Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today, we're talking about a recent publication entitled abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer, the PEACE-1 trial: A multicenter, open label, randomized, phase three study with a 2 x 2 factorial design. 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.

You can see here the citation for this recent publication in The Lancet led by Dr. Fizazi and the PEACE-1 team. The metastatic castration-sensitive prostate cancer space has evolved quite rapidly over the last five or seven years. We had Level I evidence for docetaxel coming out in 2015 and 2016 with publications from the STAMPEDE and CHAARTED trials. And subsequently, this was followed by three novel hormonal agents in 2018 and 2019. These have formed the basis of guidelines and have become the standard of care for patients with newly diagnosed metastatic disease. So after relative stagnation for quite some time, these rapid improvements have really changed the standard of care. And in addition to these systemic treatments, we in 2018 saw data from STAMPEDE showing a benefit to primary prostate radiotherapy in patients with low-volume metastatic disease. And so the question that the authors are seeking to address in PEACE-1 is whether there may be further clinical benefit from combining these treatment approaches.

And so PEACE-1 sought to evaluate the efficacy and safety of abiraterone plus prednisone, with or without radiotherapy when added to a standard of care comprising ADT with or without docetaxel. And this is a randomized, open-label, active-control, phase 3 trial with a 2 x 2 factorial design. It was conducted in 77 European sites. To be eligible for inclusion, adult men age 18 years or older had to have histologically or cytologically confirmed prostate cancer and have evidence of de novo metastatic disease based on conventional imaging. They also had to have ECOG performance status 0-1 and have received no more than three months of androgen deprivation therapy. Patients were excluded if they had pure small cell histology or had prior definitive local therapy for prostate cancer.

As you can see in the randomization stratification plan here in the top right, we have a 1:1:1:1 randomization to the forearms. This was conducted using a minimization algorithm with stratification according to study site, performance status, ADT type, planned use of docetaxel, as well as disease burden, whether involving lymph nodes, bone, or visceral disease. And so you can see the forearms all comprising standard of care.

And importantly, we had major protocol amendments along the conduct of the study as standard of care evolved. And so when the study was designed and planned, we had ADT alone as the standard of care. We added ADT plus docetaxel as a potential option. And then subsequently docetaxel became mandated as a portion of the standard of care. And this all reflects changes in practice, you can see here in this diagram as a result of publications that came out during the accrual of the PEACE-1 trial.

So in the standard of care arm, patients received ADT either with an LRH agonist or antagonist or bilateral orchiectomy. And for those who received docetaxel as part of the standard of care, they received six cycles of therapy every three weeks with G-CSF initially being recommended, and then as of 2018 being mandated. The first cycle of docetaxel had to begin within 14 days of randomization and at least six weeks after starting initial ADT. The interventions included abiraterone given in standard 1000 milligram daily doses with prednisone five milligram twice daily. And this is based on the mCRPC dosing as this was the indication for abiraterone at the time of the study design. This had to be started within six weeks of initiating ADT.

Additionally, for those patients randomized to receive radiotherapy, this was delivered in a 74 Gy in 37 fractions over to seven to eight weeks, and it started within three to eight weeks of docetaxel completion. The co-primary endpoint were radiographic progression-free survival defined according to resist version 1.1 criteria and overall survival. There are, as you can see here, a host of secondary endpoints, including both oncologic endpoints, PSA response measures, as well as quality of life metrics and some biomarker analysis. Safety and adverse events were also included as important secondary endpoints.

In terms of statistical analysis, the authors designed their original 2013 protocol based on a sample size of 916 patients. However, this was increased to 1,171 patients with the corresponding protocol amendments. The authors assumed and then subsequently tested that there would be no significant interaction between radiotherapy and abiraterone, allowing for a 2 x 2 factorial analysis. The alpha five 0.05 was split into a 0.049 allocated to overall survival and 0.001 allocated to radiographic progression-free survival.

In terms of overall survival, the author hypothesized that it has a ratio of 0.7 with a baseline median OS of 53 months, and the control arm requiring 249 events for statistical significance. And similarly, in the rPFS comparison, they hypothesized a hazard ratio of 0.60 with a baseline median RPFs of 30 months, which would require 262 events. Prior to analysis, the authors tested their assumption that there was no interaction between abiraterone and radiotherapy using Cox proportional hazard model that was adjusted for stratification factors. They found no interaction and so they combined the patients who received and did not receive radiotherapy into a single group in their course of this analysis.

