Christopher Wallis: Hello, and thank you for joining us for UroToday Journal Club discussion. Today, we're talking about a recent publication entitled abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: five-year follow-up results from the STAMPEDE Randomized Trial. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto, and 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 the International Journal of Cancer led by Dr. James. As you can see highlighted here, there have been numerous approvals of novel agents in metastatic castrate-sensitive disease, beginning with the use of docetaxel back in 2015 and followed by abiraterone, apalutamide and enzalutamide. Recently, we've seen data regarding the use of triple therapy in this disease space, but long-term data's really important to help us understand outcomes for these patients as we use these agents earlier and earlier in the disease process.

With respect to abiraterone in this disease space, LATITUDE was restricted to a high-risk subset of men and showed a benefit with a median overall survival of 52 months. STAMPEDE, in contrast, enrolled a much more heterogeneous cohort, including both the M0 and M1 patients and had their primary analysis planned at three years following enrollment. At that time, they decided to present data stratified by M0 and M1 patients, and we've recently seen results in the non-metastatic space from Dr. Attard published here and presented at ESMO, which demonstrated an overall survival benefit with the addition of abiraterone for patients with non-metastatic disease. We will recall from the first STAMPEDE analysis there was no benefit in this pooled cohort, and now we're looking at long-term followup of the metastatic subset.

So this here to highlight is a subset of the STAMPEDE trial just emphasizing this standard of care with abiraterone arm, which was reported out initially in 2017, and now the M1 alone subset is being reanalyzed and reported with long-term data. So these patients included those newly diagnosed with prostate cancer with either metastatic disease at the time of initial diagnosis or a disease relapse following initial local therapy, was said to be confirmed on conventional imaging with CT and bone scan. Patients had to to have planned long-term ADT that was started within 12 weeks of randomization and adequate performance status, according to the WHO criteria. Patients were excluded if they had clinically significant cardiovascular disease, which included severe angina, recent myocardial infarction or a history of cardiac failure.

Patients were randomized in a one-to-one fashion to either standard of care or combination therapy. Stratification was performed for randomization according to a number of characteristics, including the hospital center, age, nodal involvement, performance status, planned standard of care and use of aspirin. Standard of care here predominantly included lifelong ADT, and combination therapy was ADT plus abiraterone with prednisone. This was continued until progression or the start of second-line therapy with dose modifications allowed.

Assessment included PSA testing and clinical evaluation. In the first six months, this was performed every six weeks, and then it was performed every 12 weeks until year two, every six months until year five and then annually thereafter. Follow-up imaging was performed according to local guidelines and was not standardized as part of the protocol.

In terms of risk group, patients were evaluated with CT and bone scan at baseline with a centralized review from two independent co-authors with 10% independent review by radiologists. Patients were classified according to the LATITUDE criteria, which to highlight, define patients as high risk if they have two or more of the following criteria: Three or more bone metastases, visceral metastases, a Gleason score of eight or greater.

The primary outcome here is overall survival. Secondary outcomes include failure-free survival, progression-free survival, metastatic progression-free survival, skeletal-related events, disease-specific survival, therapy for progression, as well as toxicity and adverse events. All outcomes were analyzed according to the intention to treat principle, and time to event outcomes are assessed with stratified log-rank testing and Cox proportional hazards models. The authors further performed a sensitivity analyses to exclude patients with uncontrolled hypertension to further narrow the eligible population of patients to receive abiraterone.

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

Zachary Klaassen: Thank you, Chris. This is the CONSORT Diagram for the STAMPEDE trial, and you can see that here that there was 2,752 patients that joined STAMPEDE while abiraterone comparison was open to recruitment. Ultimately, there was 1,003 patients that had metastatic disease at randomization, including 502 that were allocated to standard of care and 501 that were allocated to standard of care plus abiraterone.

This is the baseline characteristics for this study. You can see here is the standard of care plus abiraterone. To the left of that is standard of care alone. Median age well balanced, 67 years between each group. Majority of these patients in each group were newly diagnosed metastatic prostate cancer, and a medium PSA, again, well balanced, nearly 100 in each of these groups. In terms of low-risk and high-risk metastatic disease, also well balanced, just over 40% in each group per arm. With regards to site of metastases, nearly 90% of these patients had bone metastases, about 30% of them had distant lymph nodes and roughly about 6 to 7% had visceral metastases as well.

