Advancing Knowledge About The Treatment of Advanced Prostate Cancer, Highlights from GU ASCO 2021 - Praful Ravi

May 5, 2021

Praful Ravi, MB, BChir, MRCP, and Alicia Morgans, MD, MPH highlight several prostate cancer abstracts from GU ASCO 2021 and discuss the clinical landscape for treating prostate cancer. They highlight results of the ACIS trial assessing the combination of apalutamide + abiraterone acetate as compared to abiraterone acetate alone in patients with chemo-naive metastatic castration-resistant prostate cancer (mCRPC). They also discuss the TheraP ANZUP 1603 trial which showed significant improvement in progression-free survival with a hazard ratio of about 0.6 in favor of lutetium PSMA. Lastly, they discuss the G-MINOR trial, Genomics in Michigan ImpactiNg Observation or Radiation, and the approval of gallium-68 PSMA in the United States.

Biographies:

Praful Ravi, MB, BChir, MRCP, Medical Oncologist, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, 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.


Read the Full Video Transcript

Alicia Morgans: Hi. My name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, Dr. Praful Ravi, who is a GU medical oncologist at the Dana Farber Cancer Institute. Thank you so much for being here with me today, Praful.

Praful Ravi: It's a pleasure to be here with you Alicia.

Alicia Morgans: Wonderful. Well, thank you so much for being here. I really wanted to talk with you a little bit about your thoughts on GU ASCO 2021, which was a virtual meeting, but really did pack quite a powerful punch and included some important studies for patients and clinicians who treat them. Let's start with the ACIS trial. Can you tell us a little bit about it?

Praful Ravi: Yes, absolutely. The ACIS trial was, as you said, one of the big oral presentations in the prostate section at GU ASCO. This was a trial presented by Dr. Dana Rathkopf on behalf of all the investigators. This was a first-line CRPC, castrate-resistant prostate cancer trial, looking at the addition of apalutamide, which is an AR antagonist to abiraterone, and comparing that to just abiraterone alone. The hypothesis was is if you sort of dual inhibit AR both testosterone synthesis and the AR signaling, can you get superior outcomes to just blocking testosterone synthesis with abiraterone. And the background to this is that there have been a couple of other prior studies examining the sort of dual pathway inhibition. There was the Alliance trial presented at ASCO two years ago, looking at enza plus abiraterone versus enzalutamide. And there wasn't a survival benefit in CRPC.

And there was a smaller trial from the Latin-American co-operative group presented at ASCO last year, looking at abiraterone plus apalutamide versus apalutamide versus abiraterone in sort of more earlier states of disease in men starting ADT. And there didn't seem to be a massive benefit by adding apalutamide to abiraterone. With that in mind, this was around a 1,000 patient trial, first-line CRPC and men were randomized one to one to apalutamide plus abiraterone or abiraterone alone. And the primary endpoint in this trial was radiographic progression-free survival. In terms of sort of the key results, the population of patients was sort of as expected for a first-line CRPC study, around 15% of patients had visceral disease and the primary outcome was met. The primary outcome was radiographic PFS and there was a seven-month improvement in radiographic progression-free survival with adding apalutamide to abiraterone. So it improved from 16 months to around 24 months.

However, a key secondary endpoint overall survival, there was no difference in overall survival between the two arms, both arms had overall survival around 33 to 35 months. So while there was a significant benefit in PFS or radiographic PFS, the lack of benefit in OS is suggestive that there is not a huge amount of significant survival benefit that you are getting by combining this both upfront, rather than perhaps using things sequentially. And this plus sort of the data from the other trials like Alliance and the Laycock study suggests that perhaps this doesn't really have much of a role in terms of changing practice today.

Alicia Morgans: That's interesting too because this combination approach was in patients who had received ADT alone in the metastatic hormone-sensitive state. And so these were first-line mCRPC patients. And so there is also a question I would think that there may be fewer patients who are able to get these AR targeted agents as a first-line approach in the mCRPC setting with the way that so many things are shifting. And of course, the concerns in the US at least about the potential for financial toxicity when you are using multiple agents. From your perspective, I think you said, this doesn't necessarily seem like something that will be practice-changing. Are there any other things that we can learn from or anything else that you would want the audience to take home from this presentation?

Praful Ravi: I think as you exactly mentioned, there is the safety, was as expected with adding apalutamide to abiraterone, it wasn't a huge excess of toxicity, but you get the apa side effects, the rash, maybe more blood pressure. But I think as you mentioned, financial toxicity is an important thing to consider as is the pill burden. You have abiraterone, which is four pills, apalutamide four pills, prednisone may be two pills, these are a lot of pills that you have to take every day. And if you are not really improving survival, I don't think that there is much of a role. Particularly given that these agents are now being used earlier and earlier in the hormone-sensitive setting as single agents and trials evaluating combination therapy. I think the key things to look out for are how are these agents going to work when used in CRPC, with patients having already received similar agents or other agents in the hormone-sensitive setting?

