Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. We are today, discussing a recent publication from the STAMPEDE trial entitled, Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: A meta-analysis of primary results from two randomized control phase III trials of the STAMPEDE platform protocol. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. Joining me today is my friend, 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 Lancet led by Dr. Attard and the STAMPEDE investigators. Most UroToday listeners and followers will know that in prostate cancer, most men who eventually die of their disease are diagnosed initially with non-metastatic disease, and in particular, men who have initial diagnosis of high-risk non-metastatic disease have higher rates of prostate cancer-specific mortality. This cohort is highlighted in the NCCN guidelines to the right. Treatment with radiotherapy and androgen deprivation is a standard treatment choice, as well as a surgical intervention. In contrast to local therapy, in patients with metastatic disease, treatment intensification with the use of chemotherapy or novel hormonal agents has now been proven to prolong life and provide other symptomatic benefits, making it the standard of care. However, no data thus far have demonstrated a clear benefit for this approach with treatment intensification in patients with non-metastatic disease.

You can see here, an overview of a few of the arms of the STAMPEDE platform, and today we're really focusing on that standard of care as the comparator. Two key arms here, looking at standard of care plus abiraterone and standard of care plus abiraterone and enzalutamide, and in each case, the treatment intensification was given for 2 years. You see that these trials are reporting out both M1 and M0 patient populations.

As the figure alluded to, this is actually two separate trials. One comparing the intensification with abiraterone to standard of care, and one comparing intensification using both abiraterone and enzalutamide to standard of care. Outcomes for patients with metastatic disease in these studies have been reported already, and notably, the combined arm demonstrated no additional benefit over abiraterone alone as treatment intensification. On the basis of these data, the trial management group made a number of decisions.

The first of these was to formally separate the metastatic and non-metastatic cohorts within these two trials and conduct the analyses separately. Subsequently, on the basis of the fact that no additional benefit was seen with the addition of enzalutamide, the decision was made to combine both the abiraterone intensification trial with the abiraterone and enzalutamide intensification trial. Subsequently, on the basis of event rates for the non-metastatic cohort, there was the decision to change the primary outcome from overall survival to metastasis-free survival. And again, to increase event rates, the decision was made to extend follow up in this subset for a longer duration than in the metastatic group. This plan and these changes to the analytic approach were pre-specified and published.

So you can see here, that in keeping with the remainder of the STAMPEDE trial, the key inclusion criteria were a diagnosis of prostate adenocarcinoma, and in this analysis, there had to be no evidence of metastatic disease based on conventional imaging, patients had to have a performance status of 0-2, and to enrich for high-risk characteristics, they either had to have node-positive disease or among those who were node-negative, have high-risk features including a T3 or T4 stage, PSA 40, or higher or Gleason score of 8-10. And in patients who were not newly diagnosed, but were relapsing, they had to have high-risk characteristics. Notably, in this analysis, patients were excluded if they had clinically significant cardiovascular disease, which included severe angina, recent myocardial infarction, or a history of cardiac failure.

In these analyses, there was a 1:1 randomization between a standard of care or the combination therapy of standard of care with treatment intensification. Stratification was performed according to a number of patient and treatment characteristics, including the treating center, patient age, planned use of prostate radiotherapy, nodal involvement, performance status, the type of ADT used, and the concurrent use of aspirin or NSAIDs. Patients were treated in the standard of care, with 3 years of androgen deprivation starting no more than 12 weeks before their randomization. Prostate-directed radiotherapy was mandated in all N0 patients and recommended for those who are N1. Treatment with abiraterone, corticosteroid, and enzalutamide was administered, keeping with the standard doses of these medications.

Patients were followed clinical assessment, including PSA testing and ascertainment of adverse events, initially every 6 weeks for the first 6 months, and every 12 weeks until the end of year two, then every 6 months until year five, and then annually thereafter. Imaging was performed according to local guidelines and not mandated in the study protocol. The primary outcome was metastasis-free survival, and the authors additionally assessed the number of secondary outcomes, including overall survival, prostate cancer-specific survival, failure-free survival, progression-free survival, and toxicity and adverse events.

Analytically, each trial was designed and powered separately. And while each trial met their overall sample size target, there was no prespecified subset sample size of patients with nonmetastatic disease. And so a post-hoc sample size calculation was performed showing that 315 MFS events would be required to show a 15% improvement of a base MFS rate of 70% at 5.5 years in the standard of care group, with a power of 90% and a one-sided alpha of 1.25. And this alpha was used on the basis of prior reports from these trials. Fixed effects individual patient data meta-analyses were used to pool hazard ratios across the two trials, and each trial analysis itself used Cox proportional hazards models with an adjustment for the stratification factors. There was additionally pre-specified subgroup analyses that were performed to look for evidence of effect modification. At this point in time, I'm going to hand it over to Zach to walk us through the results of this interesting analysis of the STAMPEDE trial.

