Mary-Ellen Taplin: Thank you very much, Tanya. It's a pleasure to be here.
Tanya Dorff: Well, we've all been anxiously awaiting these results from PROTEUS. This is obviously a positive study showing a metastasis-free survival benefit for the use of intensified hormone therapy around radical prostatectomy. Maybe you can speak a little bit to the design of the study, why you felt it was an important question to ask, and which patients were included.
Mary-Ellen Taplin: Yes. Thank you, Tanya. Well, in most forms of aggressive localized prostate cancer, neoadjuvant or adjuvant systemic therapy is often combined with surgery. Take, for instance, long-standing in breast cancer, colorectal cancer, bladder cancer, and others. But combined systemic therapy and surgery has not been approved in prostate cancer for a variety of reasons.
So when the androgen receptor pathway inhibitors came along, more effective forms of inhibiting the androgen receptor axis based on their efficacy in metastatic castration-resistant disease, it provided an opportunity to ask the question again in localized high-risk patients who have high rates of relapse after prostatectomy, if a systemic therapy combined with surgery approach would increase the cure rates for surgery, basically, reduce metastasis. So that's the background.
We had done a series of phase-two trials over actually 10 to 12 years together with multiple colleagues, testing androgen receptor pathway inhibitors singularly or in various combinations. And the data from the phase-two looked very promising, with some patients achieving major pathologic responses and eventually being able to show that those responses correlated with freedom from PSA failure and subsequently freedom from metastasis. So we're really excited to design the PROTEUS trial and that Janssen, now Johnson & Johnson, agreed to support it.
Tanya Dorff: And so, which high-risk patients were included? How did they have to be defined?
Mary-Ellen Taplin: Yeah, thank you for asking that. So there are co-primary endpoints with PROTEUS. There's the early endpoint of pathologic response, and then there's the later endpoint of MFS, metastasis-free survival. So, in order to reach a MFS endpoint in a reasonable period of time, we structured the eligibility to be very high-risk patients. They were patients with NCCN, standard high-risk, but in addition, there was a certain number of positive core biopsies required based on what the Gleason scores were.
So, for instance, if a patient had a collection of four... Gleason four plus threes and eights, they needed at least six positive core biopsies to be eligible. If they had Gleason nine or 10, they only need at least one core biopsy to be eligible. We also allowed patients with low-volume lymph node disease onto the trial. So this is a very, very high-risk population of patients who went on PROTEUS.
Tanya Dorff: Were they required to have a PSMA PET, and could they have findings on the PET scan?
Mary-Ellen Taplin: Yeah. So that is an interesting... The use of PSMA PET in this trial is very interesting and important to understand. So when this trial started in mid 2019, PSMA PET was not standardly available. However, as the trial went forward, PSMA PET became approved as standard imaging in this cohort of patients localized high-risk, either before local therapy or at relapse, and PSMA PET became more widely available.
So there was an amendment to the trial after about 50% of the patients were accrued to allow PSMA PET in addition to standard conventional imaging, a bone scan, and CAT scan as assessments for MFS. So the majority of patients had PSMA PETs as a baseline after prostatectomy, but we do not have PSMA PETs on patients... at baseline prior to the neoadjuvant therapy.
Tanya Dorff: Right. It's such a challenging environment, incorporating PSMA PET into everything we do. So these patients then received either six months of apalutamide neoadjuvant with their ADT or a placebo, as I understand. And I'm curious about the pathologic complete response rate, which was clearly higher in the combination. Was it what you expected, and what do you think that means for these patients?
Mary-Ellen Taplin: Thank you, Tanya, for asking the question about pathologic assessment of tumor. So there is no standard in localized prostate cancer studies for how pathologic response should be assessed. And there are a variety of ways that it has been assessed in smaller trials to date. One is pathologic complete response, which is known to be low in prostate cancer. And the other is some assessment of minimal residual disease. And that assessment can be based on a two-dimensional measure of residual tumor. And in the case of PROTEUS, we used five millimeters or less of tumor, which was a landmark that had been used in the phase-two trials.
