Outcomes of Radium-223 and Stereotactic Ablative Radiotherapy Versus Stereotactic Ablative Radiotherapy for Oligometastatic Prostate Cancers: The RAVENS Phase II Randomized Trial

Abstract

Purpose: Randomized clinical trials (RCTs) have shown progression-free survival (PFS) benefits of metastasis-directed therapy (MDT) without androgen deprivation therapy for oligometastatic castration-sensitive prostate cancer (omCSPC). Most patients with bone metastatic (BM) omCSPC recur with additional bone disease after MDT. We hypothesized the BM-targeting alpha-emitter radium-223 dichloride (Ra223) could target subclinical bone disease and delay progression.

Methods: This is an investigator-initiated, multicenter, open-label phase II RCT. Eligible men with recurrent omCSPC with ≥one bone metastasis (≤three on conventional imaging and/or ≤five on molecular imaging) were randomly assigned (1:1) to stereotactic ablative radiation (SABR) MDT alone or SABR MDT with Ra223 (six cycles). Primary end point was composite PFS.

Results: From August 9, 2019, to March 2, 2023, 64 patients were randomly assigned, 33 to SABR MDT and 31 to SABR MDT/Ra223 balancing for key covariates. Most SABR MDT/Ra223 patients (87%) received six cycles of Ra223. The median PFS was 11.8 months with SABR MDT and 10.5 months with SABR MDT/Ra223 (adjusted hazard ratio [aHR], 1.42 [95% CI, 0.79 to 2.56]; P = .24). Seven patients (11%) experienced grade 3 treatment-related adverse events (no grade 4 or 5), 2 of 33 (6%) with SABR and 5 of 30 (17%) with SABR MDT/Ra223. Patients with high-risk (HiRi) pathogenic mutations in ATM, BRCA1/2, RB1, or TP53 had worse PFS (HR, 5.95 [95% CI, 1.83 to 19.3]; P = .003). Greater T-cell receptor (TCR) unique productive rearrangements were prognostic for improved PFS independent of the treatment arm (aHR, 0.45 [95% CI, 0.21 to 0.96]; P = .04).

Conclusion: Adding Ra223 to SABR MDT in BM omCSPC does not delay progression of disease. We provide evidence for an HiRi mutational signature and TCR repertoire as prognostic biomarkers in omCSPC treated with SABR MDT, highlighting the importance of collecting biological correlates in RCTs for omCSPC.

Trial registration: ClinicalTrials.gov NCT04037358.

FIG 1.

CONSORT diagram. Ra223, radium-223; SABR, stereotactic ablative radiation.

FIG 2.

(A) PFS and (B) MFS. MFS, metastasis-free survival; PFS, progression-free survival; Ra223, radium-223 dichloride; SABR, stereotactic ablative radiation.

FIG 3.

Patients with an HiRi mutational signature have worse (A) PFS and (B) MFS. HiRi, high risk; MFS, metastasis-free survival; PFS, progression-free survival.

FIG 4.

TCR sequencing results for patients at baseline and 3 months. (A) UPRs at 3 months are prognostic for PFS. (B) Number of TCR clones showing expansion and contraction between 3 months versus baseline for Ra223 plus SABR MDT and SABR MDT alone arms. Each bar represents an individual patient. (C) Mean clonal expansion fold change for Ra223 plus SABR MDT and SABR MDT alone compared to the observation arm from the ORIOLE trial (3 month versus baseline). (D) UPR abundance at baseline and 3 months for patients with matched data in both arms. MDT, metastasis-directed therapy; PFS, progression-free survival; Ra223; radium-223 dichloride; SABR, stereotactic ablative radiation; TCR, T-cell receptor; UPR, unique TCR productive rearrangement.

FIG A1.

ADT-free survival and bone PFS. ADT, androgen deprivation therapy; PFS, progression-free survival; Ra223, radium-223 dichloride; SABR, stereotactic ablative radiation.

FIG A2.

Association between UPRs at 3 months and PFS for patients in the ORIOLE trial. PFS, progression-free survival; UPR, unique T-cell receptor productive rearrangement.