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Rashid Sayyid: Hello everyone, I'm Rashid Sayyid and I'm a Urologic Oncology Fellow at the University of Toronto, and along with Zach Klaassen, Assistant Professor and Program Director at Augusta University, we'll be presenting the latest update of ENZAMET, which was recently published in Lancet Oncology. So as we know, metastatic hormone sensitive prostate cancer does represent the heterogeneous patient population with median overall survivals, and these are with testosterone suppression alone, varying for different subsets of this group. So if we look at patients with synchronous high-volume disease, synchronous meaning de novo disease, so they present with metastases at the time of diagnosis, the median overall survival is about three years. And we see in patients with synchronous low-volume or patients with metachronous high-volume, metachronous meaning recurrent, meaning they did not present initially metastases, the median overall survival is about five years. And then we see that the median overall survival is best in patients with metachronous low-volume disease with a median OS of about eight years.

Luckily, there are numerous agents with OS benefits in the first line mHSPC setting, and these include doublet therapy options with the addition of docetaxel, enzalutamide, apalutamide and abiraterone due to testosterone suppression. But we also have, over the last 18 months, two trials, the PEACE-1 and ARASENS, that show that the addition of abiraterone or darolutamide to docetaxel and testosterone suppression improves overall survival. The good thing is we note consistent benefits across prognostic subgroups for abiraterone, enzalutamide, or apalutamide. However, we've seen inconsistent benefits for docetaxel across these subgroups. And with the latest evidence coming from the 2022 STOPCAP M1 Collaboration that showed the greatest OS benefit for docetaxel addition in high volume disease, we see about an eight to 11% five-year OS benefit. Conversely, we don't see a significant benefit in the lowest risk group of metachronous low-volume disease where in fact they had a worse overall survival with a docetaxel addition.

Luckily, ENZAMET stratified participants by CHAARTED high-volume versus low-volume a priori, and also prospectively captured the timing of metastatic presentation, meaning synchronous versus metachronous, and so by having these two variables this allows four stratification of the patients into four subgroups. Again, the synchronous high-volume or low-volume and the metachronous high-volume or low-volume. Also, a unique feature of the study design is that it allowed for concurrent early docetaxel use, which was at the patient physician discretion. And again, this allows for further stratification of these four subgroups by the concurrent docetaxel use, yes versus no. And so in 2019 we saw the first report of ENZAMET where they had the planned first interim analysis where about half of the planned deaths were observed and we see that the addition of early enzalutamide as opposed to a weaker anti-androgen was associated with a significant improvement in overall survival with a hazard ratio of .67.

However, when we look at the subgroup analyses, there was no benefit to enzalutamide addition specifically for the patients who were receiving early docetaxel. As such, the study objective of this report was to, again, report the planned primary OS analysis after 470 deaths had occurred, about 235 had occurred by 2019, and then also define the benefit of enzalutamide by the prognostic subgroups and by receipt of concurrent docetaxel. Just summarizing the study design and the participant characteristics, we know that ENZAMET is an open label randomized phase three trial across Australia, Canada, Ireland, New Zealand, UK and the USA. Patients had mHSPC per conventional imaging, meaning CT or a bone scan. Patients were randomized one to one to either enzalutamide 160 milligrams daily plus testosterone suppression, which could have been surgical or medical castration, or they received a weaker non-steroidal antiandrogen meaning bicalutamide, nilutamide or flutamide with testosterone suppression.

And the randomization was stratified by disease volume, planned use of concurrent docetaxel, planned use of bone antiresorptive therapy or the comorbidities and study site. Again, this stratification is planned to allow for a relatively equal distribution of these characteristics across the two arms and minimize any confounders. Of note, exclusion criteria included the prior seizure history and a condition predisposing patients to a seizure, and that's because we know that enzalutamide increases the risk of such events in these patients. Again, testosterone suppression was allowed up to 12 weeks prior to randomization and also allowed in the adjuvant setting, for example, if received with concurrent radiation, and this was allowed up to 24 months as long as 12 months had elapsed prior to randomization. As we mentioned before, concurrent docetaxel 75 milligrams per meter squared was allowed for six cycles every three weeks, again based on patient physician discretion.

