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Long-Term Outcomes Suggest a Sustained Clinical Benefit to Metastasis-Directed Treatment Over Observation in Oligometastatic Castration-Sensitive Prostate Cancer

Long-term follow-up findings from STOMP and ORIOLE and analysis of genomic predictors of response
31 Aug 2022
Genitourinary cancers;  Translational research

Long-term outcomes of STOMP and ORIOLE, the only two prospective studies of stereotactic ablative radiation versus observation in metachronous oligometastatic castration-sensitive prostate cancer, demonstrate sustained benefit to metastasis-directed treatment over observation. Pooling STOMP and ORIOLE and assessing the ability of a high-risk mutational signature to risk stratify outcomes after metastasis-directed treatment reveal that genomic alterations have prognostic value in this patient population and that biomarkers should be evaluated in future studies to optimise patient selection. The latest findings are published by Prof. Phuoc T. Tran of the Johns Hopkins University School of Medicine and University of Maryland School of Medicine, both in Baltimore, MD, US and colleagues on 24 August 2022 in the Journal of Clinical Oncology.

Initially STOMP and ORIOLE reports suggested that metastasis-directed treatment in oligometastatic castration-sensitive prostate cancer was associated with improved treatment outcomes. Compared with observation, metastasis-directed treatment prolonged androgen deprivation–free survival and progression-free survival (PFS). However, little is known regarding the utility of biomarkers to guide treatment for these patients.

Both, STOMP and ORIOLE, were prospective phase II studies enrolling patients with oligometastatic castration-sensitive prostate cancer, defined as no more than 3 metastases, with random assignment to observation or metastasis-directed treatment. Active systemic treatments were not allowed with metastasis-directed treatment.

Next-generation sequencing was performed on primary prostate tumour or blood from patients enrolled. A high-risk mutational signature was defined as pathogenic somatic mutations within ATM, BRCA1/2, Rb1, and TP53 on the basis of their strong association with prostate cancer outcomes. Pathogenic mutations were defined by commercial tests and the publicly available COSMIC tumour variant database.

The primary endpoint of interest was PFS; additional endpoints included radiographic PFS defined as development of new nodal lesions, intrapelvic or distant, bone, or visceral lesions or death. Time-to-event analysis was performed to detect differences in endpoints of interest using the Kaplan-Meier method, stratified by treatment or high-risk mutational status.

The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with metastasis-directed treatment compared with observation (pooled hazard ratio [HR] 0.44; 95% confidence interval [CI] 0.29 to 0.66; p < 0.001), with the largest benefit of metastasis-directed treatment in patients with a high-risk mutation (HR high-risk 0.05; HR no high-risk 0.42; p value for interaction 0.12). Within the metastasis-directed treatment cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR 0.53; 95% CI 0.25 to 1.11; p = 0.09).

The authors commented that metastasis-directed treatment is rapidly emerging in oligometastatic castration-sensitive prostate cancer. In a study with long-term follow-up from STOMP and ORIOLE, metastasis-directed treatment remained associated with improved PFS. The PFS beyond 4 years was 15-20% with metastasis-directed treatment regardless of mutation status. Thus, a sizable proportion of patients will experience durable response.

Although more follow-up is needed, the encouraging PFS suggests that in appropriately selected patients, metastasis-directed treatment without systemic treatment might be a reasonable option upfront in well-informed patients who would like to avoid side effects of androgen deprivation. Future studies, which are planned or underway, will more rigorously study this question.

Within this cohort, those treated with metastasis-directed treatment without a high-risk mutation experienced the best outcomes (median PFS 13.4 months), whereas observation in those with a high-risk mutation experienced the poorest outcomes (median PFS 2.8 months). This suggests that patients with oligometastatic castration-sensitive prostate cancer without a high-risk mutation might initially be treated with metastasis-directed treatment alone and highlights the need for novel treatment paradigms in those with a high-risk mutation. Ongoing studies combining systemic treatment (DART study) or radiopharmaceuticals (RAVENS study) might help define novel paradigms and hopefully further elucidate the role of biomarkers within this population.

The authors also reported that there are several limitations to their report. The genomic analysis did not have an a priori endpoint and was based on small sample size and prospective validation is needed. Different imaging modalities were used and with the introduction of PSMA might change in the future.

Reference

Deek MP, Van der Eecken K, Sutera P, et al. Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials. JCO; Published online 24 August 2022. DOI: 10.1200/JCO.22.00644

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