Testing the Addition of the Drug Relugolix to the Usual Radiation Therapy for Advanced-Stage Prostate Cancer, The NRG Promethean Study

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of prostateadenocarcinoma 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 180 daysprior to registration

• Prior curative-intent treatment to the prostate, by either:

• External beam and/or brachytherapy to: Prostate alone, prostate and seminalvesicles, prostate and pelvic nodes, or radiation to all three sites

• Radical prostatectomy alone, radical prostatectomy plus postoperativeradiotherapy to the prostate bed, or radical prostatectomy plus postoperativeradiotherapy to the pelvic nodes

• Must meet study entry criteria based on the following diagnostic workup within 120days prior to registration:

• History and physical examination;

• Fluciclovine or PSMA PET scan (must be positive with exception of localdisease);

• PET must be combined with either CT or MRI, but a diagnostic CT or MRIreading/interpretation is not required

• 1 - 5 oligometastatic lesions in bone and/or nodal/soft tissue sites on fluciclovineor PSMA PET within 180 days prior to registration and includes at least ONE of thefollowing:

• Bone - each metastasis is counted (for example, 2 distinct lesions in the rightilium count as 2 oligometastatic lesions)

• Extrapelvic Nodal/ soft tissue - requires at least one extrapelvic inguinal ora nodal/soft tissue lesion superior to the iliac bifurcation (that is, AmericanJoint Committee on Cancer [AJCC] M1a version 8)

• Note: Although a patient must have bone and/or extrapelvic disease to beeligible, when counting the number of oligometastatic lesions, each lymph nodelesion, whether pelvic or extrapelvic, is counted (for example, 2 distinctlymph nodes in the right external iliac basin count as 2 oligometastaticlesions; one extrapelvic and one pelvic node count as 2 oligometastic lesions,etc)

• Serum total prostate-specific antigen (PSA) =< 10.0 ng/mL that also meets ONE of thefollowing PSA recurrence definitions:

• PSA >= post-radiation therapy (RT) nadir PSA + 2 ng/mL, obtained within 180days prior to registration, if patient received-radiation therapy to intactprostate, or

• Current PSA >= 0.2 ng/mL, with a second confirmatory PSA >= 0.2 ng/mL ifpatient received a radical prostatectomy with or without post-op RT. Theinitial PSA may be outside 180 days BUT the second confirmatory PSA must bewithin 180 days prior to registration, or

• PSA > 0.2 ng/mL with at least two rises from treatment nadir with the mostrecent PSA within 180 days prior to registration, if patient received radiationtherapy to intact prostate

• Must have >= 3 PSA values within the last two years since end of primary treatmentor within the last 2 years prior to registration, whichever is less

• Note: PSA doubling time must be calculated by entering all PSA values since endof 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 180 days prior to registration

• Note: Prior androgen deprivation therapy (other than bilateral orchiectomy) isallowed 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: Insubjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, subject iseligible if direct bilirubin is =< 1.5 x ULN) (within 180 days prior toregistration)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]): =< 2.5 x institutional ULN (within 180 days prior to registration)

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral 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 unlessthe viral load becomes undetectable on suppressive therapy. Patients who areimmune 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 treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible 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 unlessthe viral load becomes undetectable on suppressive therapy

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• The patient must agree to use a highly effective contraception (even men withvasectomies) if he is having sex with a woman of childbearing potential or with awoman who is pregnant while on study drug and for 2 weeks following the last dose ofstudy drug

• The patient or a legally authorized representative must provide study-specificinformed 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 oflocal tumor recurrence in the prostate and/or periprostatic/seminal vesicle regionafter radiotherapy, or in the prostate bed after prostatectomy

• Note: if a patient had a prior local recurrence and received local salvagetherapy, the patient is eligible if there is no current evidence of disease inthe prostate/prostate bed. Patients with positive findings on examination orimaging remain eligible if biopsy of the site is negative for cancer. Patientswho have a positive PET scan in the prostate or prostate bed and have undergonelocal therapy since PET but prior to enrollment to NRG-GU011 are eligiblewithout a repeat PET scan

• Currently on androgen deprivation or anti-androgen therapy

• Spinal cord compression, or spinal intramedullary, brain, and/or visceral (forexample liver, lung, etc.) metastasis

• Note: Spinal metastases (PET-detected) with epidural extension are eligible ifthere is > 0.3 cm spatial separation between the gross tumor volume and spinalcord

• Biopsy-proven prostatic carcinoma with signet-ring, sarcomatoid, or neuroendocrinefeatures (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 continuouslydisease-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 priorradiotherapy course is > 2.0 cm distant from new lesion

• Inability to treat all oligometastatic sites with radiotherapy in the judgement ofthe 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 protocolspecified therapy

• Inflammatory bowel disease in patients in whom abdominopelvic radiotherapy isplanned

• 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, orhistory of treatment with cardiotoxic agents, should have a clinical riskassessment of cardiac function using the New York Heart Association functionalclassification)