The Upheaval in Metastatic Hormone Sensitive Prostate Cancer (mHSPC) - Chris Sweeney & Mary-Ellen Taplin
August 19, 2019
Christopher Sweeney, MBBS, Professor of Medicine, Harvard Medical School, Medical Oncologist, Dana-Farber Cancer Institute
Mary-Ellen Taplin, MD Chair, Executive Committee for Clinical Research Director of Clinical Research, Lank Center for Genitourinary Oncology Institute Physician, Dana-Farber Cancer Institute, and Professor of Medicine, Harvard Medical School, Boston, MA.
Alicia Morgans, MD, MPH, Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Watch: Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer (ENZAMET) - Tanya Dorff
Watch: Impact of Academic Collaborations in mHSPC Trial: ENZAMET - Chris Sweeney
ASCO 2019: ENZAMET, Overall Survival Results of a Phase III Randomized Trial of Standard-of-care Therapy with or without Enzalutamide for mHSPC, an ANZUP-led International Cooperative Group Trial
ASCO GU 2019: ARCHES Trial-Phase 3 Study of ADT with Enzalutamide in mHSPC
Alicia Morgans: Hi, I'm delighted to have here with me today, Dr. Chris Sweeney, a Professor of Medicine at Harvard, as well as a medical oncologist at the Dana Farber and Mary Ellen Taplin, another Professor of Medicine at Harvard and another medical oncologist at the Dana Farber, both good friends and colleagues. Thanks so much for joining me here today.
Chris Sweeney: Thanks for having us.
Mary Ellen Taplin: Thank you.
Alicia Morgans: I wanted to pick your brains on a couple things in prostate cancer. Starting with metastatic hormone-sensitive prostate cancer, a lot of upheaval in that setting. You've been involved in upheaval in that setting for many years and I really just wanted to get your thoughts, collectively, as to what are you doing now when you see a new patient with metastatic hormone-sensitive disease? Let's assume this patient has high volume metastatic disease. Let's start with that subgroup. What are you thinking about, Dr. Sweeney?
Chris Sweeney: The first thing I ascertain is, working within the United States, are they fit for chemotherapy? Then I will explore their ability to access abiraterone in the setting, which is approved for metastatic hormone-sensitive and a clear benefit in high volume disease, and there's a clear benefit for docetaxel in metastatic hormone-sensitive, high volume disease.
There are pros and cons to both approaches. The cons to docetaxel are chemotherapy, and people have a baseline aversion to chemotherapy. Very understandable, but I don't think it's either/or. It's getting both therapies into a patient at some stage. Sometimes patients are the most fit they will ever be when you start the hormones, and you'll most likely able to get the chemotherapy in up front. There's six cycles, 18 weeks. Most patients tolerate it well with some need for some supportive care, and then they're done. Then they just manage with hormones without the cost of and the chronic side effects of abiraterone.
Abiraterone is a pill. It's a hormone, and a lot of upfront attraction. However, if a copay is $5, it's a much easier proposition than a copay of $2,500. So what I say to patients is, "We will explore that. We'll see what your exposure is. We'll look for patient assistance programs to see if we can bring that price down. The long term side effects of the abiraterone are this," related to potential hypertension issues, impacting the adrenal hormones and needing prednisone, and then we lay it all out. I have them come back in a month with all that new information having them have time to absorb it, speak with their family, and then make a decision.
In my experience, when you lay it out in a very neutral zone, some patients say, "I want to get rid of the chemotherapy and be done and not be on pills." Other patients have said to me, "I've got to be in court because I'm a lawyer, and I don't want to be fatigued, so I will prefer to go with the hormone approach." So I lay it all out, and then we make a decision together.
Alicia Morgans: I love that approach. You know, collective and collaborative decision-making with patients is really, really important. And it's also important that we offer both those options to patients in the high volume metastatic setting.
Chris Sweeney: And I should emphasize, this is only viable if the patient is fit for chemotherapy.
Alicia Morgans: Yes, of course.
Chris Sweeney: And that's the first thing we should arbitrate.
Alicia Morgans: Absolutely. Now, the metastatic hormone-sensitive low volume patient population also has options, and some data that we actually haven't spoken about, although we had a conversation earlier today, thinking about radiation in addition to systemic therapy. First, Mary Ellen, for the low volume patients, do you... and some people do, so just asking neutrally... Do you offer chemotherapy to the low volume metastatic patients as well? Just abiraterone? And then what do you think about radiation of the primary in that setting?
