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Chris Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today we're talking about a recent publication entitled Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy versus Observation in Oligometastatic Prostate Cancer: An Analysis of the STOMP and ORIOLE Trials. I'm Chris Wallis, Assistant Professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia.

You can see here the citation for this recent publication in the Journal of Clinical Oncology. Oligometastatic disease, as most will know, is an intermediate state between localized disease and widely metastatic disease that was first described back in 1995. Most believe it's on the spectrum of transition between localized and widely metastatic disease. However, it offers the potential for novel treatment paradigms given the relatively low burden of metastatic disease.

One of these approaches is metastasis-directed therapy or local therapies in contrast to the initiation of systemic therapy.

Two randomized trials have assessed this so far, the STOMP and ORIOLE trials, and each of these have shown improvements with the use of MDT, and in particular, in STOMP, they show that you could substantially improve ADT-free survival and keep patients off systemic therapy.

The question is, while MDT has shown benefit, little is known regarding the use of biomarkers to select these patients for therapy. Thus, we need to better understand who is most appropriate for this treatment paradigm.

The authors use two independent phase II trials, each of which enrolled men with oligometastatic prostate cancer, which was defined as three or fewer lesions. Patients were then randomly assigned to either observation or metastasis-directed therapy with radiation. Active systemic therapy, including ADT, was not allowed.

The authors performed next generation sequencing on either prostate tumor tissue or blood, and identified a high-risk mutational signature including mutations in ATM, BRCA1/2, Rb1, and TP53. Pathogenic mutations were identified using commercial assays and the COSMIC tumor variant database.

The authors assessed their primary endpoint of progression-free survival and also consider radiographic progression-free survival. The Kaplan Meier technique was used to compare time-to-event endpoints, stratified by treatment approach and by mutational status.

At this point in time, I'm going to hand it over to Zach to walk us through the results of this analysis.

Zach Klaassen: Thanks so much, Chris, for that introduction. This is the CONSORT diagram for this analysis. You can see that in STOMP there was 62 patients randomly assigned one-to-one to MDT or observation, and in the ORIOLE trial there was 54 patients randomized two-to-one to MDT or observation. Ultimately between these two trials, tissue was unavailable on 14 patients, 102 patients had NGS, and samples with successful NGS included 70 of these 102 patients.

This is the baseline characteristics by treatment group, stratified by MDT and observation. You can see that the most common T stage for these patients was T3, 55.2% with MDT and 49% for observation. In terms of N stage, most commonly was N0, 80.6% for MDT and 77.6% for observation. With regards to Gleason score, most common was Gleason 7, and second most common was Gleason 9. With regards to number of metastases, one metastasis in 41.8% for MDT compared to 36.7% in observation, and we do see that these groups are also well-balanced for either one to three number of metastases. With regards to PSA at the time of oligometastasis, also no difference between these groups. PSA of 5 for MDT and 5.93 for observation. Metastases location was roughly 50-50 between nodal and non-nodal, and the majority of these patients, three quarters of them, had a PSA doubling time of greater than three months.

This is the time-to-event outcomes of MDT versus observation. You can see the four outcomes on the left, and I've highlighted progression-free survival, which was statistically significant between these two groups with a median time to PFS for MDT of 11.9 months compared to 5.9 months for observation, with a hazard ratio of 0.44, 95% confidence interval of 0.29 to 0.66. You can see for our PFS, CRPC, and OS, there was no difference between MDT and observation.

These are the PFS-stratified results by treatment arm. On the left you can see STOMP observation in blue, MDT in yellow, with a hazard ratio favoring MDT of 0.48 and a p-value of 0.01. Similarly, in the ORIOLE trial, there's a hazard ratio favoring MDT of 0.40 and a p-value of less than 0.01.

The next several slides we'll look at this color scheme, observation in blue, MDT in red, and this is the PFS stratified by treatment arm for men with high-risk mutations. You can see the median PFS for MDT was 7.5 months and for observation was 2.8 months with a hazard ratio favoring MDT of 0.05 and a 95% confidence interval of 0.01 to 0.28. So clearly these patients that got MDT with high-risk mutations did have a benefit.

This is PFS by treatment arm without high-risk mutations and median PFS for MDT was 13.4 months and for observation was 7.0 months, again favoring MDT, hazard ratio 0.42, and 95% confidence interval that was statistically significant at 0.23 to 0.77.

This is PFS in men treated with MDT stratified by high-risk mutation status. In men without a high-risk mutation, the median PFS was 13.4 months and with a high-risk mutation was 7.5 months, with a hazard ratio of 0.53 and a non-statistically significant 95% confidence interval of 0.25 to 1.11.

This is rPFS in men treated with MDT, stratified by high-risk mutation status and we see that men without a high-risk mutation had a median PFS have 25.3 months and those with a high-risk mutation had a median rPFS of 8.0 months, with hazard ratio of 0.43 and a 95% confidence interval 0.20 to 0.95. So we do see that men that did not have a high-risk mutation and then did receive MDT had a statistically improved radiographic progression-free survival.

Several discussion points from this study with long-term follow up of the STOMP and ORIOLE trials. MDT remained associated with improved progression-free survival. Progression-free survival more than four years was noted in 15 to 20% of men with MDT regardless of mutation status. Thus, a sizeable portion of patients will experience durable response to therapy. MDT without systemic therapy may be a reasonable option upfront in well-informed patients wishing to avoid the side effects of ADT.

Importantly, genetic biomarkers are likely to play a role in patient selection. We saw in this study that those treated with MDT without a high-risk mutation had the best outcomes, the median progression-free survival of 13.4 months and those undergoing observation with a high-risk mutation had the worst outcomes with a median progression-free survival of 2.8 months. Certainly, ongoing trials combining systemic therapy, such as the DART trial, or radiopharmaceuticals, such as the RAVENS trial, may help to define additional novel paradigms.

In conclusion, long-term outcomes of STOMP and ORIOLE demonstrate sustained benefit to MDT over observation in men with oligometastatic castrate-sensitive prostate cancer. Genomic alterations appear to have prognostic value in this patient population, suggesting that biomarkers should be evaluated in future studies to optimize patient selection.

Thank you very much for your attention and we hope enjoyed this UroToday Journal Club of the extended follow-up with the STOMP and ORIOLE trials.