Christopher Wallis: Hello and thank you for joining us for this UroToday Journal Club. We're discussing a recent publication from the ENZAMET study, entitled, Health Related Quality of Life in Metastatic, Hormone-Sensitive Prostate Cancer: ENZAMET (ANZUP 1304), an International, Randomized Phase III Led by ANZUP.

I'm Chris Wallis, an 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.

This is a citation for this recent publication in the Journal of Clinical Oncology led by Dr. Stockler and the team leading ENZAMET.

As you can see highlighted here, there has been rapid progress in the field of metastatic castrate sensitive prostate cancer over the last five years or so. ENZAMET was one of the key trials leading to FDA approval of enzalutamide in December 2019. And this has all been on the basis of improvements in overall survival.

And so we see here from the primary ENZAMET publication that the addition of enzalutamide to standard of care, which importantly here included a nonsteroidal antiandrogen, improved both overall survival and even more profoundly, PSA progression-free survival.

In this analysis, moving from these oncologic endpoints, the study investigators sought to determine the effective enzalutamide on health related quality of life from the time of randomization into a clinical progression. And this was a key pre-specified secondary analysis of the ENZAMET trial. And the authors performed two different key comparisons of health related quality of life. First, they assessed changes, longitudinally from baseline to clinical progression and then they defined an important and novel metric, called deterioration-free survival. And this accounts for both changes in quality of life and in oncologic outcomes.

To highlight the methods here briefly of the ENZAMET trial, which have been published in the past, this study enrolled men with metastatic castration sensitive prostate cancer on the basis of conventional imaging, who started androgen deprivation therapy no more than 12 weeks prior to enrollment. Patients were then randomized in a one to one fashion to receive enzalutamide at standard doses or a conventional first generation nonsteroidal antiandrogen. All men received a continuous ongoing androgen deprivation and early use of docetaxel was allowed at the patient and physician discretion. And stratification of the randomization process was performed according to the use of docetaxel, disease volume, use of anti-resorptive agents and patient comorbidity.

For this analysis, the important outcome of interest was health related quality of life. This was assessed at baseline, week four, week 12 and then every 12 weeks thereafter. The authors used a number of tools, including the EORTC, a core quality of life metric as a general measure, the EORTC QLM-PR25, is a disease specific prostate cancer metric. When we interpret these results, it's important to distinguish between scores for function, in which case zero is the worst and 100 is the best, and scores assessing symptoms where zero is the best and 100 is the worst.

In terms of statistical analysis, I alluded to it previously, but the authors used two prespecified ways of assessing health related quality of life. First, they summarized and compared health related quality of life longitudinally during the time from randomization until disease progression. And to do so, they used repeated measures models to calculate predicted group means and 95% confidence intervals is using Wald tests. And Zach will highlight these as we review the results. And second, they looked at this novel metric looking at deterioration free survival. And this was a comparison of the time to first deterioration defined either as a clinically important worsening in health related the quality of life, which they defined as a change of more than 10 points in a given domain or evidence of a clinical progression. And in keeping with any time to event endpoint, they used Kaplan Meier technique, log rank tests and Cox proportional hazard models to compare results between those randomized to enzalutamide and conventional nonsteroidal antiandrogens.

Importantly, the authors further performed post hoc subgroup analyses to assess whether baseline characteristics modified the effect of enzalutamide on health related quality of life. And they did this by adding an interaction term between these two variables into their model and all analyses performed here, included patients who had at least an assessment of health related quality of life at baseline and one subsequent assessment.

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

Zachary Klaassen: Thanks, Chris. This is table one, looking at baseline characteristics for randomly assigned treatment. You can see enzalutamide on the right and control group of on the left and these are well balanced across these specific characteristics. Looking at the median age, roughly in the late sixties for both groups. As this is an ANZUP trial, not surprisingly, majority of patients, more than 50% were from Australia. There was planned use of early docetaxel in roughly half of these patients with roughly half of these patients also having high volume disease. Looking at the M stage of diagnosis, most of these patients, almost three quarters were M1 with synchronous de novo metastatic disease and majority of these patients, more than 50%, had Gleason 8 to 10 disease. Also, if you look at the ECOG status, the majority of these patients were high functioning with an ECOG 0, of just under three quarters of the patients and roughly 11 to 12% of these patients having visceral metastases. Of note, 14 to 16% of these patients had docetaxel treatment before the randomization.

