Advanced Prostate Cancer Clinic: What’s Changing? - Maha Hussain
December 18, 2019
Maha Hussain, MD, FACP, FASCO, is the Genevieve Teuton Professor of Medicine in the Division of Hematology-Oncology, Department of Medicine, and the Deputy Director at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine.
Gordon A. Brown, DO
Lawrence A. Gervasi, MD, FACS, CPI
Timothy A. Richardson, MD
Conference Coverage: ASCO 2019: Alliance A031201: A Phase III Trial of Enzalutamide Versus Enzalutamide, Abiraterone, and Prednisone for Metastatic Castration Resistant Prostate Cancer - Medical Oncologist Perspective
Conference Coverage: ESMO 2019: CARD: Randomized, Open-label Study of Cabazitaxel vs Abiraterone or Enzalutamide in Metastatic Castration-resistant Prostate Cancer
Conference Coverage: ESMO 2019: PROfound: Phase 3 Study of Olaparib versus Enzalutamide or Abiraterone for mCRPC with Homologous Recombination Repair Gene Alterations
Maha Hussain: Thank, you Neal, very much. It's really a pleasure to be here and a great program. So I'm going to try to speak and cover multiple areas at one time. I apologize if I'm speaking too fast, but as I was telling them earlier, it's been a remarkable few years in prostate cancer in terms of the evolution of therapeutics. And so, my title is for advanced prostate cancer, what's changing? I'm going to be talking specifically about metastatic hormone-sensitive, castration-resistant, and non-metastatic castration-resistant disease. I will begin first with the metastatic castration-resistant disease because this is really where a lot of the drug development began and the progress that we have seen over the past several decades and literally just since, and I can't point out here, but since 2004, 15 years, we've really seen a plethora of clinical trials that had led to significant clinical benefit for patients, primarily overall survival advantages and definitely a quality of life improvement and pain control and so on.
The last drug that had been specifically FDA approved as part of a blanket approval, but where there is a prostate cancer cohort was pembrolizumab. As you know, it's an immune checkpoint inhibitor and the FDA approval was actually based on a basket-type trial that had patients who had microsatellite instability or mismatch repair deficient tumors. And I should point out, only about 3% of patients with metastatic castration prostate cancer potentially could qualify for this treatment. Now, there's been really significant changes that occurred over the past a few years, but specifically in prostate cancer, the investment in research has occurred at the level of castration-resistant disease, primarily looking at next-generation trials where multi-targeted strategies have been evaluated, and these multi-targeted strategies are logical. In fact, if you have two drugs that are life-prolonging, does putting them together give you a better return on investment than say sequential therapy.
Unfortunately, more is not always better. So two trials were recently reported. One is a co-active group trial that looked at enzalutamide with or without abiraterone in metastatic castration-resistant disease. This was reported at ASCO and unfortunately, the combo was no better than the single abiraterone. And the other trial was actually abiraterone with or without radium, and this was reported in Lancet Oncology and again, unfortunately, the combo was not better. The one thing that emerged from those radium based trials is the importance of bone-targeted treatments with regard to skeletal-related events. So please be mindful of prescribing patients Zometa® or denosumab if you're intending to give them bone-targeted therapy. They should be evaluated for it anyway and given, but if you're specifically intending to send them for radium, this is important.
Ongoing and pending examples are listed in there. CHAARTED 2 is a Phase II trial cooperative group looking at cabazitaxel plus abiraterone versus abiraterone in patients who might've seen Taxotere for metastatic hormone-sensitive disease. Ipatasertib is another drug combined with abiraterone. The PSMA VISION, some of you may have been participating in it and of course, immune therapy plus AR targeted therapy is being evaluated. I highlighted in turquoise below number three and number four, these are emerging trends with regard to questions that we had no answers to up until literally ESMO in October this year. One of them is what is the optimal second-line treatment post-frontline AR targeted therapy. So you have a patient with metastatic castration-resistant disease, you gave them abi or enza and they progress on that. What would be the optimal thing? Should you go to another AR targeted drug or should the patient get chemotherapy? And the other one is the role of targeted therapy. So I will begin first with the first question.
