ASCO 2022: Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Castration-Sensitive Prostate Cancer: A Pooled Analysis of the STOMP and ORIOLE Trials

( At the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, the poster session focused on Prostate, Testicular, and Penile cancers on Monday afternoon included a presentation from Dr. Mathew P. Deek describing a pooled analysis of the STOMP and ORIOLE trials examining long-term outcomes and genetic predictors of response to metastasis directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer.

The approach of MDT in oligometastatic castration-sensitive prostate cancer (omCSPC) has been associated with improved patient outcomes in retrospective data and early reports of prospective trials. In this abstract, Dr. Deek’s and colleagues performed a pooled analysis of the phase II STOMP and ORIOLE trials to examine long term outcomes of MDT and assess the ability of a high-risk (HiRi) mutational signature to provide prognostic and predictive information regarding MDT response.

They included patients with omCSPC (defined as less than 3 lesions) enrolled on STOMP (n = 62) and ORIOLE (n = 54). In each of these trials, patients were randomized to MDT or observation. The primary endpoint was progression-free survival (PFS) defined as either PSA or radiographic progression, initiation of androgen deprivation, or death. The main 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. To identify a HiRi mutational signature defined as pathogenic mutations within ATM, BRCA1/2, Rb1, or TP53, the authors performed next generation sequencing (NGS). Cox proportional hazards regressions models were used calculate hazard ratios (HR) and assess the prognostic and predictive values of HiRi mutational status.

Among the 116 patients included in these two trials, the median follow-up was 52.5 months. Over this time, median PFS was significantly longer for those patients treated with MDT (11.9 months) compared to those who received observation (5.9 months) with a pooled HR of 0.44 (95% CI, 0.29 – 0.66, p-value < 0.001).

ASCO 2022_Mathew P. Deek_STOMP_0 

A PSA decrease was two-fold more common among patients receiving MDT (84%) compared to the observation group (41%).

Using NGS, the incidence of a pathogenic mutation in a HiRi gene was 24.3%. HiRi mutation was prognostic for both PFS and FRS. In those without a HiRi mutation, the median PFS was 11.9 months compared to 5.9 months in those with a HiRi mutation (HR of 1.74, p = 0.06). Similarly, those without a high-risk mutation had a significantly longer median rPFS (22.6 months) compared to 10.0 months in those with a high-risk mutation (HR 2.62, p < 0.01).

ASCO 2022_Mathew P. Deek_STOMP_1 

Examining the interaction between mutational status and MDT, the authors found that patients with tumors without a HiRi mutation who received with MDT experienced the longest PFS (13.4 months) while those with a HiRi randomized to observation experienced the shortest PFS (2.8 months). Stratifying by both treatment arms and HiRi status identified a differential benefit to MDT, with those with HiRi mutations experiencing a larger relative magnitude of benefit to treatment: (HiRi mutation: HR of 0.05, p < 0.01; no HiRi mutation: HR of 0.42, p = 0.01; p interaction, 0.12) suggesting a HiRi mutational status can provide information regarding differential response to treatment.

Thus, the authors conclude that this pooled analysis of the only two randomized trials in omCSPC demonstrates a long-term benefit to MDT. Further, a HiRi mutational signature appears prognostic for outcomes in omCSPC and those with HiRi might have a relatively larger magnitude of response to MDT.

Presented by: Matthew Pierre Deek, MD, Rutgers Cancer Institute, Baltimore, NJ

Written by: Christopher J.D. Wallis, University of Toronto, Twitter: @WallisCJD during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.


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