But additionally, we have a very important exploratory endpoint of what's called residual cancer burden, which is a formula that takes into consideration the residual amount of tumor and the cellularity of the tumor and gives you a metric. And a favorable RCB is... been conventionally defined as less than 0.25 cubic centimeters. So in PROTEUS, we have the primary endpoint, which is measured as PCR and five millimeters or less a tumor, and that rate was statistically significantly better by 10 times, really, than the control with ADT, which was very low.
It was 1% in the ADT and 9% in the apalutamide cohort. And then the residual cancer burden was also favorable for the apalutamide cohort, where 30% in that cohort had the favorable residual cancer burden compared to 11%, and that had an odds ratio of 3.3 and a p-value of less than 0.001. So it appears, based on PROTEUS, that this combination, at least compared to ADT, is affecting a much more robust tumor response.
Tanya Dorff: Yeah, that's fantastic. I guess because we've had such low rates of pathologic complete response previously, it's probably hard for us to know how that translates into longer-term cancer control outcomes, although PROTEUS obviously did have the metastasis-free survival endpoint. So maybe we can talk a bit about that. How frequently were patients getting imaging, and what kinds of imaging, and what were those results?
Mary-Ellen Taplin: Yeah. So patients got imaging three months after the prostatectomy with bone scan, CAT scan, and were available after the amendment, also PSMA PET. And they got PSAs every three months.
If their PSAs reached biochemical failure, which was a conventional definition of a PSA of greater than 0.2, then they got imaging at that point and every six months thereafter, and MFS was a composite endpoint of reaching metastasis either by conventional imaging, PET, or histopathology, a local recurrence. And the results showed that apalutamide, compared to placebo, reduced the risk of MFS, the probability of MFS by 20%. The hazard ratio was 0.8, p-value was 0.02.
Tanya Dorff: And it seemed like those events happened fairly late, right. As I recall, the curves start to separate somewhere around the third year.
Mary-Ellen Taplin: That's right. Yeah. So patients got a year of therapy, and then the median recovery of testosterone was six or seven months. So that gets you to about 18 to 20 months before patients would be at risk for metastasis at all, based on having a recovered testosterone. So yes, the curves separate around three years, stay separated, except at the very tail of the curve, where it's unstable because there's only about a hundred patients out there.
But this is the final analysis, so we will not have any more MFS data after this. But I would like to say that the investigator assessed MFS, that was even more positive than the blinded central review endpoint, with a hazard ratio of 0.74. And I had a lot of... We at Dana-Farber, myself and my colleagues had a lot of patients on these trials, on this trial, 70 patients.
And I had to adjudicate the difference between central blinded MFS and investigator assessed MFS. And I will say that the investigators have the PSAs and what they're doing, the clinical data, and I develop more respect for the investigator assessed MFS endpoint through this trial than I had previously. And I think that's an endpoint that shouldn't be ignored.
Tanya Dorff: Absolutely. And were there biomarkers explored as part of this?
Mary-Ellen Taplin: There are a lot of biomarkers that we are exploring. We are not... We did not present that data at ASCO because the study honestly was just unblinded 12 weeks ago. So the biomarker data, as well as correlating pathology response with MFS, was not presented at ESMO primarily because the data is being generated.
Tanya Dorff: And that'll be so important, right. One of the reasons I ask about that is I'm thinking about that patient who comes in to the urologist to talk about their new diagnosis of high-risk prostate cancer, who's probably read on the internet so much negative experience of people with hormone therapy. And how do we talk to them about the benefits seen in the PROTEUS study of neoadjuvant and adjuvant doublet therapy versus just going directly to surgery?