Alicia Morgans: Yeah. Well, thank you. And I appreciate that. And I do look forward to hearing more insights as I'm sure the group will continue to perform additional analysis to help us learn more from the ACIS trial, but thank you for sharing that. And this was definitely a study of interest for sure, at GU ASCO. One of the other big splashes was an update from the TheraP trial. Can you tell us a little bit about that?

Praful Ravi: Yeah, I think, as you said, TheraP was another key oral presentation. This is a trial from the ANZUP group, in Australia and New Zealand, presented by Dr. Michael Hofman. This looked at lutetium PSMA, which is a radioligand or radiotherapeutic. It's a beta emitter. And this trial looked at patients with CRPC who had received prior docetaxel and many who had received prior AR targeted therapy and randomized men one to one to either cabazitaxel, which is approved post docetaxel or lutetium PSMA. And there had already been some data presented at ASCO in 2020, looking at the PSA50 response rate, which seemed higher, which were higher with lutetium PSMA. And this was an update looking at patient-reported outcomes, as well as more efficacy data. The key headline result from this was that there was a significant improvement in progression-free survival with a hazard ratio of about 0.6 in favor of lutetium PSMA.

And there was a doubling of the sort of RECIST overall response rate from 25% with cabazitaxel to around 50% with lutetium PSMA. This was all very encouraging. Obviously, overall survival was not an endpoint in this trial and we will be waiting to see the results from the VISION trial, which I think there has been a recent press release about. But in terms of safety and patient-reported outcomes, this is a theranostic or a therapeutic that we know can cause some bone marrow dysfunction, some issues with taste because of the expression of PSMA in the salivary glands and that was what they saw in the trial where some of these cytopenias and the dyschezia were the key side effects.

I think one of the other key takeaways, aside from needing overall survival, is obviously very encouraging and interesting. I think if one of the things that I found interesting in this trial if you look at the progression-free survival curves, they seem to diverge after around six months. They sort of stay together and then you see the benefit with the lutetium PSMA. And we don't really know the reason for this. Is this because you are only getting the benefit in men who complete all six rounds of their lutetium PSMA similar to say, radium, where we know from the sort of post-talk exploratory analyses that men getting the five or six rounds of radium are the ones who seem to derive the benefit. I think this will be interesting to look out for and obviously, we await the VISION trial where this is phase three of adding lutetium PSMA to best standard therapy or best supportive care and seeing whether there is a survival benefit with that.

Alicia Morgans: Yeah, I think, particularly as you've mentioned with the VISION press release, so saying that progression-free and overall survival seem to be improved with lutetium as compared to best supportive care, and that was at the discretion of the treating physician. But particularly in the setting of that, if lutetium becomes more widely available, I can see that the TheraP trial, even though it's only a phase two, potentially impacting the treatment landscape, particularly because as you mentioned, the adverse events were relatively well tolerated or relatively low as compared to the cabazitaxel group, which did not identify any new safety signals, but is maybe a little more challenging in terms of cytopenias and some other complications. But both of these agents are good treatments for mCRPC. I'm really encouraged that this may at least give us another option to reach for and that we may ultimately have access to, continued access to cabazitaxel, and now additional access to lutetium to really continue to lengthen the survival and improve hopefully the quality of the survival of our patients. Any other lasting thoughts for us to think about and remember from TheraP?

Praful Ravi: I think you've absolutely hit the nail on the head. Metastatic castrate-resistant prostate cancer is unfortunately not curable so it's about putting more tools into our toolbox and lutetium PSMA seems to be a very exciting tool. And we will wait to see the confirmatory results from VISION, but also trials looking at combination therapies, moving lutetium into the earlier disease settings and disease spaces to see whether we can perhaps get more durable benefit with this therapy earlier or even later on.

Alicia Morgans: Absolutely. Well, let's move on. I know you had wanted to talk about a couple of additional abstracts, the G-MINOR abstract from the Michigan group. Tell us a little bit about that.

Praful Ravi: Yeah. This was a very interesting study. This is from the Michigan Collaborative Urologic Group. And they looked at basically patients, the population of patients who undergo radical prostatectomy and have high-risk features, T3 disease, positive margins. And this is a population of patients in clinical practice, where we sort of had discussions about adjuvant therapy or early salvage or observation and then early salvage therapy. And they looked at studying a genomic classifier, Decipher in these patients and to see whether using a genomic classifier in a similar way to Oncotype is used in breast cancer. Does that impact decision-making?

