Management of mCRPC using Sipuleucel-T - Evan Yu

Sipuleucel-T (Provenge®) has been FDA approved since 2010 in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). The IMPACT (Immunotherapy for Prostate AdenoCarcinoma Treatment), was a randomized, double-blind, placebo-controlled study of 512 men with metastatic, hormone-refractory prostate cancer. Initially, the targeted patients were those with a Gleason score of 7 or less. Later this criterion was changed to include patients with a Gleason score higher than 7. Patients received intravenous (IV) sipuleucel-T (n = 341) or placebo (n = 171) at two-week intervals, for a total of three doses.  At 36 months, a survival benefit of 4.1 months was noted with sipuleucel-T; median survival was 25.8 months with sipuleucel-T and 21.7 months with placebo. Overall survival was significantly prolonged for sipuleucel-T patients (P = 0.032; HR = 0.775) at the time of cutoff. Results were consistent in multiple patient groups.
An updated analysis performed after the death of 349 patients at an estimated follow-up of 36.5 months showed that sipuleucel-T’s treatment effect remained significant (HR = 0.751; P = 0.012).
Evan Yu, MD discusses the benefits of Provenge® in clinical practice based upon these data.  He also reviews additional data from post hoc analyses of the IMPACT trial which demonstrate that men with lower PSA quartiles have better outcomes with sipuleucel-T. Additionally, he discusses ongoing studies with sipuleucel-T looking at predictive biomarkers, combination therapy with immune checkpoint inhibitors and use in the active surveillance setting.

Biographies:

Evan Yu, MD, Medical oncologist, treats prostate, bladder, and testicular cancer, and is passionate about providing a personalized medical approach to a selection of novel therapies, as well as understanding biologic mechanism of drug sensitivity and resistance. Professor, Department of Medical Oncology, University of Washington School of Medicine and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center.

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.

Read the Full Video Transcript

Alicia Morgans: Hi. I'm delighted to have here with me today, Dr. Evan Yu, who is a Professor and GU Medical Oncologist at the University of Washington. Thank you so much for being here.

Evan Yu: It's great to be back. Thanks for having me.

Alicia Morgans: Of course. Evan, I always love to pick your brain on the latest and greatest, and one drug that we haven't heard as much about in recent past, though it is FDA-approved for many years, is sipuleucel-T. And I think there's actually been some data released, and I'd love to review what's going on with sipuleucel-T, particularly as we find that a lot of these AR-targeted therapies are moving forward, and there may be opportunities to use some drugs with novel mechanisms in the mCRPC space. What's going on?

Evan Yu: I think, as you know, sipuleucel-T's been FDA approved since 2010. It's approved for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. There have been some nice post hoc analyses that have shown that the men with the lower PSA quartiles seem to do best with sipuleucel-T, so I think that's one of the things to recognize is just that the field is trying to move towards predictive biomarkers.

They're trying to identify markers like BRCA2, DNA repair gene alterations, mismatch repair gene alterations. Things that might point towards PARP inhibitors, towards immuno-oncology agents. I think along all that flurry, that sipuleucel-T probably just hasn't gotten as much attention recently. That's because there is no clear biomarker.

But at this point in time, there are plenty of studies that have looked at some immune biomarkers that I think the field probably hasn't caught onto, because they're not commercially available, that are of interest with sipuleucel-T. There are some markers that look at immune response of the T-cells. That look at antibody production. These seem to correlate with outcomes of overall survival.

At the end of the day, there are studies that are happening now that are using those biomarkers as endpoints. Are they going to lead to regulatory approval? No. But they're going to lead to improving our understanding and knowledge of who might respond well to these therapies, of what therapies might be good to combine sipuleucel-T with, etc. 

There's a lot of stuff that's actually happening. It's just, I think the field right now is caught up on DNA repair alterations, mismatch repair alterations, and rightfully so. They should be. But this is just something that, again, because there's not a gene you can point to and say, "That's mutated, and this is who it's going to work well for, sipuleucel-T." I think, for that reason, it just hasn't gotten as much attention recently.

Alicia Morgans: That makes sense. But there are still, I think, patients who might benefit. Part of understanding these biomarkers is really selecting patients who might benefit most. Who are the patients that you really are thinking about when you're looking at a patient profile and saying, "Okay. You're the right person for sipuleucel-T."

Evan Yu: As I said earlier, it's asymptomatic, or minimally symptomatic men with metastatic castration-resistant prostate cancer. Now, who do I really pick? I would say I stick more to the asymptomatic men. I stick more to those with lower PSAs. 

I alluded to this quartile analysis earlier. What they did is, in this post hoc analysis, they took men from the IMPACT randomized phase III trial, and they took the patients and broke them down in different quartiles: lowest PSA quartile, highest PSA quartile, etc. They compared the control-arm versus the treatment-arm.

The quartile with, obviously, the best hazard ratio was the quartile with the lowest PSAs. It kind of makes sense, right? Because this is a drug, I wouldn't call it a remission-inducing drug. It's probably a drug that slows down the disease. That's why you don't necessarily see a big drop in PSA. You don't necessarily see improvement in time to progression, but you do see an overall survival benefit, it is just that it's slowing the disease down. Who's apt to get the most benefit out of that? Those with the lowest burden of disease, and those with the most indolent disease.