Mary Ellen Taplin: In general, I don't offer chemotherapy, as Chris' data from the CHAARTED trial doesn't really support a clear benefit for chemotherapy in the low volume patient. I do consistently offer abiraterone. If the amount of metastases are fairly limited, we will offer radiation to the prostate. We have clinical trials that aren't available everywhere that will radiate the prostate and the limited number of metastases, as well. Outside of a clinical trial, it's unclear, to be honest, what the benefit of that approach is.
Alicia Morgans: You mean radiating the metastatic sites?
Mary Ellen Taplin: The metastasis, correct. But yes, we will consider radiation to the prostate.
Alicia Morgans: Okay. And I would love to hear your thoughts on that, too, because I think in general there is still question about the STAMPEDE data that led us to that conclusion that radiation of the primary in the setting of low volume metastatic disease would be something that, at least in that trial, seemed to prolong survival. What are your thoughts on that data?
Chris Sweeney: I think it's a very much an emerging field, and I think it's fantastic that we're actually passing up patients with poor prognosis and high burden of disease and thinking of the low burden in a separate manner. I will first of all address that I don't think there's a role for docetaxel. We will see with time with more data, but we have GETUG-12. So, GETUG-15, the French version with hormones with or without docetaxel and CHAARTED both with direct evidence showing a hazard ratio of 1.0. and when we do the test for heterogeneity, both studies are actually homogenous for high volume with benefit, and no benefit for low volume.
So the direct evidence we have for docetaxel in that setting shows no evidence of benefit. Granted, smaller numbers. STAMPEDE will report out at the end of this year, presumably at ESMO, potentially, and they will have larger numbers and be able to add to that dataset. Currently, they promote docetaxel for low volume because of their early look of M1, which includes high volume and low volume, and the M0, which includes rising PSA post prostatectomy or radiation and the adjuvant, and they say there's no difference.
But if you look at the Kaplan-Meier Curve for the M0, they're basically overlapping. And they're making a statistical inference because of the overlapping uncertainty from the forest plots. That's inferential data, not direct data, and I prefer to look at direct data. I also recognize that the low volume patients have an outcome that's measured in years. For example, a person who has prior local therapy and low volume metastasis has a median survival from starting the hormones of eight years. The patient that you're referring to, who presents with de novo metastatic disease and low volume, their median survival with hormones alone is about four to five years. So they have to be thought of differently.
I do offer radiation, and I have been doing it off protocol, even before the data, rightfully or wrongfully. But I do think there is enough data to support doing that, especially when you're treating with ADT alone. If you look at the meta analysis that comes out that has reported between the HORRAD and the STAMPEDE radiation to the prostate suggests that low burden patients clearly do benefit. So I think there's enough direct evidence to offer it.
Mary Ellen Taplin: Chris, can you just comment on your definition of low volume, and how the clinicians should think of that?
Alicia Morgans: Yeah, thank you.
Chris Sweeney: Yeah. That's a very great question. Low burden of disease is a little bit in the eye of the beholder, and how to differentiate from oligometastatic. I think we should think about oligometastatic terminology if we can give locally ablative therapy to all the disease, be it the prostate if it's intact, and the metastasis surgery or radiation, lymph nodes or bone. Low volume, it probably has some patients who are misclassified, per the CHAARTED definition. We say three or less boney metastases is low volume, and high volume are patients who have boney metastases four or more with one beyond the vertebral bodies and the pelvis.
The history for that definition comes from when we put the protocol together in 2004, yes we wrote the study in 2004, the CHAARTED study. We looked at the MD Anderson, which had a definition of three or more boney metastases having a poor outcome in one of their randomized studies, and the SWOG definition of extensive disease being any lesion beyond the vertebral body and pelvis. I thought this would misclassify some low volume patients who had an isolated rib metastasis as high volume, or extensive. So we said let's meld the two, and it seems to be its consistently identifying patients who have a much better prognosis with some reliability.
There's some refinement to be made because there are some patients misclassified with the low volume CHAARTED. For example, the patients with lung-only metastases seem to have a more indolent outcome with hormones alone, and patients who have multiple lymph node only metastases can have a short outcome with the hormones, and some have a long outcome. So there are some definitions. What if a patient has eight boney metastases in their vertebral bodies and none outside? Well, I think you can use clinical judgment to say, "Well, that's a person who has a poor prognosis."