Zachary Klaassen: Thanks so much, Chris. You can see here, this is the study profile for this analysis. You can see at the top, there was 5,488 patients randomly assigned a treatment, and we'll focus on the left side of the figure. This is the non-metastatic patients. There was 914 non-metastatic patients allocated to the abiraterone trial, and 1060 non-metastatic patients allocated to abiraterone or enzalutamide. Going below that, you can see here, there was 455 allocated to the control group in the abiraterone trial, 459 allocated to the combination therapy. In the abiraterone plus enzalutamide trial, there was 533 allocated to the control group and 527 allocated to the combination group.

This is the baseline characteristics table one for this study. On the right side, you can see this is the combination and therapy in abiraterone and combination therapy in abiraterone and enzalutamide. And to the left of this is the control groups for these two trials. So just looking at some of the highlights of these characteristics, you can see that the median age is well-balanced in the late sixties, the PSA ranged from about 32-40 across these trials. In patients newly diagnosed, there was about a 50/50, slightly more for N0 versus N1, and in patients that relapsed the N1 rate was about 1-2%. For this trial, the majority of these patients were excellent performance status, with a WHO performance status of 0 in more than 70-80% of these patients. In terms of the time from diagnosis to randomization, roughly about 7 years across these trials, with the majority of patients having a Gleason 8-10 score. In terms of the T stage at randomization, overwhelming majority were T3 to T4, more than 90%, and in terms of local radiotherapy as the standard of care for these patients, also the majority of these patients at more than 80%.

This is the primary outcome metastasis-free survival. You can see the curve on the right as well as the forest plot for the trials on the bottom. And you can see in standard of care being red and standard of care plus abiraterone and prednisolone, with or without enzalutamide in blue, that there was an early and consistent splitting of the curves favoring standard of care plus Abi, with or without enzalutamide, with a hazard ratio of 0.53 and a 95% confidence interval of 0.44-0.64.

This is the forest plot of treatment effect on metastasis-free survival for the baseline randomization stratification factors. And you can see as an overview of this figure, that the hazard ratios to the left favor combination therapy, which is essentially all of these factors, except for patients who had a performance status of 1-2, who did not have a significant benefit. But the other factors, including nodal status, age, NSAID or aspirin use, and radiotherapy planned standard of care, all favored the combination therapy for metastasis-free survival.

This is the Kaplan-Meier curve looking at overall survival, a similar curve to the MFS curve. And you can see, again, there's an early and extensive separation of these curves, particularly around 36 months after randomization, with a benefit for standard of care plus Abi, with or without enzalutamide, a hazard ratio of 0.60 and a 95% confidence interval of 0.48-0.73. Again, this is the Kaplan-Meier estimate of prostate cancer-specific mortality, looking very similar to the overall survival curves, with a split at about 36 months and a favored hazard ratio for standing a care plus Abi, with or without enzalutamide, of 0.49 and a 95% confidence interval of 0.37-0.65.

This curve looks at progression-free survival. An impressive early end extensive separation of the curves favoring, again, the combination therapy, with a hazard ratio of 0.44 and 95% confidence interval of 0.36-0.54. And finally, this is the Kaplan-Meier estimate of failure-free survival, with the combination therapy in blue favoring standard of care plus Abi, with or without enzalutamide, and a hazard ratio of 0.39 and a 95% confidence interval of 0.33-0.47.

This is the adverse events in the safety population. We'll focus on the grade 3 adverse events. You can see the control, again, on the left side of this graph and the combination arms on the right side. Not surprisingly, the combination therapy with abiraterone or enzalutamide had more grade 3 adverse events, particularly for hypertension, 14% versus 5% in the Abi arm and 2% and 1% in the control arms. Another point of interest is fatigue. Grade 3 fatigue in 10% of patients with Abi and Enza, compared to 2% in the abiraterone only and 2% and 1% in the control arms. Otherwise, these adverse events were relatively comparable across these four groups.

Several discussion points from this trial from STAMPEDE. In this primary analysis of high-risk non-metastatic patients initiating ADT, the magnitude of the beneficial effect from combining abiraterone-based treatment is notably larger than was estimated for immature data following a shorter duration of follow up. Importantly, this was also consistent across the primary endpoints and all secondary efficacy outcome measures, including overall survival. This study is the first to show a large treatment benefit for combination of fixed duration second-generation hormone therapy with ADT for non-metastatic prostate cancer.

However, the authors noted several important questions that remain to be addressed, including shorter durations of ADT could be as effective and longer duration of ADT may be even more effective, hence treatment duration could be of consideration for further testing. Secondly, this study did not include data adding an androgen receptor antagonist alone to ADT and radiotherapy, nor for the combination therapy of men undergoing prostatectomy.

So in conclusion, men with high-risk non-metastatic prostate cancer who receive ADT with combination therapy have significantly better metastasis-free and overall survival than those who receive ADT alone. Of note, 2 years of abiraterone and prednisone added to ADT and, if indicated, radiotherapy, should be considered a new standard treatment for non-metastatic prostate cancer with high-risk features. Thank you very much for your attention and we hope you enjoyed this UroToday Journal Club discussing the latest data from the STAMPEDE platform.