I really try to pick patients who have a lower PSA. Who might have a lower burden of disease on their imaging studies? That might naturally lead to the question of "Maybe we ought to be using it even earlier, right?" I mean, but that's the regulatory approval we have right now. But I certainly think, theoretically, we might get more bang for your buck if you use it even earlier.

Alicia Morgans: With so many of our treatments, I think, when we move them earlier, we find that there may be more bang for the buck, in that space. There are some studies being done, I think, active surveillance, at least, and perhaps other areas that you know about, where we could be investigating the utility of sip-T in those spaces. There are also some combination studies, as well. Can you speak a little bit to that? 

Evan Yu: Yeah. Let's start with the idea of moving it earlier. I think an ideal setting to go is to go from the metastatic castration-resistant prostate cancer to the metastatic hormone-sensitive disease space. But realistically, there's been so much excitement, with that, with abiraterone there, with docetaxel there. More recently enzalutamide. We'll see more with enzalutamide, and with apalutamide at ASCO here.

It makes it a bit challenging to know how to insert yourself in there. If you were to march forward one more step earlier, you could go to something like castration-sensitive biochemically-recurrent disease setting. But that's a very heterogeneous patient population, right? There are some patients who never need to be treated, and some patients who have a biology that behaves more like someone with metastatic disease already.

Picking out those patients is challenging, and there is a large, randomized phase III study with enzalutamide in that setting that will read out in the near future. I think we have to see what happens there.

What Dendreon has chosen to do is go really, really early. They've gone into the active surveillance space. Which is quite interesting, because we actively survey people because we think that they have a rather indolent disease, and might not need to be treated. But we recognize that there's anxiety that comes with that. We recognize that a good chunk of patients that are on active surveillance eventually do have upgrading of their disease, and do require, or at least undergo, treatment.

They have a 450 patient randomized trial, called the ProVent trial, where they're looking at Grade Group 1 and 2 patients for eligibility. They're randomizing on the study to sipuleucel-T or not. The primary endpoint of that study is looking at the percentage of patients that have upgrading of the disease. I believe it's a three-year endpoint. Trying to prove that with sipuleucel-T, they can decrease that upgrading of disease at a three-year timepoint.

It's interesting study design, and we'll have to wait and see what the results are, but certainly, they are going early. They're going really early.

Alicia Morgans: Yes, very early. I think, in the context of the landscape as it is, where we have multiple drugs trying to target the androgen-receptor. We've got chemotherapy. We've got radiopharmaceuticals. It's nice to know that we have an immunotherapy that has some benefit, particularly since we've seen some that, PROSTVAC, for example, did not seem to meet that bar. 

It's nice to just have those other options, in terms of mechanism of action, I think. If we can find that a combination, or moving it earlier, provides more disease control, and a longer time to needing either upgrading or a progression of disease, well, that would be great.

Where do you see sipuleucel-T going in the future? Because as you said, it's actually been here with us for some time, we've had this approval. Where do you see things going?

Evan Yu: Yeah, well I think we have to be honest and recognize that it's kind of a niche drug, because of the fact that it has a regulatory approval that is more for the lower-volume, indolent disease patients, with the minimally symptomatic or asymptomatic patients. I think, right now, it stays there. It has the potential to move earlier, to that active surveillance setting.

Then there are some interesting combinations. I know you asked me about that, so I'll answer that now. It's just that you mentioned immunotherapy combinations. They do have a study that's combining sipuleucel-T with ipilimumab. I believe that's being led at MD Anderson. There's another one, out at the University of Hawaii, that's with atezolizumab, which makes a lot of sense, because you prime the system, and then you want to release the brake on the T-cells there, at the tumor microenvironment. Yeah, that makes a lot of sense, as well.

Those, to be fair, those are phase II studies, and they're not going to lead to regulatory approval. But if you saw some really, really impressive data, that might lead to the development of a phase III trial down the road. Those would be things that I would keep my eyes out for.

There's also combinations with radiation that make a lot of sense. The whole idea of the abscopal effect, with "Let's kill some cells, release some tumor antigens." We have, basically, it's a vaccine cellular therapy, where we're trying to produce antigen-presenting cells here, with sipuleucel-T. 

It makes a lot of sense there to combine it with certain types of radiation therapy. I think there's one with SABR, or stereotactic ablative radiotherapy. There's another one that looks at radium-223. I think an interesting thing with the SABR trial is that they're looking at a primary endpoint of time to progression, which has never been shown to be positive with sipuleucel-T, but this is a different setting, where your theory applies a little bit of local radiation therapy to a metastasis, release those tumor antigens, come in with the sipuleucel-T, so maybe we'll see something different this time around.

Again, those are some interesting things that are happening, and we want to see something good happen as results from these studies, to lead us to the next step.

Alicia Morgans: Absolutely, so more to come. We will see where things go. For now, patient selection is really the way to go, but really an important tool in the tool-chest for those patients who meet those criteria, as you're mentioning.

Thank you so much for talking about this with me.

Evan Yu: Yeah, thanks for having me again.
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