Testing the Addition of the Drug Relugolix to the Usual Radiation Therapy for Advanced-Stage Prostate Cancer

Study Overview
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Brief Summary
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This phase II trial tests whether relugolix and radiation therapy works to shrink tumors in patients with prostate cancer that has spread in a limited way to 1 to 5 other parts of the body (oligometastatic). Testosterone can cause the growth of prostate cancer cells. Relugolix lowers the amount of testosterone made by the body. This may help stop the growth of tumor cells that need testosterone to grow. Giving relugolix with radiation therapy may help lower the chance of prostate cancer growing or spreading.

Detailed Description
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PRIMARY OBJECTIVE: I. Compare conventional radiological progression-free survival (rPFS) for positron emission tomography (PET)-detected, biochemically recurrent, oligometastatic, castration-sensitive prostate cancer patients treated with stereotactic ablative body radiation therapy (SABR) plus placebo versus (vs.) SABR plus relugolix. SECONDARY OBJECTIVES: I. Compare conventional or PET-based radiological progression-free survival (prPFS) between treatment arms. II. Compare patient-reported sexual and hormonal quality of life as assessed by corresponding Expanded Prostate Cancer Index Composite Short Form (EPIC-26) domains between treatment arms. III. Compare other measures of quality of life obtained from the European Quality of Life Five Dimension Five Level Scale Questionnaire (EQ5D-5L), European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-30), and Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue instruments between the two treatment arms. IV. Compare time to salvage therapy and time to castration-resistance between treatment arms. V. Compare local progression (SABR-targeted lesion), biochemical progression, distant metastases, prostate cancer-specific mortality, metastasis-free survival, and overall survival between treatment arms. VI. Determine adverse events rates and compare rates between the two treatment arms. EXPLORATORY OBJECTIVE: I. Evaluate genomic and peripheral tissue and blood markers of treatment response. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive placebo orally (PO) once daily (QD) on days 1-180 (three tablets on Day 1, one tablet daily on Days 2-180) and undergo SABR for 1-3 weeks in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive relugolix PO QD on days 1-180 (three tablets on Day 1, one tablet daily on Days 2-180) and undergo SABR for 1-3 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 3 and 6 months, every 6 months for 4 years, and then annually thereafter.

Official Title
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A Phase II Double-Blinded, Placebo-Controlled Trial of PROstate OligoMETastatic RadiotHErapy With or Without ANdrogen Deprivation Therapy in Oligometastatic Prostate Cancer (NRG Promethean)

Conditions
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Oligometastatic Prostate Carcinoma, Prostate Adenocarcinoma, Stage IVB Prostate Cancer AJCC v8