CARD was a randomized open-label Phase III clinical trial that was reported at ESMO and published in New England Journal of Medicine as a joint publication just literally last month. And it basically was answering the question is chemo better than an AR targeted therapy in the second-line setting? This is the design of the trial, where men with metastatic castration-resistant disease and prior docetaxel therapy, we're basically randomized to cabazitaxel or abiraterone or enzalutamide based on what they have seen prior to that. And the primary endpoint for the trial was radiographic progression-free survival. The primary endpoint was fought by central review and there were a series of secondary endpoints.
On the left-hand side here as you see is the actual radiographic progression-free survival which was in favor of the cabazitaxel. This is something I think is important to consult with patients on with regard to a standard of care type treatments. Interestingly, once we saw this data in clinic, I counseled my patients who progressed on abi and I'll say, "enza or this," but it looks like chemo is better and patients who are asymptomatic still would prefer to try an oral agent before they go actually into chemotherapy, even though we think chemotherapy is likely better. And there is a trend on the second part of the slide with regard to overall survival. The trend appears to be quite favorable with regard to cabazitaxel. The second question was the issue of targeted therapy or precision medicine or molecularly targeted treatment. As you very well know, prostate cancer has really lagged behind a lot of solid tumors with regard to targeted therapy and precision medicine strategies. The research began moving into that direction, I would say the last probably seven to eight years when emerging data regarding the genomics of prostate cancer came out of the Stand Up To Cancer.
So this was the East coast DREAM team, international DREAM team Stand Up To Cancer data that was published by Dan Robinson in 2015, and this is work that was led by Arul Chinnaiyan and colleagues from the days when I was at Michigan and of course Memorial and other multiple centers. What we did is we took men who had metastatic castration-resistant prostate cancer. These men underwent a biopsy of a metastatic site and then the tumors were sequenced. And at the end of the day, as you can see here, prostate cancer has a lot of molecular alterations as is highlighted in this particular slide. But what surfaced was actually an interesting observation that over 20% of these patients' tumors harbored DNA repair defects. BRCA2, BRCA1, ATM and others.
And that kind of stimulated interest in evaluating PARP inhibitors. This came in together with TOPARP-A, which was actually the patients included in this trial were men, their tissues were sequenced as part of the Stand Up To Cancer and what was interesting is the fact that this was a trial that was done looking at a PARP inhibitor in the second-line setting castration-resistant disease at the Royal Marsden in England. And what was interesting that came out of this trial is that just about everybody who responded, 14 of 16 biomarker positive patients responded. And then when you look at it, the patients who responded, the vast majority of them were actually men who had DNA repair defects in their tumor. So all of this, the totality of the data, the biology, the observation, led to this trial that I had the privilege of presenting at ESMO and actually Neal Shore was a partner and a major contributor to this particular trial where we looked at the first, I believe, randomized Phase III trial biomarker preselected for patients to look at the role of PARP inhibitor.
Now, the trial was designed with a key eligibility criteria that men had to have metastatic castration-resistant disease with progression on prior new hormonal agents, so progression on frontline abi or enza in the setting of castration-resistant disease. All these patients had to provide tissue predominantly from primary tumor tissue, but some patients underwent biopsies and then there was a panel of genomics that would have been acceptable for eligibility for this particular trial. The tissue was centrally tested at foundation one and then below, at the bottom part, you will see the list of the gene alterations that were included for the eligibility. Cohort B was patients who had the canonical genes, BRCA1, BRCA2, ATM. We separated them because at the time we designed the trial, these were the genes that had the most information about them from other diseases and in the setting of prostate cancer.