The authors first performed their analysis in the overall study population, allowing for a change in the standard of care over time. And then they subsequently performed a subset analysis among patients who received docetaxel as a portion of their standard of care. To date, preplanned event rates have not yet been reached, and so the analysis assessing the effect of radiotherapy is immature. However, we can examine efficacy analysis here in an intention to treat population when assessing the role of abiraterone.

Safety analysis are reported in the safety population according to treatment received. All time-to-event outcomes are assessed using a Kaplan-Meier method and Cox proportional-hazards models, which are adjusted for both radiotherapy use as well as the five stratification factors. And the authors further used these stratification factors to guide subgroup analyses. Now I'm going to hand us over to Zach to walk us through the results of the PEACE-1 trial.

Zachary Klaassen: Thanks very much, Chris, for that great introduction. This is the trial profile. As you can see here, there were 1,173 patients that were enrolled and randomly assigned. This included 296 to the standard of care arm, 293 to the standard of care arm plus radiotherapy, 292 to the standard of care plus abiraterone, and 291 to the standard of care plus abiraterone plus radiotherapy. This next level on this chart shows the number of patients that received and did not receive docetaxel, and roughly about two thirds of patients received docetaxel. When combining these arms, as Chris mentioned, there was 589 in the standard of care arm with or without radiotherapy who did not receive abiraterone, and 58 to the standard of care arm with or without radiotherapy that did receive abiraterone.

This is the baseline characteristics for this trial. This is broken down into two panels here based on the size of the table. As we can see here in the middle of the figure is the overall population, and to the right of this is the ADT with docetaxel population. And so just to highlight some of the key findings in these two panels, in terms of the patients that received or were assigned to receive radiotherapy was 50% in each of these arms. In terms of the countries of recruitment, majority of these patients, over three quarters were from France. In terms of the median age standard for this population, in the mid to late 60s. Majority of these patients, upwards of nearly three quarters of the patients had an ECOG performance status of zero. And looking at the T stage, it most commonly was T3 at roughly half of these patients.

Moving down this middle panel here, we can see that roughly just over half of the patient were N1, and the median time from diagnosis for these patients to enrollment in the trial was roughly 2.2 to 2.3 months. When looking at the localization of metastatic disease, over three quarters of these patients had bone metastases and roughly 11 to 13% had visceral metastases. When stratified by metastatic burden, roughly half to almost two thirds of these patients had high metastatic burden. And the majority of these patients, over three quarters of patients had at least in eight to 10 prostate cancer. With regards to median PSA, ranged from roughly 12 to 14 across these arms, and we would look at the medical history pertinent to some of the side effects associated with docetaxel and abiraterone. Roughly 40 to 44% of these patients had hypertension and roughly 11 to 16% had diabetes.

This is the Kaplan-Meier curve looking at the rPFS in the overall population. And for the next several slides, the color scheme will be the same such as abiraterone patients being in red and patients without abiraterone being in blue. And we can see that for rPFS in the overall population, there was a significant benefit for the abiraterone arm with a hazard ratio of 0.54 and a 99.9% confidence interval of 0.41 to 0.71. When we look at the Kaplan-Meier estimate of rPFS in the ADT plus docetaxel population, again, an early and wide splitting of the curves favoring the abiraterone arm with a hazard ratio of 0.50 and a 99% confidence interval of 0.34 to 0.71.

This next Kaplan-Meier curve looks at overall survival in the overall population. Again, benefiting the abiraterone arm with a hazard ratio of 0.82 and a 95.1% confidence interval of 0.69 to 0.98. And in the first roughly three years of follow-up, these populations are roughly the same. And then we see a splitting of curves at roughly three years favoring abiraterone. Similar results in the OS for the ADT plus docetaxel population, favoring abiraterone with a hazard ratio of 0.75 and a 95.1% confidence interval of 0.59 to 0.95. The next two slides look at the effective metastatic burden. And this is OS in the ADT plus docetaxel population with low volume metastatic burden. And we do not see a benefit for abiraterone in this population with a hazard ratio of 0.83 and a 95.1% confidence interval of 0.50 to 1.39.For the high volume metastatic burden, we do see a benefit for abiraterone. You can see here, these curves split about one to two years after follow-up with a hazard ratio favoring abiraterone of 0.72 and a 95.1% confidence interval of 0.55 to 0.95.