Intervention / Treatment
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* Drug: Placebo Administration
* Other: Quality-of-Life Assessment
* Drug: Relugolix
* Radiation: Stereotactic Body Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically (histologically or cytologically) proven diagnosis of prostate adenocarcinoma at any anatomical location (for example, prostate, metastatic site), including intraductal or ductal carcinoma, at any time before registration Age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) performance status 0-2 within 120 days prior to registration Prior curative-intent treatment to the prostate, by either: External beam and/or brachytherapy to: Prostate alone, prostate and seminal vesicles, prostate and pelvic nodes, or radiation to all three sites Radical prostatectomy alone, radical prostatectomy plus postoperative radiotherapy to the prostate bed, or radical prostatectomy plus postoperative radiotherapy to the pelvic nodes Must meet study entry criteria based on the following diagnostic workup within 120 days prior to registration: History and physical examination; Technetium TC-99m (99mTc) bone scan (Must be negative); Either computed tomography (CT) or magnetic resonance imaging (MRI) of pelvis +/- abdomen (Must be negative); Fluciclovine or prostate-specific membrane antigen (PSMA) PET scan (Must be positive with exception of local disease); Note: All 3 scans are mandatory (bone scan; CT/magnetic resonance [MR]; PET) 1 - 5 oligometastatic lesions in bone and/or nodal/soft tissue sites on fluciclovine or PSMA PET within 120 days prior to registration and includes at least ONE of the following: Bone - each metastasis is counted (for example, 2 distinct lesions in the right ilium count as 2 oligometastatic lesions) Extrapelvic Nodal/ soft tissue - requires at least one extrapelvic inguinal or a nodal/soft tissue lesion superior to the iliac bifurcation (that is, American Joint Committee on Cancer [AJCC] M1a version 8) Note: Although a patient must have bone and/or extrapelvic disease to be eligible, when counting the number of oligometastatic lesions, each lymph node lesion, whether pelvic or extrapelvic, is counted (for example, 2 distinct lymph nodes in the right external iliac basin count as 2 oligometastatic lesions; one extrapelvic and one pelvic node count as 2 oligometastic lesions, etc) Serum total prostate-specific antigen (PSA) ≤10.0 ng/mL obtained within 120 days prior to registration that also meets ONE of the following PSA recurrence definitions: PSA ≥ post-radiation therapy (RT) nadir PSA + 2 ng/mL, if patient received-radiation therapy to intact prostate, or Current PSA ≥ 0.2 ng/mL, with a second confirmatory PSA ≥ 0.2 ng/mL if patient received a radical prostatectomy with or without post-op RT Must have ≥3 PSA values within the last two years since end of primary treatment or within the last 2 years prior to registration, whichever is less Note: PSA doubling time must be calculated by entering all PSA values since end of primary treatment or within the last 2 years prior to registration (whichever is less) into the PSA Doubling Time Calculator found at MDCalc.com Serum total testosterone ≥ 100 ng/dL within 120 days prior to registration Note: Prior androgen deprivation therapy (other than bilateral orchiectomy) is allowed if discontinued prior to registration and serum total testosterone is ≥ 100 ng/dL Total bilirubin: ≤ 1.5 x institutional upper limit of normal (ULN) (Note: In subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, subject is eligible if direct bilirubin is ≤ 1.5 x ULN) (within 120 days prior to registration) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]): ≤ 2.5 x institutional ULN (within 120 days prior to registration) For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B) Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial The patient must agree to use a highly effective contraception (even men with vasectomies) if he is having sex with a woman of childbearing potential or with a woman who is pregnant while on study drug and for 2 weeks following the last dose of study drug The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information. Exclusion Criteria: Clinical, biopsy-proven, or radiologic (conventional or PET imaging) evidence of local tumor recurrence in the prostate and/or periprostatic/seminal vesicle region after radiotherapy, or in the prostate bed after prostatectomy Note: if a patient had a prior local recurrence and received local salvage therapy, the patient is eligible if there is no current evidence of disease in the prostate/prostate bed. Patients with positive findings on examination or imaging remain eligible if biopsy of the site is negative for cancer. Currently on androgen deprivation or anti-androgen therapy Definitive radiologic evidence of metastatic disease on conventional imaging, defined by one of the following: Osseous metastasis on 99mTc radionuclide bone scan, or Extra pelvic nodal/soft tissue disease (> 1.5 cm in short axis) on CT or MRI pelvis +/- abdomen Spinal cord compression, or spinal intramedullary, brain, and/or visceral (for example liver, lung, etc.) metastasis Note: Spinal metastases (PET-detected) with epidural extension are eligible if there is > 0.3 cm spatial separation between the gross tumor volume and spinal cord. Biopsy-proven prostatic carcinoma with signet-ring, sarcomatoid, or neuroendocrine features (for example, small cell) Prior metastatic or non-metastatic, invasive malignancy (except non metastatic, non-melanomatous skin cancer) unless continuously disease free for ≥ 3 years Prior chemotherapy for prostate cancer or bilateral orchiectomy Note: Prior chemotherapy for a different cancer is allowed if continuously disease-free for ≥ 3 years Prior radiotherapy to a lesion (i.e. oligometastatic recurrence by PET) Note: Lesions outside of a previously irradiated planning treatment volume (PTV) are eligible as long as the prescription isovolume dose of any prior radiotherapy course is > 2.0 cm distant from new lesion Inability to treat all oligometastatic sites with radiotherapy in the judgement of the investigator Intrapelvic lymph nodes as only site of prostate cancer recurrence Inability to swallow whole, undivided, unchewed, and uncrushed pills Known gastrointestinal disorder affecting oral medication absorption Co-morbidity defined as follows: Patients with any comorbidities that would prohibit completion of protocol specified therapy Inflammatory bowel disease in patients in whom abdominopelvic radiotherapy is planned History of congenital long QT syndrome Current severe or unstable angina New York Heart Association functional classification III/IV heart failure (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm I (placebo, SABR)<br>Patients receive placebo PO QD on days 1-180 and undergo SABR for 1-3 weeks in the absence of disease progression or unacceptable toxicity. | Drug: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SABR<br>* Other names: Stereotactic Ablative Body Radiation Therapy;|
| Experimental: Arm II (relugolix, SABR)<br>Patients receive relugolix PO QD on days 1-180 and undergo SABR for 1-3 weeks in the absence of disease progression or unacceptable toxicity. | Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Relugolix<br>* Given PO<br>* Other names: TAK-385;Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SABR<br>* Other names: Stereotactic Ablative Body Radiation Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological progression-free survival (rPFS) | The rPFS curves will be estimated by the Kaplan-Meier method and compared between the two treatment arms using a one-sided, logrank test stratified by the three randomization factors. | Time from randomization to the occurrence of radiological progression detected by conventional imaging or death from any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positron emission tomography (PET)-based radiological progression-free survival | Will be estimated by the Kaplan-Meier method and compared between treatments arms by stratified logrank test. Cox regression models will also be fit, adjusted for the stratification factors and other prognostic baseline factors, to estimate hazard ratios, together with 95% confidence intervals. | Time from randomization to the occurrence of conventional or PET-based radiological progression or death from any cause, assessed up to 5 years | 
| Metastasis-free Survival | Will be estimated by the Kaplan-Meier method and compared between treatments arms by stratified logrank test. Cox regression models will also be fit, adjusted for the stratification factors and other prognostic baseline factors, to estimate hazard ratios, together with 95% confidence intervals. | From randomization to distant metastases or death from any cause, assessed up to 5 years | 
| Overall Survival | Will be estimated by the Kaplan-Meier method and compared between treatments arms by stratified logrank test. Cox regression models will also be fit, adjusted for the stratification factors and other prognostic baseline factors, to estimate hazard ratios, together with 95% confidence intervals. | From randomization to death from any cause, assessed up to 5 years | 
| Sexual Function | Assessed by Expanded Prostate Cancer Index Composite Short Form (EPIC-26). | Up to 5 years | 
| Fatigue | Assessed by Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue short form. Longitudinal profiles will be compared using mixed effects regression. | Up to 5 years |