Long-Term Outcomes and Genetic Predictors of Response to Metastasis Directed Therapy vs. Observation in Oligometastatic Castration-Sensitive Prostate Cancer: A Pooled Analysis of the STOMP and ORIOLE Trials

Abstract

<h3>Purpose/Objective(s)</h3> Prospective reports suggest metastasis directed therapy (MDT) in oligometastatic castration sensitive prostate cancer (omCSPC) is associated with improved treatment outcomes. Here we present long term outcomes of the phase II STOMP and ORIOLE trials and hypothesize a high-risk (HiRi) mutational signature can provide prognostic and predictive information regarding MDT response. <h3>Materials/Methods</h3> Patients with omCSPC (3 or less lesions) enrolled on STOMP (n = 62) and ORIOLE (n = 54) randomized to MDT or observation were pooled. The primary endpoint was progression free survival (PFS) defined as either PSA or radiographic progression, initiation of androgen deprivation, or death. The secondary endpoint was radiographic PFS (rPFS) defined as radiographic progression or death. Both were calculated using the Kaplan-Meier method and stratified by treatment group. Next generation sequencing (NGS) was performed to identify a HiRi mutational signature defined as mutations in <i>ATM, BRCA1/2, Rb1</i>, or <i>TP53</i>. Cox proportional hazards regressions were fit to calculate pooled hazard ratios (HR) and assess the prognostic and predictive value of HiRi mutational status. <h3>Results</h3> Median follow-up was 52.5 months (mo). Median PFS was prolonged with MDT (11.9 mo) compared to observation (5.9 mo) with a pooled HR of 0.44 (95% CI, 0.29 – 0.66, p-value < 0.001). MDT was associated with PSA decrease in a majority of patients (MDT: 84% vs observation: 41%). In the MDT arm toxicity was: grade 1: 35.8%, grade 2: 3%, grade 3 or higher: 0%. On NGS, the incidence of a mutation in a HiRi gene was 24.3%. HiRi mutation was prognostic for PFS with median PFS was 11.9 mo without HiRi mutation compared to 5.9 mo with a HiRi mutation (HR of 1.74, p = 0.06). HiRi mutation was also prognostic for rPFS with median rPFS of 22.6 mo without HiRi mutation compared to 10.0 mo with a high-risk mutation (HR 2.62, p <0.01). Tumors without a HiRi mutation treated with MDT experienced the longest PFS (13.4 mo) while those with a HiRi mutation randomized to observation experienced the shortest PFS (2.8 mo). Stratifying by both treatment arms and HiRi status appeared to show a differential benefit to treatment, with HiRi mutations experiencing a larger relative magnitude of benefit to MDT (HiRi mutation: HR 0.05, p < 0.01; no HiRi mutation: HR 0.42, p = 0.01; p interaction, 0.12) suggesting HiRi mutational status can provide information regarding differential response to treatment. <h3>Conclusion</h3> Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained benefit to MDT over observation. A HiRi mutational signature appears prognostic for outcomes in omCSPC and those with HiRi might have a relatively larger magnitude of response to MDT. Future studies are needed to prospectively validate the HiRi mutational signature.