Chris Wallis:  Hello, and thank you for joining us for this UroToday Journal Club. Today we're discussing a recent publication from the CARD trial entitled "Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide". This was a randomized multicenter open-label phase 4 trial. I'm Chris Wallis, a fellow in urologic oncology at Vanderbilt. And with me today is Zach Klaassen, an assistant professor in the division of urology at the Medical College of Georgia. This here is the citation we are discussing recently published in The Lancet Oncology. And so just for a little bit of background, you can see this recent figure from a publication with UroToday highlighting recent FDA approvals in metastatic castrate-resistant prostate cancer.

And as you can tell, there's been a whole variety of changes in the last 15 years with a preponderance in the last 10 years. And so all these changes and new approvals mean that we have a plethora of treatment options and we're now in the position, which is somewhat fortunate, of having to choose how to combine treatment options and how to sequence them for maximum benefit. And that's one of the questions addressed in the CARD trial. And so relevant background comes from the work from Kim Chi and others looking at switching between androgen-access targeting agents. And so as you can see in the figure on the right, PSA responses are relatively poor when switching from abiraterone to enzalutamide or enzalutamide to abiraterone. Somewhat worse, as you can see on the far right among those who started with enzalutamide and switched to abiraterone.

So the CARD trial, which was published, the primary analysis in The New England Journal looked at patients with metastatic CRPC, who had progressive disease and had received docetaxel as well as a prior androgen-axis targeting agent, and that could be either before or after receiving docetaxel. And at the time of progression, patients were randomized to receive cabazitaxel or a switch to the other androgen-axis inhibitor. And so as was previously reported, the use of cabazitaxel as opposed to an androgen-axis inhibitor switch was associated with improved imaging-based progression-free survival as well as overall survival. However, there are other important endpoints. Overall survival obviously is one of the primary endpoints for our registration trial, so the quality of life is very important for patients during the time that they are alive. And so this was a secondary endpoint of this trial. And so to look in a little more detail of the methodology for this study, we are talking about a randomized multi-center, open-label trial conducted among 62 centers in 13 European countries.

Men are included if they had metastatic CRPC with castrate levels of testosterone. Progressive disease for the prostate cancer working group criteria had received prior docetaxel at least three cycles and had progression within the first year of being on an androgen-signaling inhibitor, so abiraterone or enzalutamide. Those patients were then randomized in a one-to-one fashion to either cabazitaxel or switched to the other, abiraterone or enzalutamide. This was an open-label design and keeping with the phase 4 methodology with patients and investigators unmasked, but study personnel masked to allocation. And randomization was stratified by ECOG Performance Status. Time to progression on androgen-signaling inhibitors and timing of androgen-signaling inhibitors either before or after the receipt of docetaxel.

And so the treatment approach is relatively standard, but in short, cabazitaxel co-administered with prophylactic G-CSF as well as prednisone and dose reductions of both chemotherapy and oral agents were allowed before treatment discontinuation. And follow-up was fairly standard with imaging laboratory investigations and adverse event monitoring. Notably for this analysis patient-reported outcomes and pain was assessed at baseline every three weeks before the initiation of treatment, during treatment, and then at the end of each treatment, and then every 12 weeks following the completion of treatment until a disease progression.

And these assessments were made using the FACT-P questionnaire, EQ-5D-5L, BPI-SF, and the WHO analgesic ladder. And so the prior publications are focused on oncologic endpoints, including the primary outcome of radiographic progression-free survival and secondary endpoints, including overall survival, PFS, PSA-response, and objective response rate. In this study, we focused on the quality of life metrics, including pain scores. And so in this study, pain response was defined as a greater than 30% decrease in pain intensity from baseline repeated on at least two consecutive measures, and pain progression, conversely, was a 30% or more increase in pain intensity from baseline, again, repeated on two measures. Symptomatic skeletal events were consequently defined as the use of external beam radiotherapy, new symptomatic pathologic fractures, new spinal cord compression, or tumor-related orthopedic interventions. And the decline in health-related quality of life was defined as a 10 point change or more in the FACT-P total score.

This shows you the inclusion criteria and allocation of these patients over time. 303 patients assessed for eligibility, and of those 48 were excluded, leaving 255 randomly-assigned relatively equally between the two arms. And we have reporting data on the vast majority. So in terms of statistical analysis, the study was powered on the basis of radiographic progression-free survival and not on the basis of any of these secondary endpoints. However, pain response and patient-reported outcomes were assessed in the intention-to-treat population among those who do perform baseline surveys and at least one other survey during followup. And as Dr. Klaassen will highlight, time to event endpoints were analyzed with the survival analysis, and patient-reported outcome changes for baseline were analyzed using mixed ANCOVA linear repeated measures models.

Zach Klaassen:  Thanks, Chris. So in terms of discussing the results, this study was from November 17th, 2015 to November 28th, 2018. And as mentioned, 255 patients were randomized. You can see table one on the left. These are well-balanced populations between the cabazitaxel group and the abiraterone or enzalutamide group. Looking at this analysis, the data cutoff was on March 27th, 2019 with a median follow-up of 9.2 months. And pain response was evaluable in 86% of the randomized patients, so the majority of the patients were included in this trial.

This is just a continuation of the table one baseline characteristics. You can see that in terms of the number of patients that had baseline FACT-P scores that are revival was 84% in the cabazitaxel group and 90% in the abiraterone or enzalutamide group. And you can see just by comparing the mean and the standard deviations that, at the entrance to this trial, these patients had a similar quality of life.