It is important to say in this trial, the primary endpoint was sort of to look at the rate of adjuvant therapy in each arm. So men with these high-risk features are randomized to sort of usual care where they are reviewing the sort of pathological findings with their oncologists and radiation oncologists, their CAPRA-S score, or to usual care plus the Decipher score. They found that the rates of adjuvant radiation were higher in men in the randomized to genomics arm, around 10% of men in the genomics arm got adjuvant RT versus 2% in the control group, but the overall rate of adjuvant therapy, including ADT.  And if you include ADT with RT, there wasn't a seemingly statistically significant difference between the two arms.

They also found that the higher the genomic classify score or the Decipher score, physicians were more likely to recommend adjuvant therapy. Really this was interesting because it is showing that using Decipher changes management. However, I would say that while A, this is interesting, B, it is important to have sort of this prospective validation of Decipher in a trial like this, but we do need to see whether that change in management actually improves survival or metastasis-free survival in patients, rather than actually just having a management change. We need to see whether that change in management translates to actual benefit for patients.

Alicia Morgans: Absolutely. I think that is always one of the challenges in these types of studies that define their endpoint around a change in management. And to that point, actually, many of the PSMA imaging trials, at least the early ones were really designed around a change in management. And there was a PSMA and MRI comparative study that was also presented at GU ASCO. And I'd love to hear your thoughts on that one.

Praful Ravi: Yeah. I think, PSMA PET, as with lutetium PSMA as a therapeutic, PSMA PET is diagnostic imaging that has received FDA approval, at least in limited areas of the US and it is widely used across the world and probably will be used widely across the US in the next few months. This was a study, another oral presentation presented from the UCLA group where they've been using gallium-68 PSMA imaging for the last few years. They looked at patients with high-risk prostate cancer who had received gallium PSMA PET scans and the multiparametric MRI. Normally with high-risk disease, we're staging with an MRI prostate and conventional scans, CT and bone scan. In their cohort, they had a gallium-68 PSMA as well as an MRI.

And they wanted to look at...we know that PSMA PET can pick up sort of distant pelvic nodal and distant metastatic disease. How does it do in sort of identifying the primary tumor? This is a relevant question because once PSMA PET is approved, is there still going to be a role for MRI in local staging? And I think the key result from this, they had about, I believe around 90 or 70 patients who had both imaging modalities done prior to prostatectomy and they found that PSMA PET wasn't able to detect the primary T lesion, but MRI seemed to be better at finding extracapsular extension or seminal vesicle invasion, than PSMA PET. At least on their analysis of a relatively small cohort. Really my takeaway from this study was that while PSMA PET is certainly going to be used in sort of distant and sort of local regional staging, and I think MRI will still have a role in sort of local T staging for high-risk disease.

Alicia Morgans: Yeah. And I agree with you, I had a similar takeaway and I think that makes sense clinically. For example, and this is one patient in one person's clinic, but for example, we recently had a patient get a PSMA PET for a rising PSA in the post salvage RT setting. And so then the patient initially had a prostatectomy, so just looking for something that we may be able to target and the patient had a local recurrence sort of close to the left seminal vesicle or at least where that would have been had the patient not already had a prostatectomy. So having the MRI to really further elucidate that pelvic region is giving our urologists some sense of whether there might be some opportunity for local salvage treatment there.

And that area is still evolving as well, but the anatomy is so well defined within MRI and of course, its activity that is just defined with a PSMA PET, that it seems like there is going to be a role I think in our treatment of these patients with both of these modalities, really having sort of strengths in different areas, but both being useful tools, as you said to have in the toolbox to really make sure we can answer the questions we need to answer, to help our patients. I really appreciate you bringing this also into our conversation. If you had to give sort of an overarching message from GU ASCO 2021 about the prostate presentations this year, what would that be?

Praful Ravi: I think in sort of summary, there wasn't anything absolutely practice-changing. However, we did see a lot of data for sort of the PSMA PET imaging and theranostic world. I think that is sort of the next field that is coming to prostate cancer. I think also presentations on the sort of using genomics to help guide decision making. These are very early stages. We are going to use them to guide decisions. Is that going to change outcomes? I think that is wherein the next few years are going to tell. I think those are my key takeaways in terms of new sort of areas of therapies and imaging, as well as using, in addition to clinical risk stratifying tools, having sort of more genomic classifiers, and seeing whether they can help us too.

Alicia Morgans: Wonderful. Well, I think that it was definitely a year, as you said, that really advanced our knowledge, but there is so much still to learn. I think we are going to have jobs for a long time, Praful, as we try to continue to understand better the really the intricacies that will allow us to match the right treatment to the right patient and to understand the biological drivers of this disease and really make a difference. Thank you so much for taking the time to share your knowledge and your expertise with us today.

Praful Ravi: It was a pleasure. Thank you.
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