mCSPC Couplet vs Triplet Therapy LUGPA 2022 Presentation - Alicia Morgans
December 15, 2022
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
APCCC 2022: Treatment Intensification Strategies in mHSPC: Triplets and More
APCCC 2021: What Is the Evidence for “Triplet Therapy”?
Alicia Morgans: I'm going to be talking about metastatic castration-sensitive prostate cancer and considering couplets and triplets. And really, I think... These are my disclosures. The main message here is that ADT alone is no longer enough for metastatic castration-sensitive prostate cancer. And I think we all know that, but then we have to decide triplets, couplets, and this is really a conversation about how we decide between those two options. There are many things that contribute to our decision-making when it comes to metastatic castration-sensitive prostate cancer or metastatic hormone-sensitive prostate cancer. And these are some of the factors as I think of them, at least, this is from some work that Misha Beltran and I recently put into the JCO, which is really thinking about cancer-related factors, patient-related factors, clinician-related factors, which we do have to acknowledge. We all have our own biases, go-tos, and things that we think will make things easier for us, too. And then treatment-related factors.
And we can think about each of these and put them together for each individual patient to come up with the best treatment for that patient. This is my decision algorithm for metastatic hormone-sensitive disease or metastatic castration-sensitive disease. Being a medical oncologist, I know that I certainly have it easy when it comes to a decision about giving chemotherapy, but I know that the folks in this room actually work very closely with medical oncologists and really do have access. You guys have phenomenal practices where you can give chemotherapy, too, if you decide you want to give a couplet... Or a triplet, rather.
This is how I think about it. So at the beginning, is this high-volume disease or is it low-volume disease? And we'll go through the data for all of this, but that's the first main branch point. For high-volume patients, I always think about if the patient's going to be chemo-fit, then can I give them that triplet therapy of ADT+docetaxel and an AR-targeted agent? If they're not going to be chemo-fit, then we might just do ADT and an androgen receptor signaling inhibitor. If the patient has low volume disease, we're really going to usually air on the side of ADT and an androgen receptor signaling inhibitor, and we have to decide about radiating the prostate. And so this is really kind of the decision tree that I think through.
We'll get to the data, as I said, in just a second, but I also want to mention that the NCCN guidelines have been updated. They include all of these options. But importantly, and I think importantly especially for this audience, I think we recognize ADT and docetaxel is actually no longer a recommended option, at least on the NCCN guidelines.
It's ADT with docetaxel, and there's strong enough compelling evidence that if you're going to use that combination, to use an AR signaling inhibitor as a maintenance or concurrent with the docetaxel. So again, ADT alone, really not preferred here. It's going to be a combination of a couplet or a triplet. So let's go through some of the data.
So couplet therapy, this is really a reflection of the APCCC. So this is the way the APCCC voted. When we met about a year ago, the majority of people said for asymptomatic synchronous low-volume disease, and those patients who could get that radical local therapy, too, we really want to use a combination of ADT and an AR targeted agent. And ADT alone, not really recommended. What I think is so important is that that has even evolved to be more striking in our most recent meeting, which was just this spring, but that data has not come out yet.
So what is this based on? So the overall survival benefit was confirmed in multiple long-term analyses. We have the data for ADT and abiraterone listed here, assessed in both the LATITUDE trial and the STAMPEDE trial, where we know that ADT and abiraterone is going to provide a better survival advantage versus ADT alone. We certainly saw this with each of our other agents, apalutamide, enzalutamide, and we have two trials here for enzalutamide, and we also have this data for ADT and docetaxel chemotherapy.
So what about triplet therapy? This is importantly going to be our combination that might be a little bit more toxic upfront, but does seem to provide a bit of a bigger bang for the buck. When the APCCC met about a year ago, they really felt like they were moving in a direction of ADT+docetaxel and ARPI for those patients with high-volume disease. Although it was split a bit with patients or providers still saying at that time ADT and an AR targeting agent was still really one of the preferred ways to go. Importantly, this vote last fall happened after PEACE-1's data came out but before ARASENS data came out, and I think I'd like to spend the rest of the time digging into these two studies to familiarize everyone with why I think triplet therapy is something that we should consider for a lot of our patients, especially if they're high-volume de novo metastatic disease and certainly must be chemo-fit.
