Unterlã¼ãÿ, Germany

Testing Longer Duration Radiation Therapy Versus the Usual Radiation Therapy in Patients With Cancer That Has Spread to the Brain

PRIMARY OBJECTIVE: I. To determine if the time to local failure is improved with FSRS compared to SRS in patients with intact (i.e., unresected) brain metastases. SECONDARY OBJECTIVES: I. To compare time to intracranial progression-free survival between FSRS and SRS. II. To compare overall survival between FSRS and SRS. III. To determine if the time to local failure is improved with FSRS compared to SRS, as evaluated by central review of imaging. IV. To evaluate if there is any difference in central nervous system (CNS) failure patterns (local versus [vs.] distant brain failure vs. both) in patients who receive FSRS compared to patients who receive SRS. V. To compare the rates of radiation necrosis in patients who receive FSRS vs. SRS. VI. To compare the time to salvage whole brain radiation therapy (WBRT) between patients who receive FSRS and those who receive SRS. VII. To compare the rates of post-treatment adverse events associated with FSRS and SRS. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo SRS over 30-90 minutes for 1 fraction on study. Additionally, patients undergo computed tomography (CT) and magnetic resonance imaging (MRI) on study. ARM II: Patients undergo FSRS over 30-90 minutes for 3 fractions on study. Additionally, patients undergo CT and MRI on study. After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year then every 6 months for 3 years.

Neoadjuvant Chemotherapy, Excision And Observation vs Chemoradiotherapy For Rectal Cancer

This study is being done to find out if this approach is better or worse than the usual approach for early rectal cancer. The usual approach is defined as care most people get for early rectal cancer. The usual approach for patients who are not in a study is surgery to remove the rectum or treatment with chemotherapy and radiation therapy, followed by surgery. There are several chemotherapy drugs approved by Health Canada that are commonly used with radiation therapy. For patients who get the usual approach for this cancer, about 90 out of 100 are free of cancer after 5 years. If a patient decides to take part in this study, they will either get a combination of chemotherapy drugs called FOLFOX or CAPOX for up to 12 weeks or will get chemotherapy with radiation therapy for up to 6 weeks. After finishing treatment, and even if treatment is stopped early, the study doctor will watch for side effects and determine which type of surgery would be best. After surgery, patients will be asked to come in every 4 months for 2 years, then every 6 months for an additional year. Then will be checked every year for 2 years. This means seeing the study doctor for up to 5 years after surgery. Patients may be seen more often if your study doctor thinks it is necessary.

Testing the Addition of High Dose, Targeted Radiation to the Usual Treatment for Locally-Advanced Inoperable Non-small Cell Lung Cancer

PRIMARY OBJECTIVES: I. To compare the overall survival in patients with stage II-IIIC inoperable node-positive non-small cell lung cancer (NSCLC) after image guided, motion-managed conventional radiotherapy to the primary tumor and nodal metastases (Arm 1) or after image guided, motion-managed stereotactic body radiation therapy (SBRT) to the primary tumor followed by conventionally fractionated radiotherapy to nodal metastases (Arm 2) both given with concurrent platinum-based chemotherapy. II. To compare progression-free survival between the experimental arm (Arm 2) and control arm (Arm 1). SECONDARY OBJECTIVES: I. To compare objective response rate (as defined by Response Evaluation Criteria in Solid Tumors [RECIST] version [v] 1.1) between the experimental arm and control arm. II. To compare the rate of local control between the experimental arm and control arm. III. To compare patterns of failure (primary, locoregional, or distant) between the experimental arm and control arm. IV. To compare changes in pulmonary function (forced expiratory volume in 1 second [FEV1] and diffusion capacity of the lung for carbon monoxide [DLCO] assessed at randomization and at 6- and 12- months following completion of radiation therapy) between the experimental arm and control arm. V. To compare changes in quality of life and patient-reported outcomes assessed from pre-treatment to 3 months following radiation therapy of each treatment arm. VI. To determine acute and late toxicity profiles of each treatment arm as measured by the Common Terminology Criteria for Adverse Events (CTCAE) v5. EXPLORATORY OBJECTIVES: I. To characterize and compare longitudinal quality of life and patient-reported outcomes of each treatment arm. II. To collect biospecimens at baseline, after SBRT (for Arm 2 patients), during last 2 weeks of chemoradiation, and after first dose of consolidation therapy, to allow for future analyses. III. To collect 4-dimensional (4D) computed tomography (CT) planning scans and radiation dose to calculate regional lung ventilation and explore pre-treatment 4D-CT based ventilation to predict pulmonary toxicity. IV. To characterize clinical outcomes, toxicities and changes in pulmonary function and quality of life among patients receiving proton and photon radiotherapy. V. To develop and characterize a machine learning/artificial intelligence algorithm for radiotherapy planning and/or quality assurance. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel intravenously (IV) followed by carboplatin IV weekly (Q7D) during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or positron emission tomography (PET)/CT during follow-up. ARM II: Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Patients are followed up every 3 months for 1 year, every 6 months during years 2 and 3, and then yearly after that for the duration of the study.

