Stereotactic Body Radiation Therapy Plus Androgen Receptor Pathway Inhibitor and Androgen Deprivation Therapy for Treatment of Metastatic, Recurrent Hormone-Sensitive Prostate Cancer, DIVINE Trial (DIVINE)

• ClinicalTrials.gov Identifier: NCT06378866
• Recruitment Status: Not yet recruiting
• First Posted: April 23, 2024
• Last Update Posted: April 23, 2024
• Sponsor: Mayo Clinic
• Information provided by (Responsible Party): Mayo Clinic

Tracking Information

• First Submitted Date: April 16, 2024
• First Posted Date: April 23, 2024
• Last Update Posted Date: April 23, 2024
• Estimated Study Start Date: May 1, 2024
• Estimated Primary Completion Date: April 30, 2029 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 16, 2024)

Modified radiographic progression-free survival (mrPFS) [ Time Frame: Up to 5 years ]

Modified radiographic progression-free survival (mrPFS) is defined as the time from the date of randomization (enrollment to study) to the date of the first occurrence of either death due to any cause or radiographic progression per prostate cancer working group 3 criteria, which are not addressable by stereotactic body radiation therapy (SBRT). Radiographic progression not addressable by SBRT includes 1) soft tissue lesions measured by response evaluation criteria in solid tumors (RECIST) v1.1 or 2) bone lesions evaluated only on bone scans per 2+2 rule (2 new lesions on the 1st post-treatment scan plus 2 additional new lesions on the subsequent scan with persistence or 2 new lesions compared to 1st post-treatment scan persisting on the follow-up scan). Date of progression is the first scan showing lesions. Radiographic progression disease that can be addressed by SBRT will not be an mrPFS event.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: April 16, 2024)

• Overall survival (OS) [ Time Frame: Up to 5 years ]
  Defined as time from the date of randomization (enrolled to study) to the date of death due to any cause.
• Biologic progression-free survival (bPFS) [ Time Frame: Up to 5 years ]
  Defined as time from the date of randomization (enrollment to study) to the date of death due to any cause or biologic progressive disease, whichever occurs first.
• Time to local progression (TLP) [ Time Frame: Up to 5 years ]
  Defined as time from date of randomization (enrollment to study) to the date of the first documented local progression. Local progression includes growth of any existing lesion by 20% or more that persists on a subsequent scan (modified from RECIST 1.1), whether or not these lesions are or can be addressed by radiotherapy.
• Time to distant progression (TDP) [ Time Frame: Up to 5 years ]
  Defined as time from date of randomization (enrollment to study) to the date of the first documented distant progression. Distant progression includes new lesions on imaging, whether or not these lesions are or can be addressed by radiotherapy.
• Adverse event (AE) rate [ Time Frame: Up to 5 years ]
  Defined as the proportion of patients experienced at least one Grade 3, Grade 4, or Grade 5 of any type of AE during the protocol defined treatment. AEs will be assessed using common terminology criteria for adverse events (CTCAE) v5.0.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Stereotactic Body Radiation Therapy Plus Androgen Receptor Pathway Inhibitor and Androgen Deprivation Therapy for Treatment of Metastatic, Recurrent Hormone-Sensitive Prostate Cancer, DIVINE Trial
• Official Title: Dynamic Investigator Initiated Enterprise (DIVINE) in Prostate Cancer
• Brief Summary: This phase II trial studies the effects of stereotactic body radiation therapy (SBRT) and the timing of treatment with androgen receptor pathway inhibitor (ARPI) plus androgen deprivation therapy (ADT) in treating patients with hormone sensitive prostate cancer that has spread from where it first started to other places in the body (metastatic), and that has come back after a period of improvement (recurrent). SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. Androgen can cause the growth of prostate cells. ADT lowers the amount of androgen made by the body. This may help stop the growth of tumor cells that need androgen to grow. Androgen receptor pathway inhibitors work by blocking the effects of androgen to stop the growth and spread of tumor cells. Giving SBRT alone with watchful waiting may be as effective in treating prostate cancer as giving SBRT together with ARPI and ADT.

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate and compare modified radiographic progression-free survival (mrPFS) in patients with metachronous recurrent oligometastatic prostate cancer treated with SBRT and 6 months ADT/ARPI followed by watchful wait (Group A) versus SBRT followed by watchful wait (Group B).

SECONDARY OBJECTIVES:

I. To evaluate and compare overall survival (OS) between two treatment groups. II. To evaluate and compare biochemical progression-free survival (bPFS) between two treatment groups.

III. To evaluate and compare time to local progression between two treatment groups.

IV. To evaluate and compare time to distant progression between two treatment groups.

V. To evaluate the toxicity profile of 6 months of ADT/ARPI as assessed per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).

TERTIARY OBJECTIVES:

I. To evaluate and compare castration-resistant prostate cancer (CRPC)-free survival between two treatment groups NOTE: CRPC-free survival: radiographic progression-free survival with castrate-level testosterone (< 50ng/mL).