This is the primary and secondary outcome measures for the study. We can see here just to sort of summarize, I've highlighted with asterisks these clinically significant and statistically significant hazard ratios. And these all favor the standard of care plus abiraterone. So we see here overall survival hazard ratio of 0.6, 95% confidence interval of 0.5 to 0.71, failure-free survival 0.34, 95% confidence interval of 0.29 to 0.40, and again, PFS significant hazard ratio of 0.58, metastatic progression-free survival 0.60, skeletal-related events 0.56, and disease-specific survival 0.49.

Looking at this from a Kaplan-Meier standpoint, we see again overall survival by treatment allocation with a standard of care plus abiraterone arm in red and the standard of care arm in blue, which will be the theme for the following figures. We see here that the standard of care plus abiraterone arm had a hazard ratio of 0.6 and a 95 confidence interval of 0.50 to 0.71. Similarly, as we mentioned in the table before, failure-free survival, a wide and consistent splitting of the curves with a hazard ratio statistically significant of 0.34.

The authors then looked at the primary and secondary outcomes by metastatic disease risk group using the LATITUDE criteria. This specifically is the low-risk group. Again, all of these group analyses favor the standard of care plus abiraterone group. We can see here a hazard ratio of 0.54 for overall survival in the low-risk group, 0.32 for failure-free survival, 0.55 for progression-free survival, 0.52 for metastatic progression-free survival, 0.47 for skeletal- related events, and 0.36 for disease-specific survival.

Again, this is looking at the high-risk criteria. And not to sound like a broken record, but again, favoring the standard of care plus abiraterone group for all of these high risk patients with regards to overall survival, failure-free survival, progression-free survival, metastatic progression-free survival, skeletal-related events and disease-specific survival.

These are the Kaplan-Meier curves for overall survival by treatment allocation among the high-risk patients. We see another strong association for abiraterone with a hazard ratio of 0.54 and a 95% confidence interval of 0.43 to 0.69. Importantly, in the low-risk metastatic disease patients, again, favoring abiraterone plus standard of care with a hazard ratio of 0.50 and a 95% confidence interval of 0.41 to 0.76.

In terms of discussion, the authors put together this very nice combined analysis from STAMPEDE and LATITUDE, which we'll walk through several important points here. With regards to LATITUDE, which is at the top of this table, the first results in 2017 in the high-risk M1 group had a hazard ratio of 0.62 with updated results showing consistent benefit for abiraterone with a hazard ratio of 0.62.

If we jump down here to the STAMPEDE abiraterone comparison, the subset of M1 any risk, the first results published in 2017, hazard ratio of 0.61. And with the updated results, we see a very strong consistent benefit for any-risk M1 disease with a hazard ratio of 0.60. Looking at the M1 high-risk patients, the first results published in 2019, hazard ratio of 0.54 with consistent hazard ratio again presented in this paper of 0.54. So meta-analyzing these data from these studies, the combined metastatic any-risk patients between STAMPEDE and LATITUDE, a significant hazard ratio favoring abiraterone at 0.63, 95% confidence interval of 0.50 to 0.71. And for high-risk patients, again, abiraterone benefit with a hazard ratio of 0.62 and a 95% confidence interval of 0.54 to 0.71.

So furthermore, this updated followup with the STAMPEDE abiraterone comparison demonstrated that the effects reported previously were robust. With 57% of patients now deceased and a median followup of more than six years, these results are unlikely to change meaningfully with any further followup. Importantly, there was no evidence of difference in effect size when the patients were separated by metastatic disease risk group using the system defined by the LATITUDE trial. This is also important because in many regions the indication and reimbursement for abiraterone in this indication is restricted to only LATITUDE high-risk patients. These long-term results are very similar to those observed with both apalutamide and enzalutamide trials with similar eligibility criteria to the metastatic population of STAMPEDE.

In conclusion, this extended analysis further reinforces the body of data on the substantial benefits of upfront targeting of the androgen receptor pathway using abiraterone acetate in all men with metastatic hormone-sensitive prostate cancer, irrespective of metastatic disease risk group. A sustained and substantial improvement in OS of all these patients was achieved with standard of care plus abiraterone, irrespective of metastatic disease risk group.

We thank you very much for your attention. We hope we enjoyed this UroToday Journal Club discussion of the long-term followup of the STAMPEDE abiraterone trial.