This table looks at baseline health related quality of life scores by the randomly assigned treatment. And just to sort of summarize this, there was essentially a completely comparable baseline quality of life scores across all of these domains between the enzalutamide and control group. And this includes the functioning status, overall health, quality of life, fatigue, nausea, pain, dyspnea, et cetera. No difference at baseline between these two groups.

This table looks at the clinical correlates of baseline overall health and quality of life. And you can see here that the blue boxes are the significant factors. Patients that had ECOG status of 0, had improved health related quality of life, as well as those that were M0 and patients that had volume of disease stratified as high had a worse quality of life. And there was no difference amongst the groups between comorbidity score, planned use of early docetaxel or age.

This is sort of a busy figure so I've highlighted the important points in the blue boxes. This is the health related quality life scores over time by randomly assigned treatment for the EORTC core quality of life questionnaire and the blue boxes highlight the factors that were noted to be improved in the control group compared to the enzalutamide group. You can see the functioning metrics, including cognitive, social, physical were all improved in the control group, as well as less fatigue, less dyspnea and less appetite loss. Of note, the overall health quality of life was no different between the enzalutamide and the control group.

This is a similar looking figure, looking at health related quality life scores over time by randomly assigned treatment for the EORTC QLM-PR25 metric. And you can see that the only difference favoring control versus enzalutamide was in urinary symptoms. Otherwise, there was no difference in bowel, ADT, sexual activity or sexual functioning status.

This figure looks at the early, which is defined as less than 12 weeks, deteriorations in health related quality life. On the left side of the figure is by randomly assigned treatment for the whole group and on the right is for physician assigned plan for early docetaxel. And so a clinically significant difference of more than 10% was deemed by the authors as being relevant. And you can see that the only metric that had this was fatigue, with looking at enzalutamide having more fatigue versus the control group, with slight differences in physical functioning, overall health, quality of life and cognitive functioning but less than this 10% difference. And these results on the right sort of mirror the randomly assigned treatment for the whole group. And there's really no difference based on planned docetaxel. Again, we see that the fatigue is more than 10% favoring the control group over enzalutamide.

This is the Kaplan Meier curve looking at deterioration-free survival, looking specifically at physical functioning. And you can see here, the next several slides will look very similar to this one, looking at event free differences at 36 months. And you can see here that there was a difference favoring enzalutamide at this 36 months. No difference in the first 12 months here and then when we get to 36 months, we see a statistically significant difference in the event rate for physical functioning favoring enzalutamide.

Again, this is looking at overall health quality life. And again, at 36 months, favoring enzalutamide with event free rate of 17% in the control group and 31% in the ENZAMET group.

Similarly, for cognitive functioning. Once we get out to 36 months, favoring enzalutamide with an event rate of 20% in the control group and 31% in the enzalutamide group.

And finally looking at fatigue, this is the one metric that was not statistically favoring enzalutamide. Again, looking at 36 months with a P value of 0.16, looking at the event rate.

Several discussion points from this enzalutamide health related quality of life study. Treatment with enzalutamide was associated with worse self-rating of fatigue, physical functioning and cognitive function, but not with overall health quality of life. Differences between the randomly assigned treatment groups and their upper 95% confidence limits were below the pre-specified threshold for a minimum clinical important difference of 10 points. These findings add to the evidence about potent inhibitors of androgen signaling in hormone sensitive prostate cancer with enzalutamide having little effect on overall health quality of life in ENZAMET, similar to the findings from ARCHES trial of enzalutamide, the TITAN trial of apalutamide and the LATITUDE trial of abiraterone. However, unlike ARCHES, TITAN and LATITUDE, modest detrimental effects of enzalutamide on fatigue, physical function and self-rated cognitive function that occurred early, were of clinically of important magnitude in a minority of patients and did not worsen over time, especially looking at these 36 month analyses.

In conclusion, the addition of early enzalutamide to standard of care, including testosterone suppression with or without early docetaxel, improved overall survival during three years of follow up with modest impairments in fatigue, physical function and self-rated cognitive function, but not overall health quality of life in men recently diagnosed metastatic hormone sensitive prostate cancer.

These impairments did not worsen over time and better disease control, improved deterioration-free survival rates at three years because the modest detrimental effects on the aspects of health related quality of life were outweighed by subsequent delays in disease progression. In summary, longer follow up will reveal the effects of enzalutamide beyond three years of analysis.

Thank you very much and we hope we enjoyed this UroToday Journal Club discussion, looking at the ENZAMET quality of life recently published study in the Journal of Clinical Oncology.