Cohort B was anything else that was not a BRCA1, 2 or ATM. Men were randomized two to one to allow PARP or a physician choice agent. This was not a blinded study, it was an open-label study. I should point out at time of progression on the hormonal agent, the patients were allowed to cross over and the primary endpoint was radiographic progression-free survival. So I want to highlight a few things here. Just to highlight the feasibility of this approach. Surprising to me, men in their mid to late 80s and early 90s, in fact, were enrolled on the study. Again, highlighting the feasibility of doing this approach there. A lot of the patients actually, about a fifth of them, had de novo metastatic disease, a diagnosis was generally predict for the worst prognosis. While you see the PSA medians may not be balanced, the interquartile were comparable in there. And what was I think interesting is that a fifth of these patients, in fact, have seen both abi and enza and about 60 plus percent of these patients have seen chemotherapy, including about a fifth to a quarter have seen both cabazi and Taxotere.
So essentially you're talking about a very heavily pretreated patient population. The good news is the following, is that when it comes to the primary endpoint, which is what's on the left here, the radiographic progression-free survival by independent central blinded review was very much in favor of olaparib, with a essentially doubling of the median survival and more importantly about a 66% reduction in the hazard ratio, with the risk of death or disease progression. And the separation of the curves occurred very early in the process. Other secondary endpoints also showed this favorable trend including the radiographic progression-free survival in the cohort overall. Confirmed measurable disease response was much higher in the olaparib-treated patients compared to the controlled patients, time to pain progression, a very relevant clinical endpoint in prostate cancer, was better and so was an early trend or early observation on trends that favor olaparib with regard to overall survival, but the data is not completely mature yet. And I want to just share it with you.
We do anticipate that once there is enough events, sometime next year, the overall survival data, hopefully it will be reported. The one thing that I think is important for you from the practice perspective to recognize is that not all DNA repair genes are equal. There are different presence. In fact, when we did this testing, seven of 15 genes had alteration frequencies that are very small to even include them in there. Basically less than five patients, and close to 4,000 men were screened internationally. 97% of the patients were randomized too, based on alterations in eight out of 15 genes that are highlighted in there. Not surprisingly, BRCA2 seems to be the biggest driver of things.
One thing I should point out is that there are in just about every other subgroup, there appears to be a trend in favor of olaparib. Obviously these are not powered and this is a complicated analysis, but I think it gives you some feel for when you're talking to patients and counseling them.
Now this is where we are with metastatic castration-resistant disease. I want to move into the metastatic hormone-sensitive disease and the non-metastatic castration-resistant disease. As you all know, the basic principles in oncology is moving effective treatments into earlier phases of the disease where essentially the impact is higher and the, I call it "return on investment" so to speak in terms of improvement in outcomes and prolongation of survival is much better compared to end-stage disease.
The first example was the evaluation of docetaxel in the metastatic hormone-sensitive space in combination with chemotherapy. You're all familiar with CHAARTED which demonstrated that there is an unprecedented improvement in median survival with the combination of docetaxel with hormone therapy.
Interestingly CHAARTED demonstrated that the value is primarily in the high volume patients and for sake of time, I'm not going to define that, but I'm happy to answer questions afterward. The low volume patients, and this is data on the other curve on the other side of the slide, where it was updated data from CHAARTED published in 2018 reaffirming the original observation that was seen. The second example of earlier is better is LATITUDE, and this is a trial that evaluated the addition of abiraterone and prednisone to androgen deprivation treatment in the context of metastatic hormone-sensitive disease. Again, Karim Fizazi published and presented the data in 2017 and at GU ASCO, they updated the data and again a median overall survival of over a year. Again, very much unprecedented improvement in overall survival based on the benefit, even though they chose a higher risk population. I should point out that the FDA approved indication is actually in all comers with metastatic hormone-sensitive disease.
And finally ENZAMET, which looked at enzalutamide and apalutamide in the context of the other trial, both of which again demonstrated an overall survival advantage in earlier trends, very much in favor of the addition of AR targeted drug to androgen deprivation therapy.