So this is the table looking at the results in terms of time to deterioration. You can see that I've- it's a bit of a busy table. I've put a box around the hazard ratio here in the middle, and you can see that the metrics with an asterisks were the ones that were statistically significant. So time to deterioration overall survival was 13.6 median months for cabazitaxel, 11.0 months for abiraterone or enzalutamide with a significant hazard ratio of 0.64 and a 95% confidence interval of 0.46 to 0.9. Similarly, we see a strong hazard ratio, favoring cabazitaxel in terms of pain progression and the brief pain inventory score, not reached in the cabazitaxel group and median of 8.5 months in the abiraterone or enzalutamide. Another important metric that was positive, and we'll see this again in the graphs, is that emotional wellbeing significantly favored cabazitaxel with the hazard ratio of 0.46. The median time to deterioration was not evaluable in the cabazitaxel group and was 13.7 months in the abiraterone or enzalutamide group.

Looking at this table of symptomatic skeletal events, you can see here on the top row that 19% of patients in the cabazitaxel group had an SSE, compared to 28% in the abiraterone or enzalutamide group. And this was actually achieved despite lower use of denosumab or bisphosphonate in patients treated with cabazitaxel, which was 21% versus abiraterone or enzalutamide at 37%. In terms of the median time to symptomatic skeletal event was not reached for the cabazitaxel group compared to 16.7 months for the abiraterone-enzalutamide group with a hazard ratio of 0.59. It's close to the statistically significant hazard ratio, a 95% confidence interval of 0.35 to 1.01.

In these next two graphs, we'll look at the percent of patients with improvement based on each cycle. And so this table here is for FACT-P. And just to sort of summarize what this is showing, is that this green box shows improve FACT-P score by cycle, and you can see here on the left is cabazitaxel, and on the right is the abiraterone for each cycle. And you can see that the green box continues to improve, deteriorates a little bit at cycle six, and then improves again at cycle seven. And if you compare these side by side, each cycle has improvement in FACT-P with the cabazitaxel group compared to the abiraterone group. And this is quite similar as well in the EQ-5D-5L tool as well. As you can see once again, improvement for cabazitaxel on the left versus abiraterone on the right all the way through cycle 8.

In terms of the change from baseline in health-related quality of life scores, there are several figures over the subsequent slides, which I'll walk you through. In general, all of these six figures, there was no difference between cabazitaxel and abiraterone or enzalutamide. You can see cabazitaxel is highlighted in blue and abiraterone or enzalutamide, in red. So there is no difference in terms of FACT-P score, Fact-P general, trial outcome index, emotional wellbeing, social or family wellbeing, as well as physical wellbeing. The median time to FACT-P total score deterioration was 14.8 months for cabazitaxel compared to 8.9 months with abiraterone-enzalutamide with a hazard ratio of 0.72, 95% confidence interval of 0.44 to 1.2.

This is a continuation of this figure, and we can see that once again, functional wellbeing, prostate-specific concerns wellbeing, and the EuroQol-5D visual analog score were not significant. However, this EuroQol-5D dimensions, five-level utility score index did favor cabazitaxel as did the pain-related subscale wellbeing.

The next three sides will show the time to deterioration in FACT-P as subscales. You can see here that, once again, cabazitaxel is in blue, abiraterone is in red. There was no difference in these three metrics in terms of FACT-P, FACT-G, as well as trial outcome index. Subsequently once again, no difference between physical wellbeing and social or family wellbeing, but as we showed previously in the table, emotional wellbeing significantly improved with cabazitaxel compared to abiraterone-enzalutamide with the stratified hazard ratio of 0.46. And you can see a pretty early split in these curves here right from the beginning in terms of emotional wellbeing.

And finally, once again, no difference between functional wellbeing prostate-specific concerns and pain-related subscale between these two groups.

So this is an important secondary paper from the CARD study. It does bring up several important discussion points. And what we saw in this study was that cabazitaxel significantly improved pain responses and prolonged time to pain progression versus abiraterone or enzalutamide. What was also encouraging was the cabazitaxel over the reduced probability of SSEs, despite the lower use of denosumab or bisphosphonates. What the ERA223 trial showed us was that there was a high level of abiraterone radium-223 patients that had symptomatic skeletal events and very low use of BPAs. And so subsequently in the ongoing EORTC-1333/PEACE III trial, which is randomizing radium-223 plus enzalutamide versus enzalutamide alone, the bone protective agents are now mandated. So I think this is important as we've shown that the fracture rate can be high without BPAs and the cabazitaxel group actually had reduced SSEs, despite lower use of these agents.

And finally, cabazitaxel had no deleterious effects on patient-reported outcomes compared with second androgen-signaling targeted inhibitors. And so this is important as chemotherapy often gets a rap that quality of life may decrease. This study of the CARD trial PORs shows that there was no difference between cabazitaxel and the ARIs. So in conclusion, in medical oncology, effective interventions are often not the best choice for patients' perspective secondary adverse events that affect health-related quality of life. Cabazitaxel was not associated with a detrimental effect on the quality of life in these patients with metastatic castration-resistant prostate cancer. And so ultimately, favorable quality of life data plus the previously published OS benefit in the CARD trial should assure patients and treating physicians that these patients can tolerate and benefit from chemotherapy, and also highlight the importance in the context of back-to-back ARIs are not durable in the second-line setting and should be the platform for cabazitaxel. Thanks so much for your attention to this year's UroToday Journal Club. We appreciate it. Thank you.