This is the tabular form of the efficacy outcomes in the ITT population. Essentially, we have just discussed the primary outcomes in the overall population, as well as the ADT with docetaxel population. Some additional important secondary outcomes in the overall population, CRPC survival also favoring abiraterone with a hazard ratio of 0.40 and 95% confidence interval of 0.35 to 0.47. And again, prostate cancer specific survival favoring abiraterone with a hazard ratio of 0.75 and 95% confidence interval of 0.61 to 0.91. Essentially you'll see many of these secondary outcomes in ADT with docetaxel population favoring the abiraterone arm. But as we discussed in the previous slide, the one outcome that did not favor abiraterone was the overall survival in patients with low volume metastatic burden as highlighted by this asterisk.

This is the forest plots looking at the rPFS in the population with ADT plus docetaxel, as well as the overall population on the left. You can see the forest plot for overall, and in the right side you can see ADT with docetaxel population. And just a general overview on this overall population shows benefit, essentially favoring a standard of care plus abiraterone. We see some crossing of hazard ratio of one with the docetaxel not being received secondary to physician decision although the sample size is small. Again, also a surgical castration, but essentially the rest of these metrics, looking at radiotherapy, ECOG performance, ADT, and metastatic burden all favoring the abiraterone arm.

When we look at the ADT with docetaxel attack arm, again, very similar results to the overall population with the caveat for low metastatic burden not having a significant benefit for standard of care plus abiraterone. This is the overall survival forest plots. We can see the overall population here. Again, not quite as clean as for the rPFS population, but we do see a benefit across several of these metrics. Particularly in the overall population, we see the overall benefit has a ratio 0.82 in the 95% confidence interval of 0.69 to 0.98. In the ADT plus docetaxel population, again, quite similar to the overall population, we do again see no benefit in a low metastatic burden in both these populations with hazard ratios crossing the 1.0 metric.

This is the adverse event in the safety population. This is again highlighting ADT with docetaxel population in the middle of this table, and the ADT without docetaxel population to the right of this. And so as you'd expect in a trial with several combinations of therapy, any adverse events occurred in every patient. In this trial were severe adverse events occurring in 63% of the abiraterone arm with docetaxel and 66% in the abiraterone arm without docetaxel. This is in comparison to 52% and 41% in those arms that did not have abiraterone. Looking down at the frequent serious adverse events, we do see some increased hypertension in the patients that received abiraterone, 22% and 29%. And we do see some neutropenia in the patients that received docetaxel at 10% and 9%.

So several discussion points from the PEACE-1 trial. This is the first trial to show that a triple systemic therapy consisting of ADT, docetaxel, and a second-generation androgen signaling inhibitor extended rPFS and OS in patients with de novo metastatic castrate sensitive prostate cancer. Docetaxel and abiraterone have distinct mechanism of action and do not display absolute cross-resistance. Abiraterone improves OS after docetaxel treatment and docetaxel retains some activity after abiraterone failure. Thus, these observations provide a rationale for survival benefits resulting from their combination in this trial. Importantly, even though abiraterone can inhibit CYP3A4, which is involved in docetaxel elimination, there was no increased risk of toxicity when used in combination in this trial.

So in conclusion, PEACE-1 not only confirms that combining abiraterone with standard of care improves outcomes in men with de novo metastatic castrate sensitive prostate cancer, but it shows that combining abiraterone with ADT and docetaxel improves OS and rPFS, as well as other efficacy endpoints with little toxicity increase. As PEACE-1 only included patients with de novo disease, it is still unclear whether this triple therapy may benefit patients with metachronous disease. These findings cannot directly address whether this triple therapy combination is superior to ADT and abiraterone.

And finally, longer follow-up is required to answer whether combining such an intensive first line systemic treatment with radiotherapy to the primary tumor may provide further clinical benefits for patients with metastatic castrate-sensitive disease. And then this analysis will be performed when the preplanned number of rPFS and OS events is reached in the population of men presenting with low-volume metastatic disease. We thank you very much and we hope we enjoyed this UroToday Journal Club discussing the recently published PEACE-1 trial in The Lancet.