The reason we did the qualifier beyond the vertebral body and pelvis is because some patients have DJD, which get read as metastases. So it was in the absence of good imaging to really classify, that was the rationale. A whole other conversation is the person who's low volume by conventional imaging, but widespread with PSMA PET, that's another URO Today conversation.
Mary Ellen Taplin: Mm-hmm.
Alicia Morgans: Yeah.
Chris Sweeney: And I refer people to an article first authored by Neha Vapiwala, ECOL colleague?
Alicia Morgans: Yes, yes.
Chris Sweeney: Where title has “putting the horse before the cart”, where we can actually learn how to annotate volume more accurately as a biomarker with PSMA PET imaging, but we've got a lot of work to do.
Alicia Morgans: Absolutely. What do you think about systemic therapy, though? If you're thinking about radiating the prostate, per STAMPEDE, in low volume disease, only about 18% of patients actually had docetaxel. There were a portion of patients on that trial that had chemo-hormonal therapy, or sort of optimal systemic therapy as we knew it, and then there were the rest. What are your thoughts about whether the systemic therapy is really additive to what we're doing with radiation versus not? I don't think there's actually a clear answer that we can give there, but what are your thoughts?
Chris Sweeney: I'm going to ask Dr. Taplin, who is a clinical trial guru.
Alicia Morgans: Yes.
Chris Sweeney: And intimately involved with the cooperative groups about her opinion about the value of doing this SWOG study, the Brian Chapin study of best systemic therapy hormones for six months, plus or minus abiraterone or docetaxel if there in a response where randomizing them to radiation surgery, or just systemic therapy alone in the advent of this data from Europe. Is that study still a reasonable study? I've got an answer, but I'd love to hear yours.
Mary Ellen Taplin: I think it's reasonable. I don't think we have any... We've never had any prospective data comparing surgery and radiation, for one thing, and people have a lot of biases of what they want to do. So it'll give us at least, I don't know if it's powered to actually look at that, because I think it's just giving patients the options, but I think that will be an interesting part of that study.
Chris Sweeney: I 100% agree.
Alicia Morgans: There's also the systemic therapy component of that trial.
Chris Sweeney: Exactly.
Alicia Morgans: Which I really like. We do not have this trial open, in full disclosure, for multiple reasons.
Mary Ellen Taplin: Yeah, we don't either. Yeah.
Alicia Morgans: But the six months of best systemic therapy allowing the patients to declare themselves, essentially, are you going to be a responder, or are you going to rapidly progress through this, that to me is almost like a safety.
Mary Ellen Taplin: Before the local therapy.
Alicia Morgans: Before the local therapy.
Mary Ellen Taplin: Yeah.
Alicia Morgans: That, I think, is a critically important component of that trial.
Chris Sweeney: I 100% agree. To put that another way, if we now look at our recent experience with CARMENA in kidney cancer in the GU world, nephrectomy plus interferon was better than interferon alone. Ineffective systemic therapy, or less effective systemic therapy, local control mattered. Now, once we get to systemic therapy with sunitinib, we see less of a benefit for the upfront nephrectomy. Some patients got it at the back end if they had control. So I think the CARMENA experience tells us we cannot rely on old datasets to say how it impacts our current, how it should be rolled into our current management.
So I think the SWOG study is very, very appropriate with complete informed consent, for sure. I do know it's actually causing, I think the word would be some very interesting conversations between the UK and the US.
Alicia Morgans: Yes. Twitter is afire.
Chris Sweeney: Twitter is afire, and what the different guidelines are. We tried to get it into this European Urology focus edition, but there was just a little bit too much... It didn't quite enough have time to get to the point of how to do that, but look out for a debate between the UK and the US for the value of the SWOG study coming out soon.
Alicia Morgans: Okay. That's definitely something on the radar. But just to comment one more time on systemic therapy in the setting of radiation, what do you think about systemic therapy, particularly optimizing systemic therapy? Are we really going to be adding a lot to the radiation? There are folks who say the benefit of radiation may overcome the benefit of systemic therapy. They may not be additive, I guess is the point. You'd be exposing patients to additional systemic therapies when all you need to do is radiate the prostate. I'm not saying that that's my view, necessarily. I'm just curious as to your thoughts.