Cognitive Training for Cancer Related Cognitive Impairment in Breast Cancer Survivors

The goal of this trial is to determine the efficacy of advanced cognitive training for cancer survivors suffering from cancer- and cancer-treatment-related cognitive dysfunction. For millions of cancer survivors, cognitive dysfunction is a prevalent, severe, and persistent problem that has long been associated with poor work-related and health-related outcomes. Evidence suggests that a significant subset of breast cancer survivors (BCS) incur cognitive changes that may persist for years after treatment. Unfortunately, the scientific basis for managing these cognitive changes is extremely limited. Available evidence from pilot studies, including our work, suggests that advanced cognitive training, which is based on the principles of neuroplasticity (ability of brain neurons to re-organize and form new neural networks), may be a viable treatment option. However, previous trials to date have been limited by lack of attention-controlled designs, small samples of BCS, or limited outcome measures. Therefore, to overcome limitations of past studies and build on our pilot results, the purpose of this 2-group, double-blind, randomized controlled trial is to conduct a full-scale efficacy trial to compare advanced cognitive training to attention control in BCS.

Testing the Use of Ado-Trastuzumab Emtansine Compared to the Usual Treatment (Chemotherapy With Docetaxel Plus Trastuzumab) or Trastuzumab Deruxtecan for Recurrent, Metastatic, or Unresectable HER2-Expressing Salivary Gland Cancers

PRIMARY OBJECTIVES: I. To determine if trastuzumab emtansine (ado-trastuzumab emtansine [T-DM1]) shows better progression-free survival (PFS) when compared to docetaxel plus trastuzumab (TH) in recurrent and/or metastatic (R/M) HER2-positive salivary gland cancer (SGC) patients who have not previously received HER2 therapy for unresectable or recurrent and/or metastatic disease, as determined by local assessment. (HER2-Positive Cohort) II. To determine the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria with DS-8201a (trastuzumab deruxtecan) in R/M HER2-low expressing SGC patients. (HER2-Low Expressing Cohort) SECONDARY OBJECTIVES: I. To compare the overall response rate (ORR) by RECIST v1.1 criteria between arms. (HER2-Positive Cohort) II. To compare overall survival (OS) between arms. (HER2-Positive Cohort) III. To compare toxicity using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria between arms. (HER2-Positive Cohort) IV. To assess patient-reported toxicity, as measured by the patient reported outcome (PRO)-CTCAE, between arms, and explore patient-reported symptomatic adverse events (AEs) for tolerability of each treatment arm as measured by the PRO-CTCAE. (HER2-Positive Cohort) V. To assess PFS with DS-8201a (trastuzumab deruxtecan) in HER2-low expressing SGC patients. (HER2-Low Expressing Cohort) VI. To assess OS with DS-8201a (trastuzumab deruxtecan) in HER2-low expressing SGC patients. (HER2-Low Expressing Cohort) VII. To evaluate toxicity of DS-8201a (trastuzumab deruxtecan) using CTCAE v5.0. (HER2-Low Expressing Cohort) EXPLORATORY OBJECTIVES: I. To assess the ORR in patients who receive crossover treatment to T-DM1/TH following disease progression on the TH arm/T-DM1 arm. II. To collect blood and tissue specimens for future translational science studies to examine how tumor genetics, HER2 signaling output/expression, HER2 tumoral heterogeneity, and androgen receptor expression/signaling impacts H and T-DM1 efficacy in the HER2-positive cohort and DS-8201a (trastuzumab deruxtecan) efficacy in the HER2-low expressing cohort. OUTLINE: Patients with HER2-positive disease are randomized to 1 of 2 arms. Patients with HER2-low expression disease are assigned to Arm III. ARM I: Patients receive docetaxel intravenously (IV) over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive trastuzumab IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients on Arm I (TH) can cross over to Arm II (T-DM1) after first progression. Patients undergo a computed tomography (CT) scan or magnetic resonance imaging (MRI) and echocardiography (ECHO) or multigated acquisition (MUGA) scan throughout the trial. Patients may also undergo blood sample collection during screening and on study, as well as a biopsy during screening. ARM II: Patients receive trastuzumab emtansine IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients on Arm II (T-DM1) can cross over to Arm I (TH) after first progression. Patients undergo a CT scan or MRI and ECHO or MUGA scan throughout the trial. Patients may also undergo blood sample collection and during screening and on study, as well as a biopsy during screening. ARM III: Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan or MRI and ECHO or MUGA scan throughout the trial. Patients may also undergo blood sample collection and during screening and on study, as well as a biopsy during screening. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for an additional 3-5 years, then annually.

