World-wide oligometastatic prostate cancer (omPC) meta-analysis leveraging individual patient data (IPD) from randomized trials (WOLVERINE): An analysis from the X-MET collaboration.

15 Background: Metastasis-directed therapy (MDT) for omPC has demonstrated progression-free survival (PFS) benefit in multiple phase 2 randomized clinical trials (RCTs) yet has fallen short of demonstrating benefit for later endpoints. The X-MET collaboration amalgamates IPD from RCTs investigating oligometastatic cancers, incorporating new trials when published. Within X-MET, WOLVERINE combined IPD from all published omPC MDT RCTs. Methods: Trial search identified 5 omPC RCTs of MDT and standard of care (SOC) vs. SOC alone: STOMP (NCT01558427), ORIOLE (NCT02680587), ARTO (NCT03449719), SABR-COMET (NCT01446744), and EXTEND (continuous and intermittent androgen deprivation therapy [ADT] baskets; NCT03599765). IPD were retrieved for all trials. PFS was defined as biochemical or radiographic (RECIST 1.1) progression or death. Castration-resistance free survival (CRFS) was analyzed in castration-sensitive prostate cancer (CSPC) patients and was defined as development of castration-resistant prostate cancer (CRPC) or death. Meta-analyses were conducted using fixed- and random-effects models to calculate pooled hazard ratios (HRs). As a complementary approach, HRs were computed utilizing Cox regression stratified by trial. The analysis plan was archived in Prospero: CRD4203479078. Results: This analysis included 472 patients, 224 randomized to SOC and 248 randomized to MDT+SOC, with a median follow-up of 41 mo. The majority were CSPC (58%), treated with ADT (74%) +/- androgen receptor pathway inhibitors (ARPI; 54%), and had a previously treated primary prostate (82%). For both analyses, MDT significantly improved PFS, radiographic PFS (rPFS), and CRFS (Table). Meta-analysis utilizing fixed- and random-effects yielded similar results. Overall survival (OS) was excellent in both arms (3- and 4-year OS: MDT+SOC 92% and 87% vs. SOC 86% and 75%) and exhibited near-significant association with MDT. The benefit of MDT for PFS persisted across most subgroups including castration status, prior primary treatment, staging imaging, and ADT/ARPI use (all HR < 0.52, all P < 0.05, all P[interaction] > 0.05). Conclusions: Leveraging IPD from all published omPC RCTs, WOLVERINE demonstrated for the first time a significant benefit of MDT for longer term endpoints including rPFS and CRFS, in addition to a near-significant association with OS. Furthermore, MDT benefit persisted across the entire omPC disease spectrum ranging from de novo to metachronous and CSPC to CRPC. Association between MDT and outcomes. Cox regression: HR (95% CI) Random-effects model: HR (95% CI) PFS 0.45 (0.35-0.58), P<0.0001 0.44 (0.35-0.57), P<0.0001 rPFS 0.59 (0.46-0.76), P<0.0001 0.60 (0.43-0.85), P=0.0039 CRFS 0.58 (0.37-0.91), P=0.020 0.58 (0.37-0.92), P=0.019 OS 0.64 (0.40-1.01), P=0.057 0.63 (0.39-1.004), P=0.051