Mary Ellen Taplin: Yeah. And as data's evolving, my bias would be that the systemic therapy is very important. In every stage of aggressive prostate therapy, the systemic therapy improved outcomes over and over, compared to no systemic therapy or less intense systemic therapy. So I would be personally hesitant to think that radiation, whether it's higher dose or external plus brachy. Maybe in a very small subset that needs to be defined, that approach would be acceptable, but in the context of likely systemic disease, however, we define that, I think the systemic therapy would be a very important component.
Alicia Morgans: And in my practice, when I see these low volume metastatic patients, we're doing radiation to the primary, and we're doing ADT plus abi.
Chris Sweeney: Mm-hmm.
Alicia Morgans: So I've had conversations with some folks from STAMPEDE who've said, "Well, we can't necessarily make those jumps." And we're also in different regulatory environments, where I can make that leap, and I don't know that they necessarily are able to do that. But that's my practice. On trial, now that we have actually a collaborative trial with your group open, we'll be radiating the metastatic sites, as well, only on trial. But what are your thoughts?
Chris Sweeney: Absolutely. It'll be interesting to see if the STAMPEDE are offering the docetaxel, based on their dataset, but that's another question.
Alicia Morgans: Yes.
Chris Sweeney: So, two things, we will get, I think, good information about abiraterone and radiation to the prostate from PEACE-01.
Alicia Morgans: Yeah.
Chris Sweeney: The study being led by Karim FIzazi that's fully accrued. It also had patients getting docetaxel, as well, but we'll hopefully have some data within two years. Hopefully sooner.
Alicia Morgans: Yes.
Chris Sweeney: Issue one. Right now, I will propose intensification of systemic therapy, if it were me and I was a young person with prostate cancer. And young is in the eye of the beholder. So I will actually do two years of hormonal therapy with abiraterone, if they are a good abiraterone candidate and it's not going to send them broke. So it's the plus/minus around it's the optional extra, and if they can do it. Then I would add radiation to the prostate and to the bone metastases, and I would stop therapy after two years. That's somewhat controversial.
There are studies of best systemic therapy plus/minus radiation to all the disease, including the prostate, if they're de novo. And I am a little bit distressed by those studies, because they are condemning them to lifelong castration, and we've all got anecdotes where some of us have stopped the hormones after the systemic therapy and the local ablative therapy to all known metastatic disease, and five years later their testosterone was recovered, and their PSA has never risen. I think we need to revisit getting back to putting treatment breaks in, because I think we owe it to our patients not to sit on our laurels and say can we actually think about timeframes of five and ten years with quality of life being an important parameter, one of your key goals in life.
Alicia Morgans: Yeah.
Chris Sweeney: And I 100% support. And I think recovery of testosterone for metabolic health, as well as quality of life and sexuality is very important.
Alicia Morgans: Sort of a breast cancer model, in a sense. I mean, five years, ten years, that's mostly in the adjuvant setting, but thinking about cessation and is there a trial that is being worked on, developed with cessation in mind?
Mary Ellen Taplin: Yeah. One of our colleagues, Atish Choudhury, is proposing it to the cooperative group, to the alliance group of in patients who've had deep, durable responses to abiraterone of stopping either the abiraterone alone, or stopping all the hormone therapy, looking at an intermittent approach. And that's being evolved.
Chris Sweeney: And it's the evolving conversation where there's some degree of equipoise is whether you can stop everything or whether you need to continue the testosterone suppression or maybe an AR inhibitor, without the testosterone suppression, or stopping it altogether.
Alicia Morgans: yes.
Chris Sweeney: So, it's going to wind its way through and be open for comments for quite a while.
Alicia Morgans: Yes.
Chris Sweeney: And we'll have new data at ASCO 2019 about the role of enzalutamide in metastatic hormone sensitive setting.
Alicia Morgans: Yes.
Chris Sweeney: And apalutamide, building upon what we see with ARCHES delaying of radiographic progressions free survival in the metastatic hormone-sensitive setting. I think how we're designing trials now may need to be reconfigured once we see the data from ASCO 2019.
Alicia Morgans: It'll be a big year, and I really appreciate you having a conversation about where things stand now, thinking about where they're going in this relatively rapidly evolving space, metastatic hormone-sensitive disease. So thank you both for your time today.
Chris Sweeney: Thank you, Dr. Morgans.
Mary Ellen Taplin: Thanks a lot, Alicia.