C), viral hepatitis, or human immunodeficiency virus within 6 months prior to randomization.
* Current untreated hypertension (systolic \>= 160 mmHg or diastolic \>= 100 mmHg). Patients with one blood pressure reading with systolic \< 160 mmHg and diastolic \< 100 mmHg within 90 days of registration would be eligible for study.
* Individuals with a history of another malignancy are not eligible if:

  * The cancer is under active treatment
  * The cancer can be seen on radiology scans
  * If they are off cancer treatment, but in the opinion of their oncologist, have a high risk of relapse within 5 years.
* 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 (NCI-CTCAE version 5.0 Grade 2), psychiatric illness or social situations that would limit compliance with study requirement
* Any condition that, in the opinion of the site investigator, would preclude participation in this study

Primary outcomes:
measure: The percentage of patients with a PSA nadir <= 0.5
timeFrame: 6 months from end of treatment
Secondary outcomes:
measure: The percentage of patients with good erectile function at 3 months from end of treatment
timeFrame: 3 months from end of treatment
measure: PSA progression free survival
timeFrame: 3 years
measure: Metastasis free survival
timeFrame: 3 years
measure: Cause specific survival
timeFrame: 3 years
measure: To evaluate differences in long-term maintenance of erectile function
timeFrame: 3 years
measure: Rate of Toxicity
timeFrame: 3 years
measure: Quality of Life impact as measured by Expanded Prostate Cancer Index (EPIC)-26
timeFrame: 3 years
measure: Global health impact as measured by Patient-Reported Outcome Measurement Information System (PROMIS) Global Health Score
timeFrame: 3 years
measure: Memory as measured by the St. Louis University Mental Status Examination (SLUMS)
timeFrame: 3 years
measure: Quality of Life impact as measured by Patient-Reported Outcome Measurement Information System (PROMIS) Sexual Function and Satisfaction Measures (SexFS) Brief Profile Version 2.0.
timeFrame: 3 years
measure: Testosterone kinetics
timeFrame: 3 years
measure: Cardiovascular events
timeFrame: 3 years
measure: Time to re-initiation of ADT
timeFrame: 3 years
Other outcomes:
Locations:
city: Stamford
country: United States
facility: Stamford Hospital
state: Connecticut
city: Boston
country: United States
facility: Beth Israel Deaconness Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Milford
country: United States
facility: Dana-Farber/Brigham and Women's Cancer Center at Milford Regional Medical Center
state: Massachusetts
city: South Weymouth
country: United States
facility: Dana-Farber/Brigham and Women's Cancer Center in Clinical Affiliation with South Shore Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St. Louis
state: Missouri
city: Omaha
country: United States
facility: XCancer Omaha / Urology Cancer Center
state: Nebraska
city: Garden City
country: United States
facility: NYU Long Island
state: New York
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: Syracuse
country: United States
facility: Associated Medical Professionals of NY
state: New York
Study officials:
affiliation: Brigham and Women's Hospital
name: Martin T. King, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Roy A, Green O, Brenneman R, Bosch W, Gay HA, Michalski JM, Baumann BC. Assessing Inter-Fraction Changes in The Size and Position of The Penile Bulb During Daily MR-Guided Radiation Therapy to The Prostate Bed: Do We Need to Adjust How We Plan Radiation in The Post-Radical Prostatectomy Setting to Reduce Risk of Erectile Dysfunction? Clin Genitourin Cancer. 2022 Jun;20(3):e227-e232. doi: 10.1016/j.clgc.2022.01.006. Epub 2022 Jan 11.