So, why have we done this study? There's a clear clinical unmet need where high-risk localized or locally advanced prostate cancer patients undergoing a radical prostatectomy are often not cured with single modality treatment. We know that the relapse rates are as high as 50% within five years, and importantly, their death rates are nearly 20% within 10 years. And so clearly a regimen, ideally in a multimodal fashion, that lowers recurrence rates and improves the survival by decreasing disease burden targeting any micrometastasis is critical to help improve the relapse and death rates in this high-risk cohort of patients.
And so, what about previous trials of neoadjuvant therapy in radical prostatectomy patients? There's been a smattering of these trials over the past few decades, and overall they've been unsuccessful, and have certainly not changed routine clinical practice. If we focus on the more recent trials that have incorporated androgen receptor pathway inhibitors, also led by Dr. Taplin in 2014, we had a phase two trial of Abi with an LHRH agonist versus an LHRH agonist alone for about three months, and then followed by both Abi and LHRH in both arms for 12 weeks total. So, one arm got three months of Abi and the other arm got a total of six months of Abi before surgery. And we see here that the pathologic complete response and minimal residual disease was about 50% to 60%, and the rate of T2 disease or less was improved at 52% versus 41%. And node positivity was improved significantly from 24% to 11%, and the positive margin rate was significantly improved, going down from 19% down to 10%.
We also had the PUNCH trial, which was published out of Memorial Sloan Kettering a few years ago in 2020, where Dr. Eastham led this phase three trial of neoadjuvant chemo hormonal therapy, so docetaxel with ADT for 18 to 24 weeks, followed by surgery, versus a true control arm of upfront surgery alone in clinically localized high-risk prostate cancer. This was a big trial with almost 800 patients enrolled. So, while this trial failed to meet the predefined primary endpoint, which was three-year biochemical progression-free survival, with only a 5% improvement, not meeting the predefined cutoff, overall, biochemical progression-free survival was improved, with a meaningful hazard ratio of almost 0.7.
Metastasis-free survival was also improved, with a hazard ratio of 0.7, and we also saw significant improvement in pathologic outcomes. So, T2 disease node negative was at 28% up from 12%. The positive margins were less, down from 54% to 33%. Seminal vesicle involvement was also significantly improved by nearly 20%, and node positivity was improved by 11%. So, we saw both meaningful survival benefits as well as meaningful improvements in pathologic outcomes. But despite these results, overall, this was deemed a negative trial and was not incorporated into the guidelines, and we haven't really seen an uptake of docetaxel with ADT in the neoadjuvant setting for these high-risk patients.
So, why ERLEADA? Why apalutamide in this setting for the PROTEUS trial? This androgen receptor pathway inhibitor is approved in two settings, for non-metastatic CRPC based on the results of the SPARTAN trial, as well in combination with hormonal therapy ADT for patients with hormone-sensitive metastatic prostate cancer, based on the results of the TITAN trial. There's a precedent for using this drug in the advanced stage disease. And so, the study investigators hypothesized that 12 cycles of perioperative apalutamide and ADT compared to placebo and ADT, so not really a true control arm, because we don't routinely give ADT pre-op, would improve the efficacy and safety compared to placebo alone in these high-risk localized or locally advanced prostate cancer patients, specifically undergoing a radical prostatectomy.
And so, this was a phase 3, double-blind placebo-controlled trial that was conducted at 184 sites across 18 countries, and of note, it was designed and sponsored by Johnson & Johnson. With regards to patient eligibility, which is really important when you think about who are these patients, and how do we incorporate the results of this trial into our practice, it's important to know that these were high-risk, either localized or locally advanced, per the NCCN criteria. So, we all know the criteria, high Gleason score, eight or higher, and the PSA, the clinical stage based on DRE. And importantly, these patients had no metastasis on conventional imaging, but if they had node positivity, that was allowed. It's important also to highlight again that this was not based on PSMA PET. This was based on conventional imaging alone. And it was important that they were at acceptable cardiovascular risk to receive ADT for a total of 13 months, because we do know that ADTs and ARPIs do worsen that, so we want to make sure there was a safe population to evaluate this in.
And this was the study design. This is from a slide that was presented at ASCO recently. So, we see here we have upwards of 2,000 patients, 2,109, with high-risk prostate cancer, localized or locally advanced, again, based on conventional imaging. And these patients were randomized equally in a one-to-one fashion to either apalutamide, given at a dose of 240 milligrams daily with ADT, versus placebo plus ADT. And then after they completed the 12 weeks pre-op, they received a total of two weeks of a hormone break, after which they underwent a radical prostatectomy with an ADT. And then afterwards, they received adjuvant apalutamide plus ADT versus placebo plus ADT, again for an additional six cycles we see here. And then post-treatment, they underwent a PSMA PET every three months after the end of therapy, PSA, again every three months, and then they underwent both conventional PSMA PET imaging at biochemical failure if they have a PSA of 0.2 or higher, defined as failure, every six months thereafter.
The primary endpoints were dual in nature. Here we had either pCR or MRD, stands for pathologic complete response or minimal residual disease, and that was defined as a largest tumor in size, less than five millimeters in size, and having T2 disease or less. And then the other primary endpoint was metastasis-free survival. Initially that was based on conventional imaging, but due to the approval of PSMA PET in the biochemical recurrence setting, and the study amendment was incorporated in April 2022 that allowed for the use of PSMA PET for staging in the metastatic setting. And Zach will talk about that later and the results and why that is important.
