In a phase II trial (RAVENS) reported in the Journal of Clinical Oncology, Wang et al attempted to determine whether the addition of the bone metastasis–targeting agent radium-223 to stereotactic ablative radiotherapy improved progression-free survival as metastasis-directed therapy in patients with oligometastatic castration-sensitive prostate cancer and bone metastasis.
Study Details
In the investigator-initiated, open-label, North American multicenter trial, 64 patients were randomly assigned between August 2019 and March 2023 to receive stereotactic ablative radiotherapy at 28 to 50 Gy in two to five fractions with (n = 31) or without (n = 33) radium-223 at 55 kBq/kg in 4-week intervals for six total injections. Patients had metachronous oligometastatic castration-sensitive prostate cancer with one to five bone metastases. The primary endpoint was composite progression-free survival, with progression defined as at least a 25% increase in prostate-specific antigen, radiologic disease progression, symptomatic disease progression, or initiation of androgen-deprivation therapy.
Key Findings
Median progression-free survival was 10.5 months in the radium-223 group vs 11.8 months in the control group (adjusted hazard ratio [HR] = 1.42, 95% confidence interval [CI] = 0.79–2.56, P = .24). No benefit in the radium-223 group vs the control group was observed for metastasis-free survival (adjusted HR = 1.09, 95% CI = 0.92–2.51, P =.84) or androgen-deprivation therapy–free survival (adjusted HR = 1.53, 95% CI = 0.65–3.41, P = .30). No delay in bone progression-free survival was observed for the radium-223 group vs the control group (P = .63).
Among all patients, those with high-risk pathogenic mutations in ATM, BRCA1/2, RB1, or TP53 had significantly worse progression-free survival vs those without these alterations (HR = 5.95, 95% CI = 1.83–19.3, P = .003). Among all patients, greater T-cell receptor unique productive rearrangements were associated with improved progression-free survival (adjusted HR = 0.45, 95% CI = 0.21–0.96, P = .04).
Grade 3 treatment-related adverse events (no grade 4 or 5 events were observed) were reported in five patients (17%) in the radium-223 group (decreased lymphocytes in four, musculoskeletal pain in one) and two patients (6%) in the control group (decreased lymphocytes, fatigue, and insomnia).
The investigators concluded: “Adding [radium-223] to [stereotactic ablative radiotherapy metastasis-directed therapy] in [bone metastasis oligometastatic castration-sensitive prostate cancer] does not delay progression of disease. We provide evidence for [a high-risk] mutational signature and [T-cell receptor] repertoire as prognostic biomarkers in [oligometastatic castration-sensitive prostate cancer] treated with [stereotactic ablative radiotherapy metastasis-directed therapy], highlighting the importance of collecting biological correlates in [randomized clinical trials] for [oligometastatic castration-sensitive prostate cancer].”
Ana P. Kiess, MD, PhD, of the Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by Bayer HealthCare, Movember Foundation–Distinguished Gentleman’s Ride-Prostate Cancer Foundation, the National Cancer Institute, and the Department of Defense. For full disclosures of all study authors, visit the Journal of Clinical Oncology.