Study to Evaluate Weight Gain as Assessed by Change in BMI Z-score in Pediatric Subjects With Schizophrenia or Bipolar I Disorder

Testing the Addition of the Chemotherapy Drug Lomustine (Gleostine) to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Methylated Glioblastoma

PRIMARY OBJECTIVE: I. To determine if the regimen with the two alkylating agents temozolomide and lomustine with radiotherapy (RT) significantly prolongs overall survival (OS) versus (vs.) standard chemoradiotherapy with temozolomide in patients with newly diagnosed glioblastoma (GBM) with MGMT promoter methylation. SECONDARY OBJECTIVES: I. To determine if the regimen with the two alkylating agents temozolomide and lomustine with radiotherapy (RT) significantly prolongs progression-free survival (PFS) vs. standard chemoradiotherapy with temozolomide in patients with newly diagnosed GBM with MGMT promoter methylation. II. To compare the two different chemotherapy regimens on patient-reported outcomes (PROs), as measured by the MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT) in patients with newly diagnosed GBM with MGMT promoter methylation. III. To determine if the regimen with the two alkylating agents temozolomide and lomustine with radiotherapy (RT) is associated with inferior short-term change in PROs as measured by MDASI-BT vs. standard chemoradiotherapy with temozolomide in patients with newly diagnosed GBM with MGMT promoter methylation. IV. To assess toxicity in the two different chemotherapy regimens. EXPLORATORY OBJECTIVES: I. To assess the association between absolute lymphocyte counts and outcomes. II. To assess the association between CD4+ lymphocyte counts and outcomes. III. To compare the two different chemotherapy regimens in terms of long-term PROs as measured by MDASI-BT at years 1 and 2. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo radiation therapy 5 days per week and receive temozolomide orally (PO) once daily (QD) for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive temozolomide PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) throughout the trial. ARM II: Patients undergo radiation therapy 5 days per week for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive lomustine PO on day 1 of each cycle and temozolomide PO QD on days 2-6 of each cycle. Treatment repeats every 42 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial. After completion of study treatment, patients are followed up every 3 months for year 1, every 4 months for year 2, and then every 6 months thereafter.

Testing the Use of Chemotherapy After Surgery for High-Risk Pancreatic Neuroendocrine Tumors

PRIMARY OBJECTIVE: I. To evaluate recurrence-free survival (RFS) in participants with resected pancreatic neuroendocrine tumors (pNETs) randomized to treatment with capecitabine + temozolomide (CAPTEM) compared to observation only. SECONDARY OBJECTIVES: I. To evaluate overall survival (OS) in participants randomized to treatment with CAPTEM compared to observation only. II. To evaluate the safety and tolerability of CAPTEM compared to observation only. BANKING OBJECTIVE: I. To bank specimens for future correlative studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive capecitabine orally (PO) twice daily (BID) on days 1-14 and temozolomide PO once daily (QD) on days 10-14. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Patients undergo surveillance with no active treatment. After completion of study treatment, patients are followed up every 6 months for 3 years and then annually until 5 years from randomization.

Five or Ten Year Colonoscopy for 1-2 Non-Advanced Adenomatous Polyps

Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer death among men and women in the United States (US). The lifetime risk of colorectal cancer in both men and women in the US is approximately 6%. About 93% of colorectal cancer (CRC) diagnoses are in patients older than 50 years (Siegel 2014). Randomized controlled trials show that screening for CRC significantly decreases CRC incidence and mortality (Schoen 2012, Atkin 2010, Mandel 1999, Mandel 2000). CRC screening has received a Grade A recommendation from the US Preventive Services Task Force. In the U.S., colonoscopy is the most utilized screening modality for CRC. On a population basis, screening rates, which were around 40-50%, have now increased to 65%, and a goal to increase to 80% compliance is being promoted (CDC 2011, CDC 2013, Meester 2015). Adenomatous polyps are the acknowledged precursors of colorectal cancer. Identification and removal of adenomas is the mechanism by which screening is effective in reducing CRC incidence and subsequent mortality. "Advanced" adenomas are adenomas which are greater than or equal to 1 cm, or have a "villous" component (tubulovillous or villous), or have foci of high grade dysplasia. Advanced adenomas are associated with increased long-term risk of cancer, even years after colonoscopy (Click 2018). The prevalence of advanced adenomas at screening colonoscopy is 5-10% (Ferlitsch 2011, Imperiale 2014). Non-advanced adenomas are adenomas greater than 1 cm with neither villous components nor high grade dysplasia. Non-advanced adenomas are much more common than advanced adenomas, present in around 30% of colonoscopy exams (Ferlitsch 2011, Imperiale 2014). After detection of adenomas, patients are advised to return periodically for surveillance colonoscopy. Patients with 1-2 non-advanced adenomas are recommended by guidelines to return in 5 - 10 years for follow-up surveillance colonoscopy (Lieberman 2012). However, there are no guidelines on how to triage individuals to 5 as opposed to 10 years. Furthermore, there is limited evidence supporting the effectiveness of surveillance colonoscopy in reducing CRC incidence. A retrospective study in patients with advanced adenomas demonstrated benefit (Atkin 2017), but the study was not randomized and did not include patients with 1-2 non-advanced adenomas. The only randomized trial of surveillance colonoscopy was reported in the early 1990's, when participants were randomized to 3 vs. 1- and 3- year surveillance (Winawer 1993). No difference in advanced adenoma detection was observed when comparing participants examined at the two screening intervals, and as a result, guidelines were modified with participants advised to return every 3 years after adenomatous polyp detection. The recommended interval for non-advanced adenomas was gradually lengthened to the current standard, but there is no randomized, controlled data to support that interval. Furthermore, observational data of surveillance colonoscopy practice in the U.S. demonstrate that recommended intervals are often not adhered to, and individuals return for repeat testing well ahead of guideline recommendations (Schoen 2010, Lieberman 2014). Furthermore, if anything, retrospective, natural history studies of non-advanced adenomas do not support the association of non-advanced adenoma with a higher risk of subsequent colorectal cancer (Atkin 1992, Spencer 1984, Loberg 2014). For example, in a classic study from the United Kingdom, patients with small rectosigmoid adenomas, even if multiple, did not have an increased risk of CRC compared to the general population, over a 14-year mean follow-up time (Atkin 1992). In a recent observational study from Norway, participants with a low-risk adenoma followed over a median of 7.7 years (maximum 19 years) without subsequent surveillance colonoscopy, had a lower CRC mortality than the general population (Loberg 2014), implying that although the initial colonoscopy may be protective, subsequent follow-up colonoscopy was not required. More recently, several studies have reported that individuals with non-advanced adenomas do not have an increased risk of colorectal cancer compared to those with no adenomas (Click 2018, Lieberman 2019, Lee 2019). Another recent major development affecting screening is that practitioners of colonoscopy are now recommended to monitor and insure their adenoma detection rates are high. Data from Poland (Kaminski 2010) and Kaiser Permanente in California (Corley 2014) have demonstrated that a higher adenoma detection rate (ADR) is associated with a lower long-term risk of interval CRC, or cancer occurring after colonoscopy. Our understanding of these observations is premised on the notion that leaving pre-neoplastic tissue (adenomas) in situ, (such as what occurs with a lower ADR), increases the chance that an adenoma left behind will subsequently transform into cancer. The concern over interval cancers has stimulated quality concerns about the practice of colonoscopy. Guidelines for a recommended ADR at screening colonoscopy are rising, from the initial targets of 15% in women and 25% in men (Lieberman 2012) to 20% in women and 30% in men or 25% overall. ADRs in clinical studies are now commonly over 30% and some practitioners report rates exceeding 50%. However, adenomas that are detected when the ADR is high or as it increases over time are generally small, non-advanced adenomas. Current clinical practice favoring colonoscopy-based screening with increased emphasis on detection of adenomas, most of which will turn out to be small, non-advanced adenomas, will greatly increase demand for utilization of surveillance colonoscopy exams in the coming decades. Yet, the evidence for determining the benefit, optimal timing, and recommended frequency of surveillance colonoscopy is unknown. A randomized, clinical trial to demonstrate the difference in yield between 5- or 10-year surveillance for participants with non-advanced adenoma is needed to guide clinical practice. Only a randomized trial will be authoritative enough to define good clinical practice and directly influence clinical care.