II. Determine the efficacy of extracellular vesicles (EVs) as a minimal residual disease (MRD) marker.

III. Determine the efficacy of EVs as an early indicator of disease relapse. IV. Characterize duration of response. V. Determine whether early ADT and ARPI hasten CRPC. VI. Determine how circulating tumor deoxyribonucleic acid (ctDNA) compares as a biomarker to EVs.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP A: Patients undergo SBRT and receive ARPI (abiraterone and prednisone, apalutamide, darolutamide, or enzalutamide) and ADT (leuprolide, triptorelin, histrelin, goserelin, degarelix, or relugolix). Cycles repeat every 4 months (16 weeks) for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients then undergo watchful waiting thereafter until disease progression.

GROUP B: Patients undergo SBRT with watchful waiting. Cycles repeat every 4 months (16 weeks) in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo blood sample collection and positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), or bone scan.

Upon completion of study interventions patients are followed up every 6 months for up to 5 years.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Recurrent Castration-Sensitive Prostate Carcinoma
• Stage IVB Prostate Cancer AJCC v8
• Recurrent Prostate Cancer
• Castration-resistant Prostate Cancer

Intervention

• Drug: Abiraterone
  Given abiraterone
  Other Name: CB 7598
• Drug: Apalutamide
  Given apalutamide
  Other Names:

  • ARN 509
  • ARN-509
  • ARN509
  • Erleada
  • JNJ 56021927
  • JNJ-56021927
• Procedure: Biospecimen Collection
  Undergo blood sample collection
  Other Names:

  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
• Procedure: Bone Scan
  Undergo bone scan
  Other Name: Bone Scintigraphy
• Procedure: Computed Tomography
  Undergo CT
  Other Names:

  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • Computerized Tomography (CT) scan
  • CT
  • CT Scan
  • tomography
• Drug: Darolutamide
  Given darolutamide
  Other Names:

  • Antiandrogen ODM-201
  • BAY 1841788
  • BAY-1841788
  • BAY1841788
  • Nubeqa
  • ODM 201
  • ODM-201
• Drug: Degarelix
  Given degarelix
  Other Names:

  • ASP3550
  • FE200486
  • Firmagon
• Drug: Enzalutamide
  Given enzalutamide
  Other Names:

  • ASP9785
  • MDV3100
  • Xtandi
• Drug: Goserelin
  Given goserelin
  Other Name: ICI-118630
• Drug: Histrelin
  Given histrelin
• Drug: Leuprolide
  Given leuprolide
  Other Name: Leuprorelin
• Procedure: Magnetic Resonance Imaging
  Undergo MRI
  Other Names:

  • Magnetic Resonance
  • Magnetic Resonance Imaging (MRI)
  • Magnetic resonance imaging (procedure)
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI
  • MRI Scan
  • MRIs
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • sMRI
  • Structural MRI
• Other: Patient Observation
  Undergo watchful waiting
  Other Names:

  • Active Surveillance
  • deferred therapy
  • expectant management
  • Observation
  • Watchful Waiting
• Procedure: Positron Emission Tomography
  Undergo PET
  Other Names:

  • Medical Imaging, Positron Emission Tomography
  • PET
  • PET Scan
  • Positron emission tomography (procedure)
  • Positron Emission Tomography Scan
  • Positron-Emission Tomography
  • proton magnetic resonance spectroscopic imaging
  • PT
• Drug: Prednisone
  Given prednisone
  Other Names:

  • .delta.1-Cortisone
  • 1, 2-Dehydrocortisone
  • Adasone
  • Cortancyl
  • Dacortin
  • DeCortin
  • Decortisyl
  • Decorton
  • Delta 1-Cortisone
  • Delta-Dome
  • Deltacortene
  • Deltacortisone
  • Deltadehydrocortisone
  • Deltasone
  • Deltison
  • Deltra
  • Econosone
  • Lisacort
  • Meprosona-F
  • Metacortandracin
  • Meticorten
  • Ofisolona
  • Orasone
  • Panafcort
  • Panasol-S
  • Paracort
  • Perrigo Prednisone
  • PRED
  • Predicor
  • Predicorten
  • Prednicen-M
  • Prednicort
  • Prednidib
  • Prednilonga
  • Predniment
  • Prednisone Intensol
  • Prednisonum
  • Prednitone
  • Promifen
  • Rayos
  • Servisone
  • SK-Prednisone
• Other: Questionnaire Administration
  Ancillary studies
• Drug: Relugolix
  Given relugolix
  Other Names:

  • N-(4-(1-((2,6-Difluorophenyl)methyl)-5-((dimethylamino)methyl)-1,2,3,4-tetrahydro-3-(6-methoxy-3-pyridazinyl)-2,4-dioxothieno(2,3-d)pyrimidin-6-yl)phenyl)-N'-methoxyurea
  • Orgovyx
  • Relumina
  • TAK 385
  • TAK-385
• Radiation: Stereotactic Body Radiation Therapy
  Undergo SBRT
  Other Names:

