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Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we are discussing a recent publication entitled, Overall Survival of Men with Metachronous Metastatic Hormone-sensitive Prostate Cancer Treated with Enzalutamide and Androgen Deprivation Therapy. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt. With me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia. This is the citation for this recent publication in European Urology, led by Dr. Christopher Sweeney and the ANZUP Trials Group.

Most UroToday viewers and readers will know that the disease space of metastatic castration-sensitive prostate cancer has moved quite quickly from CHAARTED, GETUG, and STAMPEDE data supporting the use of docetaxel just over 5 years ago. We have now had three more agents enter the disease space, and the trials supporting these are highlighted on the edges of this slide. And now we are looking at digging a little further into these studies to better understand which patients really derive the greatest benefit and how we may optimize care.

And so, in doing this, we are operating on the basis of the fact that hormone-sensitive prostate cancer, even when metastatic, is still a very heterogeneous condition. And those with de novo metastatic disease have a particularly poor prognosis, with historical studies suggesting a median overall survival of 3 years or so when treated with ADT monotherapy. However, those who have the metachronous disease, that is the development of metastases after their initial diagnosis with localized disease, having a much better prognosis. And this is particularly true for patients who have a low volume of metastatic disease with a median overall survival of up to 8 years. And so, we know from a subset analysis of the CHAARTED study that the effective docetaxel appears to be differential according to disease volume, with a greater benefit in those with high-volume disease. However, such an effect is not seen, at least so far, with respect to androgen-axis targeting agents like apalutamide, enzalutamide, or abiraterone. And so, in patients with low-volume metachronous disease, we do not have specific data to guide the treatment of these patients, and that was the goal that these authors set out to assess.

And so just to briefly remind you, ENZAMET is a trial with randomization between enzalutamide or a first-generation nonsteroidal anti-androgen as well as ongoing ADT in patients who have the metastatic castration-sensitive disease, and use of docetaxel was allowed, but not mandated in this trial and about half of patients received planned early docetaxel. As you can see here, both overall survival and progression-free survival were significantly improved among the patients who received enzalutamide.

When we look at the forest plot from this original trial, you can see that volume of disease appears to somewhat, although not statistically significantly, modify the benefit of enzalutamide. And so, this was the area that these authors assessed further in the present manuscript. To summarize, the ENZAMET trial included patients with mCSPC who had initiated ADT no more than 12 weeks prior. Patients were 1:1 randomized to enzalutamide versus standard non-steroidal anti-androgen and stratification was performed for randomization according to planned docetaxel use, disease volume, use of bone targeting agents, and comorbidity. The overall endpoint was overall survival.  The secondary endpoints included progression-free survival, clinical progression-free survival, adverse events, and toxicity. This is a schematic of what I've just described.

In this analysis, the authors utilized the interim overall survival analysis at the time when median follow-up was 34 months. The patients of particular interest here were those with the metachronous disease, and this was 312 patients in the overall cohort of whom 83% had had prior local therapy. And within this further subset, the low-volume disease was present in 205 patients of whom 81% had had a local prior therapy.

And so, in this analysis, the authors compared 3-year overall survival rates, as well as the hazard ratio for enzalutamide versus non-steroidal anti-androgen for overall survival according to metachronous disease versus de novo or unknown, and then they further substratified this into those with high-volume disease and low-volume disease. They tested for the interaction of the benefit of enzalutamide according to disease course, that is whether it was metachronous versus de novo. And then, in addition, to further support the findings within the concept of the ENZAMET trial, the authors pooled data from the TITAN trial with these secondary analyses of ENZAMET to look at the outcomes of using androgen-axis targeting in men with the metachronous metastatic hormone-sensitive disease.

At this point in time, I will pass it over to Zach to walk us through the results of the subset analysis of ENZAMET.

Zachary Klaassen: Thanks, Chris. The hazard ratio for overall survival with the addition of enzalutamide in patients with metachronous metastases was 0.56 with a non-statistically significant confidence interval of 0.29 to 1.06. However, when we look at the patients with low-volume disease, the hazard ratio was 0.40 with a 95% confidence interval of 0.16 to 0.97. They also looked at the 3-year overall survival. You can see here in this table that among all patients without enzalutamide, was 83%, which was the same for low-volume patients. However, with enzalutamide, all patients, the 3-year overall survival was 89%, and in low-volume patients was 92%.

This plot looks at the overall survival by metastatic disease status at first diagnosis of prostate cancer and volume of metastases. At the very bottom, you can see here, this is the original ENZAMET publication data, with a hazard ratio of 0.67 favoring enzalutamide at a 95% confidence interval of 0.52 to 0.86, and a differential looking at the 3-year OS benefit of 0.80 for enzalutamide and 0.72 for the non-steroidal control arm.

When we move back up to the top of the table, we can see here, as I mentioned previously, the metachronous cohort, the hazard ratio of 0.56, and the 95% confidence interval of 0.29 to 1.06, and when we look at the high-volume, this is where we see no net benefit, at least in this analysis, for enzalutamide, with a hazard ratio of 0.86 and a 95% confidence interval of 0.33 to 2.22. Again, to highlight, the low-volume metachronous benefit for enzalutamide with a hazard ratio of 0.40 and a 95% confidence interval of 0.16 to 0.97.

The authors then looked at the incorporation in the updated TITAN data. This is over a median 44-month follow-up, and this showed that apalutamide imparted an overall survival benefit in the metachronous metastatic hormone-sensitive group of 144 patients without a breakdown by volume of disease, but in this overall analysis of these 144 patients, a hazard ratio for overall survival was an impressive 0.39 and a 95% confidence interval of 0.22 to 0.69, favoring apalutamide.

They then presented a meta-analysis of these two groups looking at overall survival in men with the metachronous disease treated with AR inhibition. As we've discussed in the last couple of slides, the ENZAMET hazard ratio of 0.56, in the TITAN cohort, 0.39. So, a benefit in TITAN, not a benefit in ENZAMET in terms of the metachronous cohort. However, when this was meta-analyzed, the hazard ratio was significant at 0.46 and a 95% confidence interval of 0.30 to 0.70.

So, several discussion points from this study we've discussed. In this analysis of metachronous metastasis among men with metastatic hormone-sensitive prostate cancer treated with potent androgen receptor inhibition, there was a pooled survival benefit of 54% decreased risk of death. In the ENZAMET trial, this overall survival benefit, which was a 60% decreased risk of death, was also observed among patients with low-volume metastases. The less than clear treatment effect among men with the high-volume metachronous metastatic hormone-sensitive disease is likely secondary to the frequent use of concurrent docetaxel in this subgroup, and this is consistent with the overall results presented in the interim analysis of ENZAMET, in that at this point, there is no clear overall survival benefit for men receiving enzalutamide with concurrent docetaxel.

In conclusion, this updated analysis from TITAN and existing data from ENZAMET in the metastatic hormone-sensitive prostate cancer population demonstrates a clinically meaningful and consistent survival advantage with the addition of enzalutamide or apalutamide in men with the metachronous metastatic hormone-sensitive disease. This also included men with low-volume metachronous metastatic disease. Ultimately, this information can be used to inform guidelines and design of future trials for men with metachronous low-volume metastatic hormone-sensitive prostate cancer, including those being evaluated for metastasis-directed therapy.

Thank you very much and we hope you enjoyed this UroToday Journal Club discussion.