The questions that I would say that we have to face now is how best to choose in your practice, and how do you counsel patients? You have now multiple trials that demonstrated multiple agents having a survival advantage. Clearly, with the docetaxel, I would say the volume of disease is a factor. Surprising to me, when I counseled patients in my clinic on docetaxel versus oral therapy, the trend is a 50/50 choice for docetaxel as opposed to oral therapy. I think when it comes to decisions, it's a shared decision, and I think when I say how best to choose, it's a trade-off between toxicity, feasibility, therapy duration, physical costs, monetary costs, as you know we have. And one of the questions that I think I was asked and I kept thinking about it and I think it's a real legitimate question, is androgen deprivation alone a legitimate option in some patients? And I would say yes and happy to answer in what kind of setting.
Now some of the questions that are being evaluated and discussed right now is the role of treating the primary in the context of patients who have metastatic disease and a primary that has not been treated. STAMPEDE data suggests that in fact if you have a patient who has metastatic disease and their prostate primary has not been treated, if they have a lower volume disease, not a very high volume disease, there is an advantage potentially and this is the curve on the center here. There is a potential overall survival advantage in the setting and there is prospective trials that are trying to ask the questions specifically.
The second ongoing question is the issue of oligometastatic disease and how best to handle it and I'm not going to go through it. You have the slides in there, but I think what we know is this. Targeting disease in bone or lymph nodes with radiation alone, potentially can delay the start of systemic therapy. I would argue is that clinical benefit and to me, clinical benefit is prolonging life and reducing the potential morbidity from the disease. There are less of, again, clinical trials trying to address these questions and there certainly are many questions in this space in terms of what counts as oligomets, what location would you consider oligomets biologically and so on. And so this is an area that is being addressed and I'd like to refer you to a manuscript we recently published in JCO, trying to argue and discuss all of these points that I'm making for you. And this particular slide just highlights how many clinical trials are going on right now in the hormone-sensitive space trying to address many, many questions including multi-targeted strategies, management of the primary disease and management of oligometastatic disease.
Finally, I want to end with the space of non-metastatic castration-resistant prostate cancer. As you know, this is what I would call a fake terminology and that it's really not metastatic. It's just that it's not visible metastatic disease based on the current imaging that we have. So this is clearly micrometastatic disease and reflected by the fact that the PSA is rising in the context of castrate testosterone. As you know, a lot of bone-targeted therapy trials were done in this space and the data that came in from these trials indicate that the development of metastases, visible metastatic disease, in this patient population is very predictable and is associated with increasing PSA doubling time and PSA level and basically the benchmark was the doubling time of 10 months and less.
Now, I would point out that these data that I'm showing you is based on patients who have bony metastatic disease progression because again, we're talking about bone-targeted therapy. Three randomized clinical trials got reported back to back, literally within less than a year looking at AR targeted drugs, apalatuamide, enzalutamide and darolutamide. All of them look at men who had a PSA doubling time of less than 10 months, no visible metastatic disease by conventional imaging and all of them basically showed that there is an improvement in time to metastases, or metastases-free survival, of literally over a year, which is critically significant. All of these drugs I would argue are fairly comparable in terms of the outcomes. Three of them are right now FDA approved and obviously the issue comes up which of these drugs you want to choose. And this is something certainly we can discuss afterward.
So I want to end with my conclusion, before Neal gets the bell going. Was it the cow or the bell or whatever? Is that in castration-resistant disease we have, I think relatively speaking, embarrassment of riches, although a lot of improvement is still needed because we're really not curing this disease. I think that emerging data would favor in second-line cabazitaxel over an AR targeted drug. And I would argue if the patient is symptomatic that would make more sense. Those patients who potentially have DNA repair defect could certainly be eligible for PARP inhibitors. The FDA I think is looking at this moment. I think there are many agents and combinations in testing, so stay tuned. In the hormone-sensitive space, I think clearly therapy intensification has delivered on that. The question comes up how much more therapy intensification would be a value and is more always better in this space. And what about the role of local therapy including focal to metastatic disease?