So PEACE-1 is a large and somewhat complex study that was developed in Europe, run out of France, and this study really looked at de novo metastatic hormone-sensitive disease, and these patients were randomized into one of four arms. You could see standard of care, which for the majority of patients in this analysis I'm about to present, included ADT and docetaxel versus standard of care plus abiraterone; standard of care plus radiation to the prostate; and standard of care plus radiation plus abiraterone.
The radiation data is not yet mature, and so the investigators really analyzed the ADT+docetaxel with and without abiraterone data at this point in time. Importantly, the primary endpoint here is radiographic progression-free survival, and they also included an overall survival endpoint. So here we can see that in these patients, again, this is with or without radiation because radiation does not seem to have affected their endpoints, at least at this point in their analysis. Patients who received ADT and docetaxel did appear to have a longer radiographic progression-free survival when given abiraterone versus ADT plus docetaxel alone. And you can see that as these curves separate really rather quickly and definitively.
Here we can see that overall survival was also improved when we combined ADT+docetaxel plus abiraterone versus ADT and docetaxel alone. On the right, this is really separating out... It separates out the few patients who did get ADT alone as the initial control arm. Importantly, you can see these hazard ratios really strong demonstrating that survival benefit. I do want to emphasize again, this is de novo metastatic hormone-sensitive patient population. So we think that this is a more aggressive phenotype.
The ARASENS trial really, though, suggests a similar advantage to this type of an approach with a triplet. These were patients who could have high-volume or low-volume disease. They could have de novo metastatic or recurrent metastatic hormone-sensitive disease. A majority of patients enrolled, though, did have high-volume disease. We think, from what we can figure out from the baseline characteristics, although this was not sort of determined prior to enrollment, at least in the data that's been released, and a majority appear to have de novo metastatic disease. Patients were randomized one-to-one to receive ADT docetaxel plus darolutamide versus ADT and docetaxel. And the primary endpoint here is overall survival.
Here we again consistently see that differentiation and benefit of adding an AR targeted agent onto an ADT docetaxel backbone. That's a clear and early separation of curves, demonstrating overall survival to ADT+docetaxel plus darolutamide versus ADT and docetaxel alone. Secondary endpoints demonstrate a longer time to castration-resistant prostate cancer, as well as time to pain progression. ENZAMET also had an assessment that helps us understand the triplet, although this, I think, is a little bit more complex.
Metastatic hormone-sensitive disease, which included high- and low-volume patients, patients received ADT and enzalutamide versus ADT and the nilutamide, flutamide, or bicalutamide. Non-steroidal patients could have had docetaxel. They were evaluated for progression-free survival and overall survival endpoint. Here we can see that the addition of enzalutamide to whatever they were given as the control arm, ADT plus docetaxel or ADT alone, did improve their overall survival. And when we look at the subgroup analyses, there is a suggestion that this is a pretty consistent benefit potentially on top of docetaxel, but the study was not as clean.
There should be an analysis that comes out, I think in the literature relatively soon, demonstrating the benefit in the docetaxel population, though we're still waiting for that. So in conclusion, ADT intensification for patients with metastatic castration-sensitive disease is the standard of care. So ADT alone is not enough.
Treatment of patients with de novo high-volume metastatic disease. For patients who are fit for docetaxel, I think that this is the opportunity for us to use a triplet, ADT+docetaxel for six cycles and either abiraterone, darolutamide, or enzalutamide as our partner, and we continue that for maintenance. If they're unfit for docetaxel, ADT and an AR targeting agent.
And for low-volume disease, there is not sufficient evidence, I think, to really push a docetaxel triplet in that setting, although we can offer it to really motivated patients. But ADT and an AR targeted agent and radiation to the prostate is really what I would recommend in that setting for a low-volume patient. Thank you.