Clinical trial NCT06378866: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Recurrent Castration-Sensitive Prostate Carcinoma
Stage IVB Prostate Cancer AJCC v8
Recurrent Prostate Cancer
Castration-resistant Prostate Cancer
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
First posted: 2024-04-23
Enrollment: 220
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 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.

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

Primary outcomes:
measure: Modified radiographic progression-free survival (mrPFS)
timeFrame: Up to 5 years
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: Up to 5 years
measure: Biochemcial progression-free survival (bPFS)
timeFrame: Up to 5 years
measure: Time to local progression (TLP)
timeFrame: Up to 5 years
measure: Time to distant progression (TDP)
timeFrame: Up to 5 years
measure: Adverse event (AE) rate
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic in Rochester
name: Jacob J. Orme, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: