Hormone-Sensitive Metastatic Prostate Cancer

Transcript:Raoul S. Concepcion, MD, FACS: In this last segment, we’re going to move into probably an area that’s, again, moving away from the castration resistant prostate cancer space to this very narrow space which many people believe we’re going to see more and more of: patients that present with metastatic prostate cancer but are hormone-naive. They’ve not been exposed to androgen deprivation therapy. And there have been 2 reported trials over the past couple years that have specifically addressed how we might more appropriately manage those patients. Jorge, tell us a little bit in the time remaining about CHAARTED and STAMPEDE.

Jorge A. Garcia, MD, FACP: I’m excited about the oral therapies. I think the oral therapies are great, but the use of early chemotherapy has drastically changed how I practice. Basically, there are 3 main trials. There are the French data (GETUG-AFU 15), the ECOG 3805 data (CHAARTED), and recently the UK data (STAMPEDE). So let me just talk first about the ECOG data. The ECOG data was a very simple trial. We medical oncologists, to some extent, are very linear, so if you have an agent that works really well in the advanced setting, the question is can you actually move that agent even earlier. And there is some biologic rationale to use docetaxel earlier in that context, animal models and so forth.

So what the ECOG group set out to do was to actually address a very specific question. If I start with upfront docetaxel, would I change the survival of those patients who are hormone-naive, so-called hormone sensitive or castration sensitive? So there was a randomized phase III trial in the United States, 790 patients plus, randomized 1:1 to either ADT, androgen deprivation therapy, or ADT and 6 cycles of docetaxel-based chemotherapy, using the standard dose of 75 mg/m2. Prednisone was not required in that trial as we did for TAX 327 and SWOG 9916.

The primary end point of the trial was very simple. It was actually survival. To me, the survival is quite drastic. If you look at the overall patient population, there is a 13-month difference in median survival in favor of those men who went on to get ADT and docetaxel. So, from that data itself, I learned 2 things. Number 1) that I can see a patient and look at that patient straight in the eyes and tell them if you have metastatic disease, your median survival is 44 months because that’s the median survival for advanced disease in that context. Number 2) If you get chemotherapy up front, then you can improve that median survival by 13 months. The hazard ratio is 0.61 in that context.

Now, the biggest controversy that we have perhaps about the ECOG data is who is worthy for chemotherapy. And by that I mean, we did a pre-specified analysis looking at low-volume patients or high-volume patients. And, if you look at the median survival for low-volume patients, the median survival for both arms has not been reached. If you look at the median survival for patients with high-volume metastases, there is a 17-month improvement in favor of those men who actually had docetaxel up front.

So that has actually put a lot of pressure in the system, because the question is how do you define volume? So volume has been defined in many different ways over the last 20 years, but the definition that CHAARTED used was simple. If you have visceral metastases, and/or if you have more than 4 bone lesions, one of which has to be outside the skeletal, the vertebral, or the pelvic region, you are high volume. Everybody else is low volume. And to me, that is concerning. We know high-volume patients still benefit the most from those therapies.

Raoul S. Concepcion, MD, FACS: So just to be clear, that is a definition that has been used before in clinical trials.

Jorge A. Garcia, MD, FACP: Yes, correct, we have.

Raoul S. Concepcion, MD, FACS: Because I think people need to understand that.

Jorge A. Garcia, MD, FACP: We have used that definition. So, when you look at the CHAARTED data, there is no doubt that adding chemotherapy up front drastically impacts survival. The question now remains is low volume. Should low-volume patients go on and get systemic chemotherapy? Now, the STAMPEDE data actually look at a very, very similar patient population. It was a 6000 patient trial in the UK with a clinical trial design that allows you to move and exchange agents that were interesting when we developed the trial but over time have become obsolete. In that context, they used celecoxib and many other things.

Those data have been reported in 2 ways. The median survival for those patients who were randomized to ADT alone is, again, 44 months, reported last year or the year before. The median survival for those men who actually have systemic disease who move on to either ADT or ADT plus docetaxel is, again, a 10-month survival improvement in the overall patient population. But when you take the patients with M1 disease, there is a 22-month median survival improvement in favor of those who received ADT plus docetaxel-based chemotherapy. Now, what has created again the complexity of understanding this data is the previous French data, GETUG 15, which was actually exactly the same as CHAARTED, looking at ADT against ADT plus chemotherapy.

And, in that trial’s updated analysis this year, there was no difference in survival for those who got ADT plus docetaxel compared with ADT alone. So the biggest question is how come the French data are negative, and yet we have the American data and now the UK data demonstrating a significant survival improvement. And those are the questions that we have right now.

Judd W. Moul, MD, FACS: Number 2) there were 350 patients in the French trial. That’s the first thing. It was less power for that study.

Charles J. Ryan, MD: I believe there was a lower cumulative dose of docetaxel delivered as well.

Jorge A. Garcia, MD, FACP: There’s a lot of ways to dissect the French data. Obviously, one is sample size. But I think, perhaps the biggest one, in my opinion, is what many others have actually discussed in the past, which is when you look at the timing of when GETUG 15 was conducted in the French region, they didn’t have any of their oral agents approved in the French system. When we finished CHAARTED in America, abiraterone was approved, enzalutamide was approved, and cabazitaxel was approved. So a lot of patients moved from that upfront chemotherapy and went on to receive subsequent therapy, whether it was oral therapy or cabazitaxel.

Charles J. Ryan, MD: So, in other words, a patient who was on the controlled arm of CHAARTED may have progressed at a time when subsequent therapy wasn’t available, because abiraterone and enzalutamide weren’t approved. Whereas, a person who got the chemotherapy, not only did he benefit from the chemotherapy, but also that window opened when he got abiraterone.

Raoul S. Concepcion, MD, FACS: Plus, also in STAMPEDE, didn’t they show that the addition of bone targeting therapy, and I believe they used zoledronic acid, did not change the overall survival?

Charles J. Ryan, MD: And that had been shown in the US study as well.

Jorge A. Garcia, MD, FACP: I hope that part of the trial actually settles the question as to whether or not patients with castration-sensitive disease with bone metastases deserve to be on a bisphosphonate. In my opinion, the answer is no. So it is fair to say that when you look at ADT alone in the STAMPEDE data against ADT plus zoledronic acid, the combination of zoledronic acid and ADT was superior to ADT alone.

But then if you look at ADT against chemotherapy and ADT, the median survival was far better, mathematically speaking, compared to the median survival on the ADT/zoledronic acid. And therefore, in my personal opinion, I do not believe men with castration- sensitive disease with bone metastases need to receive bisphosphonates or RANK ligand inhibitors for a skeletal-related prevention. That’s one thing. The other topic is whether or not they need bone health, and whether or not we should actually be using some of these agents to prevent and minimize bone loss. But I think the concept of putting people on zoledronic acid up front should be revised.

Charles J. Ryan, MD: And yet it’s happening all the time.

Jorge A. Garcia, MD, FACP: Correct.

Charles J. Ryan, MD: Because in the breast cancer world and in the lung cancer world, oncologists are putting patients on the bisphosphonates early on. So it’s not uncommon for me to get a referral from an oncologist, and those patients are already on those therapies. There are patients who have very extensive bony disease at the time of diagnosis, and some of the subset analyses suggest that those patients may benefit. So I don’t look down on that. It’s just the 1, or 2, or 3 bone met patients—I don’t think they need it.

Raoul S. Concepcion, MD, FACS: Wasn’t it about 25% of patients on CHAARTED actually had their primary already treated?

Michael Fabrizio, MD, FACS: Yes.

Raoul S. Concepcion, MD, FACS: As a urologist, we would be very interested in looking at that population. What does that particular phenotype look like in terms of when they progress?

Transcript Edited for Clarity