Mary-Ellen Taplin: Yep. I think that's a great question, and these data are not comparing to standard of care approaches such as straight going to surgery, as you mentioned, or long-term hormones, 18 to 24 months together with radiation. So when we have that patient in front of us who has high-risk disease, and it'll be important to really consider the PROTEUS eligibility, that these are not patients with one or two core biopsies of Gleason eight. These are patients with very high-risk disease and even low-volume nodal disease.
And I think we'll have to look at the individual patient, their age, their goals, their comorbidities, and discuss if this becomes standard of care, discuss three potential standard of care options, and the potential trade-offs. One of the things in PROTEUS is that the patients who got the apalutamide had 30% less postoperative radiation, either adjuvant or salvage, most of it was salvage.
And so for me, for my patients, I think that's one potential advantage of this approach because what I like to call double local therapy prostatectomy and radiation can lead to more genital urinary complications, such as urinary incontinence and erectile dysfunction. So it's going to have to be a trade-off in the discussion.
This was a total of one year of hormone therapy. If you start with surgery and get salvage therapy, that's six months of hormone therapy generally. If you start with radiation, that could be two years of hormone therapy. So I think it really... that's what medical oncologists and urologists are good at, looking at the individual patient in front of you and assessing the pros and the cons of these various approaches.
Tanya Dorff: That's a really interesting and compelling, I think, rationale to think about the trade-offs in terms of salvage therapy or adjuvant radiation. And I think the tolerability was fairly good in this study, right, that there was no increase in perioperative complications, so we can reassure patients they're not going to face a greater risk from the surgery than they would had they not received the neoadjuvant doublet.
Mary-Ellen Taplin: That's correct. I will say that standard of care approaches for prostatectomy vary across the world, and that became very evident to us in PROTEUS because there was an increased risk of some cardiovascular complications in the perioperative period.
And we actually assessed everything and did an amendment that required a cardiovascular assessment and being... having individual patients being given an individual risk score and recommendations for perioperative anticoagulation, which, honestly, when we designed the trial, we thought they were pretty standard recommendations around the world, but it turns out that wasn't the case.
And in addition, in some centers, patients are taken to prostatectomy at ages that, at least in my institution, we typically don't do say over 75 in the 75 to early 80 age group. And there were more serious complications in the older patients by more than 50%. So I think what will need to be emphasized with this approach, if it becomes a standard of care option, is not only is it important to assess a patient's risk for ADT, for androgen receptor pathway inhibitors, but also to assess their risk for prostatectomy just in general.
Tanya Dorff: That's fascinating. Well, I think we've learned so much from this study. Congratulations to you and all the investigators for doing this important work. And what would you say is the bottom-line take-home message?
Mary-Ellen Taplin: I would say that PROTEUS is a landmark study for a number of reasons. It's the largest study ever done in a localized population of patients, 2,100 men, international studies, so a culturally and racially diverse group.
And it's unique in that it has a early endpoint of pathology assessment and a later endpoint of metastasis-free survival, both very positive. The regimen was well-tolerated, and it appears that it would be a very good additional standard of care treatment options for patients who have localized high-risk disease and are at risk for relapse.
Tanya Dorff: Absolutely. And I think it shows us the prostate cancer research community that this can be done, and as we get novel therapies, this will be the landmark, the benchmark for us thinking about how else we can improve upon cure rates in the very high-risk localized population.
Mary-Ellen Taplin: That's right. There's still a lot of patients in this cohort that relapsed, and one of the powers of this work will be the biomarker assessment to predict who will relapse after an approach like this, a prostatectomy, and then be able to do investigations based on biomarkers that will develop in terms of what's driving the tumor, and applying adjuvant therapy in future work. So I think we... this is a start, but there's a lot of progress that can be made off of information we'll glean from PROTEUS in the years to come.
Tanya Dorff: Yes. It sounds like much more that we'll be learning that will be forthcoming. Thank you so much for taking time to share this with us today.
Mary-Ellen Taplin: Oh, you're welcome. It was my pleasure.