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Metastasis-Directed Radiotherapy for the Treatment of Men with Oligometastatic Prostate Cancer, METANOVA Trial
Trial Status: active
This phase II trial tests the safety, side effects and effectiveness of metastasis-directed radiotherapy (MDRT) in treating men with prostate cancer that has spread from where it first started to a limited number of other places in the body (oligometastatic) treated with long-term androgen deprivation therapy (ADT). Prostate cancer is the second leading cause of cancer death and approximately 10% of patients are metastatic at the time of diagnosis. The usual treatment for metastatic cancer may include lifelong treatment with hormone therapy, known as ADT, and radiation therapy to the prostate. ADT uses drugs, such as relugolix, degarelix, and leuprolide, to block production or interfere with the action of male sex hormones. Androgen receptor signaling inhibitors, such as abiraterone, prednisone, enzalutamide, and apalutamide, blocks or interferes with the activity of androgen receptor. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. MDRT is radiation therapy that targets metastatic sites in the body. MDRT may be a safe, tolerable and/or effective in treating men with oligometastatic prostate cancer after treatment with ADT.
Inclusion Criteria
Patient must be ≥ 18 years of age
Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
Histologic confirmation of prostate adenocarcinoma of the prostate gland, with evidence of metastasis on imaging by conventional imaging (MRI, CT, or 99mTc bone scan) or PSMA PET/CT. Biopsy of sites of metastasis is strongly encouraged, but not required.
* There must be at least 10-15 unstained slides from 2 cores of the highest tumor cellularity available
Newly diagnosed disease with no prior treatment (surgery, radiation or systemic treatment, ie hormone therapy or chemotherapy) to the primary disease.
* Patients may have started luteinising hormone-releasing factor (LHRH) agonist or antagonist therapy, and/or androgen receptor signaling inhibitor (ARSI) as long as it was not started more than 30 days before the patient is enrolled on this study
In patients who undergo only conventional imaging, oligometastatic disease is defined as 1-5 discrete metastatic sites in the bone and/or extra-pelvic lymph node (LN) stations.
* Extra-pelvic LN stations are superior to the regional/pelvic LN stations. Pelvic LN stations commence at the bifurcation of the aorta and bifurcation of the proximal inferior vena cava to the common iliac veins.
** Radiographic criteria for a LN to be considered a metastatic focus is defined as short-axis diameter in the axial plane of ≥ 1.0 cm, with irregular border and/or heterogeneous morphology
In patients who undergo PSMA PET/CT (in the presence or absence of conventional imaging), oligometastatic disease is defined as 1-10 PSMA avid bone lesions and/or extra-pelvic LN stations. The molecular imaging reporting and data system (MI-RADS) reporting system will be followed to guide PSMA PET interpretation
* In patients extra-pelvic nodal (M1a) disease only by PSMA PET/CT and M0 by conventional imaging (i.e. extra-pelvic LN did not meet size criteria by CT), patient must meet 2 of 3 following criteria in order to be eligible:
** Prostate specific antigen (PSA) ≥ 40
** Evidence of cN1 disease (pelvic LN)
** Decipher score ≥ 0.89
Adequate organ and marrow function to receive treatment per treating physician
Medically fit for treatment and agreeable to follow-up
Ability to understand and the willingness to sign a written informed consent
Note: Metastatic sites are defined as any bony metastasis or extra-pelvic nodal station. > 1 lymph node in the same nodal station will be considered 1 metastatic site. Extra-pelvic nodal stations include popliteal, inguinal/femoral, para-aortic, mesenteric, splenic, gastric, hilar, mediastinal, supraclavicular, infraclavicular, axillary, and cervical. Nodal stations are divided at the midplane of the body into left and right stations, and are each counted separately as metastatic sites
Exclusion Criteria
Castration resistant prostate cancer (CRPC)
Evidence of visceral or intracranial metastases
Patient receiving any other investigational agents for cancer
Patient is participating in a concurrent treatment protocol for cancer
Unable to lie flat during or tolerate PET/MRI, PET/CT or stereotactic body radiation therapy (SBRT)
Prior definitive treatment to the primary prostate cancer or pelvis
Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes (glycosylated hemoglobin [HgA1c] > 10), active pituitary or adrenal dysfunction, or psychiatric illness/social situations that would limit compliance with study requirements
History of another active malignancy within the previous 2 years, except for non-melanoma skin cancer, non-muscle invasive bladder cancer, or a malignancy that is considered cured with minimal risk of recurrence
Active Crohn’s disease or ulcerative colitis despite medical management
Refusal to sign informed consent
Any condition that in the opinion of the investigator would preclude participation in this study
Additional locations may be listed on ClinicalTrials.gov for NCT06150417.
I. Failure-free survival (FFS): Time from randomization to first evidence of at least one of: biochemical failure; progression either locally in lymph nodes, or in distant metastases (according to Prostate Cancer Working Group 3 [PCWG3] and Response Evaluation Criteria in Solid Tumors [RECIST] 1.1); skeletal related event (where confirmed disease progression); any salvage intervention (local or systemic) required after 12 months (m) of planned standard of care (SOC) therapy; or death from prostate cancer.
SECONDARY OBJECTIVES:
I. To compare additional measures of efficacy, including overall survival (OS), radiographic progression-free survival (rPFS), time-to-next-intervention (TTNI), time-to-castration-resistant prostate cancer, and prostate-specific cancer mortality (PCSM).
II. To describe the toxicity and effects on patient-reported quality of life by collecting sexual domain (Expanded Prostate Cancer Index Composite [EPIC]-26), hormone domain (EPIC-26), urinary domain (EPIC-26), bowel domain (EPIC-26), and skeletal-related events (SRE).
CORRELATIVE OBJECTIVES:
I. To identify imaging features on conventional and prostate specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) imaging that predict which patients will benefit most from MDRT.
II. To identify molecular features from the primary, metastases, and circulating disease to develop a predictive biomarker of which patients benefit most from MDRT.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM 1: Patients receive 12 months of standard of care systemic therapy consisting of relugolix orally (PO) once daily (QD), degarelix subcutaneously (SC) once every 28 days, or leuprolide. Patients also receive 12 months of standard androgen receptor signaling inhibitor therapy consisting of abiraterone PO QD with concurrent prednisone PO QD, enzalutamide PO QD, or apalutamide PO QD. After at least 8 weeks of systemic therapy, patients may undergo definitive radiation therapy (RT) 2-3 days or 5 days per week for 4 weeks, or patients may undergo radical prostatectomy (RP) after 12 weeks of systemic therapy. Patients also undergo collection of blood samples throughout the trial, and undergo biopsy, bone scan, CT, magnetic resonance imaging (MRI), PSMA PET/CT, and/or PET/CT at screening.
ARM 2: Patients receive standard of care systemic therapy plus androgen receptor signaling inhibitor therapy and undergo definitive RT or RP as in Arm I. Patients also undergo MDRT over 1-7 treatments for 1-3 weeks. Patients also undergo collection of blood samples throughout the trial, and undergo biopsy, bone scan, CT, MRI, PSMA PET/CT, and/or PET/CT at screening.
After completion of study treatment, patients are followed up every 3 months for year 1, every 4-6 months for year 2, then every 6 months for years 3, 4 and 5.