  • SABR
  • SBRT
  • Stereotactic Ablative Body Radiation Therapy
• Drug: Triptorelin
  Given triptorelin
  Other Names:

  • 6-D-Tryptophan-LH-RH
  • 6-D-Tryptophanluteinizing Hormone-releasing Factor
  • AY-25650
  • AY25650
  • CL-118,532
  • CL118532
  • Detryptoreline

Study Arms

• Active Comparator: Group A (SBRT, APRI, ADT)
  Patients undergo SBRT and receive ARPI (abiraterone and prednisone, apalutamide, darolutamide, or enzalutamide) and ADT (leuprolide, triptorelin, histrelin, goserelin, degarelix, or relugolix). Cycles repeat every 4 months (16 weeks) for up to 6 months in the absence of unacceptable toxicity. Patients then undergo watchful waiting thereafter until disease progression.
  Interventions:

  • Drug: Abiraterone
  • Drug: Apalutamide
  • Procedure: Biospecimen Collection
  • Procedure: Bone Scan
  • Procedure: Computed Tomography
  • Drug: Darolutamide
  • Drug: Degarelix
  • Drug: Enzalutamide
  • Drug: Goserelin
  • Drug: Histrelin
  • Drug: Leuprolide
  • Procedure: Magnetic Resonance Imaging
  • Other: Patient Observation
  • Procedure: Positron Emission Tomography
  • Drug: Prednisone
  • Other: Questionnaire Administration
  • Drug: Relugolix
  • Radiation: Stereotactic Body Radiation Therapy
  • Drug: Triptorelin
• Experimental: Group B (SBRT, watchful waiting)
  Patients undergo SBRT with watchful waiting. Cycles repeat every 4 months (16 weeks) in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Procedure: Biospecimen Collection
  • Procedure: Bone Scan
  • Procedure: Computed Tomography
  • Procedure: Magnetic Resonance Imaging
  • Other: Patient Observation
  • Procedure: Positron Emission Tomography
  • Other: Questionnaire Administration
  • Radiation: Stereotactic Body Radiation Therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: April 16, 2024): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 30, 2029
• Estimated Primary Completion Date: April 30, 2029 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age ≥ 18 years

• The following disease characteristics:

  • Clinical confirmation of metachronous (metastatic) recurrent hormone-sensitive prostate cancer
  • Five (5) or fewer metastases with at least one metastasis beyond the pelvis on advanced molecular and/or conventional imaging
  • Serum testosterone > 100ng/dL
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2
• Hemoglobin ≥ 8.0 g/dL (obtained ≤ 15 days prior to registration)
• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (obtained ≤ 15 days prior to registration)
• Platelet count ≥ 80,000/mm^3 (obtained ≤ 15 days prior to registration)
• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x upper limit of normal (ULN) ( ≤ 5 x ULN for patients with liver involvement) (obtained ≤ 15 days prior to registration)
• Calculated creatinine clearance ≥ 30 ml/min using the Cockcroft-Gault formula (obtained ≤ 15 days prior to registration)
• Provide written informed consent
• Ability to complete questionnaire(s) by themselves or with assistance
• Willingness to provide mandatory blood specimens for correlative research
• Willingness to provide tissue specimens for correlative research
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

Exclusion Criteria:

• Any of the following because this study involves an investigational agent, the genotoxic, mutagenic, and teratogenic effects of which on the developing fetus and newborn are unknown

  • Pregnant persons
  • Nursing persons
  • Persons of childbearing potential or able to father a child who are unwilling to employ adequate contraception
• Prior metastasis-directed therapy

• Any of the following prior therapies:

  • Surgery ≤ 3 weeks prior to registration
  • Chemotherapy for prostate cancer at any time
  • Androgen receptor pathway inhibitor such as abiraterone, apalutamide, darolutamide, or enzalutamide in the last 2 years

• Uncontrolled intercurrent non-cardiac illness including, but not limited to:

  • Ongoing or active infection
  • Psychiatric illness/social situations
  • Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
  • Any other conditions that would limit compliance with study requirements
• Receiving any other investigational agent which would be considered as a treatment for prostate cancer.
• Failure to recover from acute, reversible effects of prior therapy regardless of interval since last treatment EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for at least 3 months since completion of prior treatment
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Or psychiatric illness/social situations that would limit compliance with study requirements
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm

• Other active malignancy ≤ 3 years prior to registration

  • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix
  • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment such as chemotherapy or antihormonal therapy for their cancer
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT06378866
• Other Study ID Numbers: MC230502; NCI-2024-02978 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 23-012176 ( Other Identifier: Mayo Clinic Institutional Review Board ); MC230502 ( Other Identifier: Mayo Clinic in Rochester )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Mayo Clinic
• Original Responsible Party: Same as current
• Current Study Sponsor: Mayo Clinic
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Jacob J. Orme, M.D., Ph.D.; Mayo Clinic in Rochester

• PRS Account: Mayo Clinic
• Verification Date: April 2024