Two Studies for Patients With Unfavorable Intermediate Risk Prostate Cancer Testing Less Intense Treatment for Patients With a Low Gene Risk Score and Testing a More Intense Treatment for Patients With a Higher Gene Risk Score, The Guidance Trial

PRIMARY OBJECTIVES: I. To determine whether men with National Comprehensive Cancer Network (NCCN) unfavorable intermediate risk (UIR) prostate cancer and lower Decipher genomic risk (Decipher score < 0.40) treated with radiation therapy (RT) alone instead of 6 months androgen deprivation therapy (ADT) + RT experience non-inferior rate of distant metastasis. (De-intensification study) II. To determine whether men with NCCN UIR prostate cancer who are in the higher genomic risk (Decipher score >= 0.40) will have a superior metastasis-free survival through treatment intensification with darolutamide added to the standard of RT plus 6 months ADT. (Intensification study) SECONDARY OBJECTIVES: I. To compare overall survival (OS) between the standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. II. To compare time to prostate specific antigen (PSA) failure between the standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. III. To compare metastasis free survival (MFS) based on conventional imaging between the standard of care (RT plus 6 months of ADT) and de-intensification intervention (RT alone). IV. To compare MFS based on either conventional and/or molecular imaging between the standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. V. To compare cumulative incidence of locoregional failure based upon conventional imaging and/ or biopsy between standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months ADT plus darolutamide) interventions. VI. To compare cumulative incidence of distant metastasis based upon conventional imaging between standard of care (RT plus 6 months of ADT) and intensification intervention (RT plus 6 months ADT plus darolutamide). VII. To compare cumulative incidence of distant metastasis based upon either conventional and/or molecular imaging between standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. VIII. To compare prostate cancer-specific mortality between the standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. IX. To compare sexual and hormonal related quality of life, as measured by the Expanded Prostate Cancer Index Composite-26 (EPIC), between the standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. X. To compare fatigue, as measured by the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue instrument, between the standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. XI. To compare cognition, as measured by the Functional Assessment of Chronic Illness Therapy-Cognitive (FACT-Cog) perceived cognitive abilities subscale, between the standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. EXPLORATORY OBJECTIVES: I. To compare changes in cardio-metabolic markers, including body mass index, lipids, blood glucose, complete blood count (CBC), comprehensive metabolic panel (CMP), and hemoglobin (Hgb) A1c, between the standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. II. To compare PSA failure-free survival with non-castrate testosterone and no additional therapies between the standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. III. To compare cumulative incidence of locoregional failure based upon either conventional and/or molecular imaging between standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. IV. To compare castrate-resistant prostate cancer (CRPC) between the standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. V. To compare bowel and urinary function related quality of life, as measured by the Expanded Prostate Cancer Index Composite-26 (EPIC), between the standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. VI. To compare time to testosterone recovery (defined as a T > 200ng/dL) between the standard of care (RT plus 6 months of ADT) and intensification (RT plus 6 months of ADT plus darolutamide) interventions. VII. To compare health utilities, as measured by the European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L), between the standard of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide) interventions. VIII. To develop and assess a machine learning/artificial intelligence algorithm for radiotherapy planning and/or quality assurance. IX. To perform future translational correlative studies using biological data, Decipher results, and clinical outcomes. OUTLINE: DE-INTENSIFICATION STUDY: Patients with Decipher score < 0.40 are randomized to 1 of 2 arms. ARM I: Patients undergo radiation therapy (RT) using a recognized regimen (2-3 days a week or 5 days a week for 2-11 weeks) in the absence of disease progression or unacceptable toxicity. ARM II: Patients undergo RT as Arm I. Patients also receive androgen deprivation therapy (ADT) consisting of leuprolide, goserelin, buserelin, histrelin, triptorelin, degarelix, or relugolix at the discretion of the treating physician, for 6 months in the absence of disease progression or unacceptable toxicity. Patients may also receive bicalutamide or flutamide for 0, 30 or 180 days. INTENSIFICATION STUDY: Patients with Decipher score >= 0.40 are randomized to 1 of 2 arms. ARM III: Patients receive treatment as in Arm II. ARM IV: Patients receive RT and ADT as in Arm II. Patients also receive darolutamide orally (PO) twice daily (BID). Treatment repeats every 90 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 3, 6, 12, 24, 36, 48 and 60 months.