The key secondary endpoints were event-free survival, which was the time from randomization to biochemical failure that was an event, local recurrence or regional recurrence, or distant metastasis. So basically, anything in that setting. And it's important to note that adjuvant or salvage radiotherapy was given at the treating physician's discretion. They also looked at first subsequent local or systemic treatment, metastasis-free survival, PSA-free survival. And importantly, not just any PSA-free survival, it's eugonadal PSA-free survival. It's important, because you don't want the PSA to be low just because they're suppressed. Once they recover their testosterone in a meaningful way, what happens to the PSA? And so, we saw that as well in the EMBARK trial. They've looked at this outcome, so these authors have also incorporated this in this study. Looked at castrate-resistance-free survival, testosterone recovery, very important quality of life outcome for our patients, as well as safety and adverse events.
Next, Zach will go over the results and give us discussion to contextualize results of this trial for our patients.
Zachary Klaassen: Rashid, thanks so much. So, let's look at the demographics and clinical characteristics of these patients. This is a median age of 66. We can see here that as a global study, about 20% were Asian, about 70% were white. When we look at the median PSA level, 14.8, which fits with the criteria, as you laid out nicely. In terms of tumor T stage, about 44% were T2, but we did see about one-third of patients who were T3 or higher. Interestingly, about 12% were N1 disease, and not surprisingly, the majority of these were Gleason eight or higher, with roughly 60% of these being Gleason nine or 10, so true high-risk patient population in this study.
This is the dual primary endpoint median follow-up of 61.7 months. The PCR or minimal residual disease was 8.9% in the apalutamide arm compared to 1% in the placebo arm. It's a odds ratio of 10 in terms of favoring the apalutamide arm. The other dual primary endpoint was metastasis-free survival. This also significantly favored the apalutamide arm, hazard ratio of 0.80, confidence interval, 0.67 to 0.96.
There are several key secondary endpoints and we'll walk through these. This is event-free survival on the left favoring the apalutamide arm, hazard ratio of 0.71, statistically significant. On the right, first subsequent local or systemic therapy, a very relevant endpoint for patients, 0.65, 95% confidence interval, 0.57 to 0.73, again, favoring the apalutamide arm.
Distant metastasis or conventional imaging on PSMA PET also favoring the apalutamide arm, hazard ratio of 0.68, 95%, confidence interval is 0.55 to 0.83. And then on the right, freedom from disease at four years, an absolute improvement of roughly 3.6% favoring apalutamide, 21.9%, versus 18.3%. Again, P value of 0.04.
A few more important sort of secondary exploratory post-hoc endpoints I'll walk you through. In terms of time to castrate-resistance not reached for both arms, hazard ratio of favoring apalutamide, time to recovery of testosterone from baseline, no difference, so apalutamide not significantly increasing that timeline. Again, this confidence interval crossing one. Time to testosterone recovery from the end of 12 month perioperative treatment, 8.1 months versus 6.6. And then we see here again, no difference between these two arms, so really that 12 months of APA added to the ADT is not increasing the time for testosterone recovery.
Adverse events, kind of what we'd expect from 12 months of apalutamide. If we look at Grade 3/4 adverse events in the apalutamide arm, 39.6 versus 31 in the ADT plus placebo arm. As expected, the hot flushes were a little bit more in the apalutamide arm. Overall 63.4%, most of these Grade 1 and Grade 2. And then we see the usual postoperative adverse events we would expect, urinary incontinence, erectile dysfunction, with no appreciable change between these two arms. So, no surprises on the adverse events, given the safety profile of apalutamide.
There's been a lot of discussion at ASCO and certainly on social media, and we chose to focus on what the authors discussed in this paper, and certainly there'll be more discussion and more data being presented subsequently for PROTEUS. But what PROTEUS showed is that six months of APA plus ADT versus placebo plus ADT before radical prostatectomy at a nine time higher rate of pathologic complete response or minimal residual disease. If we look at the 12 months of perioperative APA plus ADT versus placebo plus ADT, 20% improvement in metastasis-free survival, delayed subsequent therapy by a median of six years, and patients were NED for a median of four years.
Of course, there are several limitations from a big trial that spans many years, as we see in PROTEUS. After the global approval of PSMA PET during the trial, the use of PSMA PET added as an amendment for staging in PROTEUS, this does add complexity to the trial design and interpretation, particularly the lack of baseline PET staging. The comparative group of ADT plus placebo, this is treatment intensification sort of beyond the current guidelines for these patients, but this was allowed for maintenance during the trial, and was approved by regulatory input. There is, however, a PROTEUS substudy that is looking at APA plus ADT plus ARPI versus ARPI alone, so we'll look forward to those studies as well.
Importantly, there is no difference in overall survival. It was short follow-up. 8.5% of patients died in the APA plus ADT group. But it's important to look at the substudy ... or the subgroup of patients that were more than 75 years of age. There was 105 patients. 15.2% of these patients died, and so it is important to think about treatment intensification, including surgery, in these elderly patients.
So, take-home messages, PROTEUS showed that six cycles of ADT plus apalutamide before and after radical prostatectomy in high-risk localized and locally advanced prostate cancer significantly improved disease control versus ADT plus placebo. This also improved long-term oncological outcomes, with several patient-specific important outcomes, like time to next therapy. New therapeutic approaches with an established safety profile that may prevent or delay metastatic disease are crucial to improving the lives of our patients with prostate cancer, so we congratulate the PROTEUS investigators.
We thank you for listening to this Journal Club on PROTEUS, published New England Journal of Medicine.