And the reason that this was permitted, was during the study design the CHAARTED results were published and as such the authors at that time created a modification in the protocol and incorporated this as a stratification factor after the initial 88 participants had been accrued. Patients were allowed to receive up to two cycles of docetaxel prior to randomization. Blood tests, meaning electrolytes, liver function tests and PSA, along with adverse events were assessed over three months and then repeat imaging in the form of CT and bone scan were done at the time of PSA or clinical progression or per clinician discretion. The primary outcome was overall survival and this was defined from the time of randomization. Notable secondary outcomes include PSA progression-free survival, clinical progression-free survival, the safety outcomes, the health-related quality of life and cost utility outcomes, which were reported in separate studies, as well as prostate cancer specific survival which was a post-hoc exploratory endpoint.

With regards to the sample size, the plan was for 1,100 participants along with 470 deaths, would've given greater than 80% power to detect a hazard ratio of 0.75 at a type one error of 0.05, assuming a three-year OS of 65% in control arm. Again, they applied measures to minimize type one inflation with the O'Brien-Fleming air spending function. And as with most of these studies, the intent to treat principle was followed. Survival analyses or data were summarized using Kaplan Meler curves and Cox proportional hazards regression modeling to estimate the hazard ratios. And the tests of interactions were used to evaluate the treatment heterogeneity across the subgroups. They also performed subgroup analyses for OS, PSA, progression-free survival and clinical progression-free survival. The main ones were by whether the patient had visceral metastasis, yes versus no, whether they had metachronous versus synchronous disease, the disease volume low versus high, and whether docetaxel was planned early, yes versus no.

Also, a point of emphasis for them was conducting a two-way subgroup analysis for docetaxel use and disease volume. And so this allows for the creation of four groups. So docetaxel, yes, no, disease volume, yes, no, that creates four subgroups. They further augmented that with a three-way subgroup analysis where they incorporated as well the timing of metastasis, meaning synchronous versus metachronous, and this allowed for up to eight subgroups. And at this point I'll turn over the presentation to Zach.

Zach Klaassen: Thanks so much, Rashid. So this is the trial profile for ENZAMET and this is similar to the original publication, so we'll go over this for completing the sake. For this trial there was 2,253 men that started testosterone suppression and assessed for eligibility. Ultimately 1,125 men were randomly assigned including 562 to these non-steroidal antiandrogen arm of the trial, of which 558 men received at least one dose of treatment as well as 563 that were randomized to enzalutamide of which all these patients received at least one dose of treatment. And these patients were the ones that made up the intention to treat analysis for this trial. Looking at the baseline characteristics, we can see that for enzalutamide and the control group, the median age was 69 years. The majority of these patients, more than 50%, were randomized in Australia. The second most common area randomization was Canada at nearly 20%.

We can see that the majority of these patients, almost three quarters, had an excellent performance status of ECOG-0. With regards to the planned use of early docetaxel, 44% for the control group, 45% for enzalutamide, actual use of early docetaxel was 43% for the control group and 43% for enzalutamide. For volume of disease, roughly a 50/50 split between high and low disease. As you can see at the bottom of this table, visceral metastases, 12% for each of these groups. Liver metastases, 2%. And for metastatic status at first diagnosis, roughly 60% of these patients had M1 disease at the time of diagnosis. So this is the primary outcome of overall survival. So at a median follow-up of 68 months, we see that the median was not reached in either the control group or the enzalutamide group, with enzalutamide in green and control group in blue.

However, this did favor enzalutamide with a hazard ratio of 0.70 and a 95% confidence interval of 0.58 to 0.84. And we do see an early and consistent splitting of the curves, particularly after 12 months of follow-up. This is looking at PSA progression-free survival. Again, a clear benefit for enzalutamide. The median PSA progression-free survival for the control group was 22 months compared to 68 months for enzalutamide with a hazard ratio of 0.44 and a 95% confidence interval of 0.38 to 0.52. This looks at clinical progression-free survival, another clear benefit for enzalutamide, the median clinical PFS for the control group was 25 months compared to 81 months for enzalutamide with a hazard ratio of 0.45 and a 95% confidence interval of 0.39 to 0.53.