I think what's clear is moving effective treatment to earlier stages of the disease gives you a better return on investment with regards to the patient's outcome, but how does that impact resistance mechanisms and the biology of the cancer, efficacy of other treatments, optimal treatment sequencing, longterm adverse events and so on. And what about therapy de-intensification and we can certainly talk about that and longterm responders, and the role of other targeted therapies in molecularly preselected patients. At the end of the day, I would say conquering cancer is the objective and this is really done through research and excellence in care and I made a list of what I think is next. Certainly, better imaging gives us a window of opportunity. Maximizing the antitumor effect in my book, the best cancer cell is a dead one. And then of course looking at better personalizing the care at the phenotypic and genotypic level, and then enhancing survivorship and addressing cost and value to the patients. And with that, I want to thank you very much.
Ben Lowentritt: Thank you so much, Doctor Hussain. I think we have a few questions on the panel and if you have questions please put them into the iPads on your desk.
Gordon Brown: Our first question was about patients that present to you de novo with metastatic hormone-sensitive prostate cancer. And you talked about... we struggle with and counseling our patients. Should they get chemotherapy first, an oral oncolytic? Do you have anything that sways you one way or another? I think you said your patients go like 50/50.
Maha Hussain: Thank you. So in the hormone-sensitive space, what we know is this. If the patient has low volume disease as defined by CHAARTED, and I want to argue that CHAARTED was the only trial that a priori when we designed it, stratified patients by disease extent and those of you who remembers the days of flutamide in hormone therapy and bicalutamide and orchiectomy plus flutamide and so on. In those trials that were done, intergroup trials, the trials were designed to look at sites of disease as a potential prognostic factor. And what was found is this. If you have disease in both axial and appendicular skeleton or you have visceral disease, then that pretends for a worse outcome. When CHAARTED was designed, was designed basically trying to combine the MD Anderson criteria of bad disease with the SWOG criteria and they came up with a different criteria that required, at a minimum, one lesion at the appendicular skeleton and/or visceral disease.
And so what is clear is this, if you have a patient who has two lesions, let's say two vertebral lesions, I showed you the two sets of data. The original and the subsequent data. There's really no indication that those patients benefit from chemotherapy. So these patients, I personally do not counsel them on chemo. What I counsel on chemo is the patients who have the high volume or a higher risk disease by the CHAARTED criteria and info is provided.
And at the end of the day, honestly, I don't favor one or the other, I explained to them, "Chemo, intense, it's five months. You have multiple issues, but you're done. Oral therapy continues." And certainly for some patients who have longterm AFib and cardiovascular issues, and this, as you know, the lingering effect. Surprising to me, and by the way, I do not counsel them the first minute when they're with me. I usually get ADT started, give them a couple of months to settle, gradually give them the information and then by month two and three we make the decision. And again, surprising to me, the patients feel comfortable making their own decisions.
Timothy Richardson: When looking at different therapies to sequence in, you're always excited to hear from an oncologist like yourself about how they prefer to do it because it seems that it always differs in some way from how urologists do it. Specifically talking about radium-223, can you speak about when you feel the optimum time is to layer in radium-223? Do you still use it monotherapy? Do you use it combo therapy with one of the orals, and also does it matter whether the patient got upfront chemo versus an upfront abi oral, et cetera.
Maha Hussain: So I think this is a great question. So with radium, I don't use it as frontline. And part of the reason is this, is you have so much mileage with say abi or enza upfront in castration-resistant disease and knowing that there's micrometastatic disease, so I tend to stick with that first. Where I tend to use radium is if you have patients who have bone-only disease, where there is, let's say, they're not fit for a clinical trial or they don't want to be in a clinical trial and there's only bone disease. That is when I actually offer it as part of a discussion regarding potential other options including chemotherapy, and selectively some patients choose it.
What is interesting sometimes is there are certain preferences for patients with regard to what they have to do, for example, lifestyle. When you pee, what do you do afterward, do you wipe after yourself, you do this, you do that. One of my patients to my surprise actually chose enza over radium just because he didn't want to go through the inconvenience of things. So there are different personal preferences, but that's when I generally offer it. In second line as part of the package. And I actually don't want one to wait until there's lots of bone disease because I figure like any disease, any drug, lesser disease potentially gives you a better mileage that way.