The next several slides we'll dig into some of the nuances of the overall survival and look at some of the subgroups as well as some additional Kaplan Meler curve. So this is a pre-specified subgroup analysis for overall survival and I've highlighted the top in the red. These are some of the key subgroups for this analysis. So the first one is volume of disease and we see that regardless of low or high volume disease the enzalutamide group did have a statistically significant benefit compared to the control group. However, when we look at planned early docetaxel, for those that did have planned early docetaxel there was no statistically significant benefit for enzalutamide with a hazard ratio of 0.82, 95% confidence interval of 0.63 to 1.06. But for those that did not have planned early docetaxel there was a significant benefit for enzalutamide with a hazard ratio of 0.60 and a 95% confidence interval of 0.47 to 0.78.

Again, looking at the remaining subgroups in this four plot, we see that there's some additional points of interest. Regardless of Gleason score there was a benefit for enzalutamide. Regardless of ECOG performance status there was a benefit for enzalutamide. Of note, one subgroup that did not have benefit was visceral metastases. However, this was a small number of patients in this trial. This looks at the overall survival by disease volume and docetaxel among all patients in the trial, so when we look at this on the left, this is volume of disease high versus low, and this is for patients that had planned docetaxel as part of the trial. And we can see that for both of these there was no statistically significant benefit for enzalutamide. However, when we look at those patients that had high versus low disease that did not have planned docetaxel, there was a statistically significant benefit for enzalutamide in both the high and low volume patients.

Next several slides, we'll look at some additional Kaplan Meler analysis, this is OS by subgroup for synchronous metastatic disease selected to receive docetaxel. And we see that in this subgroup analysis there was a statistically significant benefit for enzalutamide with a hazard ratio of 0.73 and a 95% confidence interval of 0.55 to 0.99. However, when we look at the OS by subgroup from metachronous disease for those that were selected for docetaxel, there was no significant benefit for enzalutamide in this group of those that had metachronous disease that were planned for docetaxel use. This 4-plot looks at the subgroups of synchronous metastatic disease selected to receive docetaxel, and we can see here that for these patients that had low-volume disease there was no statistically significant benefit as well as no statistically significant benefit for high-volume disease. We can see particularly for those with low-volume disease, this was a small sample in this trial, although the hazard ratio was 0.57 so I think there may be some potential benefit here, but at least in this trial with the lower sample size this was not statistically significant.

With regards to adverse events between these two groups, we have the enzalutamide group on the right and the control group on the left, and we'll focus on the grade three adverse events for this discussion. If we go right to the bottom, any grade three adverse event in the control group was 37% and in the enzalutamide group was 58%. Generally no difference between grade four and grade five adverse events. With regards to adverse events of specific interest, we see that fatigue, not surprisingly, was higher in the enzalutamide group for grade three, 6% versus 1% in the control group. We do see slightly higher grade three adverse events for fractures in the enzalutamide group at 4% versus 1% in the control group. And generally comparable adverse events throughout the rest of these subgroups was slightly increased for hypertension at 10% versus 5% for the control group.

So by way of discussion with a median follow-up of more than five years, the ENZAMET trial found that enzalutamide plus standard of care had sustained improvement of overall survival, PSA progression-free survival and clinical progression-free survival versus non-steroidal antiandrogen plus standard of care for metastatic hormone sensitive prostate cancer. However, as we discussed in the previous slides, the magnitude of effect of enzalutamide on overall survival varied across subgroups and with the use of concurrent docetaxel. ENZAMET was not designed to measure benefit of adding docetaxel to testosterone suppression plus enzalutamide. However, assessing these patients does offer several important insights. First, those with the worse prognosis most likely to benefit from docetaxel plus testosterone suppression are also likely to most likely benefit from docetaxel plus testosterone suppression plus enzalutamide.

Secondly, docetaxel plus testosterone suppression plus enzalutamide improved overall survival, as we showed previously with a hazard ratio of 0.73, in men with synchronous metastasis. And this is similar to the addition of abiraterone in PEACE-1 and similar to the addition of darolutamide in ARASENS. So in conclusion, patients with metastatic hormone sensitive prostate cancer of any volume should be offered optimal hormonal therapy plus a more effective androgen receptor inhibitor such as enzalutamide. Until further data are available, a joint patient and physician decision is needed to individualize treatment with the addition of primary prostate radiotherapy or docetaxel to this regimen. Thank you very much for your attention. We hope you enjoyed this UroToday Journal Club of the recently published ENZAMET updated analysis in Lancet Oncology.