Lawrence Gervasi: Great talk, thank you for being here. So when we refer specifically to the patient with CRPC, in the era of targeted therapies and with trying to understand which therapy to put in which position, I'm curious to hear your insights as it relates to the timing of a genetic sequencing and analysis for these patients. One.
Two, I want to understand if there are other targets other than BRCA1, 2 and ATM. What do you think holds some promise for us? Get your thoughts.
Maha Hussain: Thank you. So I think we are in a discovery mode. We know that prostate cancer is complex and it has a lot of genomic alterations. What we really don't know is the best timing of when to consider targeted treatment. And just for the sake of time, I didn't put a slide, and I'm happy to share it with whomever they want. Whoever is interested. There was actually an autopsy series from, I believe, 10 patients. I think the original cases were from Hopkins which was published. Where they did is basically picked on multiple areas from each autopsy thing. Ribs, lymph nodes, lung, liver, whatever disease and surprisingly, there was a lot of heterogeneity between patients but also in the same patient. So this is my point where I would say there was work also from Scott Tomlins and colleagues when I was at Michigan when they looked at basically the molecular profile of early-stage disease, metastatic hormone-sensitive disease and then castration-resistant disease. And clearly you see there is a trend in terms of the genomics alterations and so ideally you would think it ought to be earlier, not later.
Having said that, where we're going to be showing the proof of benefit is going to be, at least in metastatic disease. Surprisingly actually we recently completed a trial looking at patients who have RB intact tumors based on metastatic disease, biopsy in hormone-sensitive disease, targeting them with a CDK 4/6 inhibitor, palbociclib, which is basically standard of care in breast cancer right now. And despite the fact that we combined it and we preselected and all of that, there was nothing there. So what I think we need is we need a lot of research in the hormone-sensitive space before we can actually move things. And certainly, I think the PARP inhibitors are working their way in that direction, definitely. But I would say where you would do the genomics, I would argue that definitely if a patient is high-risk, family history and so on with regard to genetic counseling, so germline testing would be a good idea. And I would say definitely when the patient is metastatic, if you have tissue, send it. It doesn't hurt because at some point they will become castration-resistant. But definitely very early stage castration-resistant disease.
Neal Shore: So finally, last question for time. So you presented all this great data of numerous trials now that show the benefit of couplet therapy as opposed to mono ADT therapy. But you did tantalize us by saying there's still an indication where you would give monotherapy ADT alone in someone with newly diagnosed metastatic disease. I'd like you to comment on that and have you seen some of this market data that still I'm seeing in the United States, 60 to 70% of patients are still only receiving monotherapy ADT. And your thoughts on that?
Maha Hussain: I think this is a great question and the reason I brought it up is because I literally again saw this gentleman for the fourth time just in the last four months. So this is a gentleman in his late 80s. His ejection fraction is 20%. Has pleural effusions from all kinds of causes. Practically whatever he's admitted, he has metastatic disease. In the beginning, when I saw him, I'm thinking, "If we stabilize him, I'm going to maybe add something." But as you know, abi, enza, apa, all of them are going to have cardiovascular issues and he certainly is not somebody I'm going to give chemo to. So there's going to be those situations whereby I would say you'd have to be very selective in choosing the drugs. And I'm sorry, what was the other question?
Neal Shore: So how do you react to the fact that some market data says 70% of patients now in the United States of 2018 who had metastatic disease, high volume, low volume, are still just getting ADT alone.
Maha Hussain: I think that's horrible, personally, and I think this says we need to do a better job educating physicians. But I also think as physicians it is our obligation, we've taken the oath. And our obligation is to be as update as can be. And I also think this is where advantages in structures that were created whereby people are focusing on the days of doing A to Z is over with, even in the field that I'm in. And I do think sub-specialization becomes very important or focusing on certain areas because the knowledge is evolving so rapidly. But I think also patient education is another factor.
Neal Shore: Fantastic. Thanks so much.