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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 a friend and colleague Dr. Maha Hussain, who is a Professor of Medicine and a GU Medical Oncologist also at Northwestern University. Thank you so much for being here with me today, Maha.

Maha Hussain:  Thank you very much for having me.

Alicia Morgans:  Wonderful. Well, I wanted to talk with you today about your latest New England Journal of Medicine paper. It sounds like you've had three this year, so it's been a wonderful year and this latest is an update on the PROfound trial, which you also presented at ESMO last year. Really an update on overall survival and some other updates in terms of exploratory analysis. Can you remind us what the PROfound trial was? And then we'll get to talking about what you found.

Maha Hussain: Sure. So the PROfound trial actually was the first Phase 3 clinical trial that when we designed it, the intent was to apply precision medicine to prostate cancer based on accumulating data regarding the presence of homologous repair defects in prostate cancer. Data stemming from the Stand Up to Cancer. And of course, the TOPARP-A Trial demonstrated a benefit in the subgroup of patients who had again the HRR mutations.

And so when we designed the trial, we really aimed high. We wanted to pre-select for patients who have the appropriate mutations. The intent was obviously to have this trial address several questions. And at the time of the study design, we actually separated the HRR mutations between the BRCA1, BRCA2, and ATM because this is what I would call the canonical type cohort. And then there was a whole list of other mutations that at least had some suggestive data, but they were not necessarily proven yet with regard to the potential effect of a PARP inhibitor.

And so the trial was designed with a 2:1 randomization. The intent was to look at radiographic progression-free survival, which was done through a central reviewer for this study. And obviously, there were a series of secondary endpoints, and the overall survival was one of the secondary endpoints. The trial met its primary endpoint of radiographic progression-free survival, which we reported at ESMO last year. And the publication came out in the New England Journal this summer. And then it met several of the secondary endpoints. And of course, the most critical endpoint in the business we're in obviously is overall survival.

And amazingly again, overall survival was significantly improved, despite the fact that the trial included patients who really were heavily pre-treated. So at a minimum, they had to have at least one AR targeted drug being enza or abi as frontline. But the data clearly, as we published, these patients were heavily pre-treated. Several of them have seen multiple chemotherapies before, some of them have seen both abi and enza.

And one of the issues that was raised at the time is, is it appropriate to have people see abi, enza, and get into the study and get assigned to a physician choice, abi and enza again, something like that. And at the time of the study design, there were really not many options for these patients and the study was international. So this is essentially a touch better than placebo from that perspective.

Alicia Morgans:  Well, and that's important because I think one of the most important messages of PROfound has really been that it might not be the best use of our time and our resources to really do these back to back AR directed therapies. But when you were doing this trial, we were in a very different world.

Maha Hussain:  Exactly, exactly.

Alicia Morgans:  So can you tell us a little bit about the overall survival findings? So we got findings from cohort A, cohort B as well.

Maha Hussain: Yes. So basically the overall survival data showed that the cohort A, which is the primary cohort had a significantly longer overall survival. The median was actually 19 months in the olaparib arm and 14.7 months in the control arm. And this is actually despite, again, crossover did occur in the cohorts. But basically, the overall survival, when you look at the risk of death reduction, when you look at the overall population before crossover like just for the primary analysis in the context of cohort A, there was a 31% reduction in the risk of death with the hazard ratio being 0.69.

If you actually adjust for the crossover, and two-thirds of the patients, in fact, crossed over to olaparib, that hazard ratio goes down to .42. And so clearly a benefit was pretty profound there. It's interesting that the cohort, patients with cohort B, which is the non-BRCA1, 2, and ATM, there was a survival trend, but it was not statistically significant, but the trend was there. And when you adjust for the crossover, the hazard ratio is 0.83. This is clearly highlighting the fact that not all HRR genes are equal. And certainly, there are selective benefits in some of the patients.

Alicia Morgans: Absolutely. And I think it was so interesting the way that you and the other investigators actually really kind of drill down on that. You had some beautiful exploratory endpoints that you looked at specifically, response by specific alterations. Can you tell us a little more about that?


Maha Hussain:  Yeah and I'm more than happy to perhaps share some slides regarding this because obviously going through it one by one is going to be not easy. But definitely, there were some benefits that we are seeing in some cohorts of patients that to my surprise, I thought they were not likely to respond. So clearly the biggest benefit was in the BRCA1, BRCA2, and in the ATM. What's interesting, in the ATM and these are secondary sort of post hoc analyses, is that the patients within the context of the ATM cohort if they've seen Taxotere they have a better chance of responding compared to if they had not.

So I do think, again, these are what I would say are interesting findings that definitely would need validation, but it actually is okay to use it from a clinical practice. You have a patient in front of you and we have this data. In this case, I think clearly counseling the patient on their choices of treatment is important. But I think if they have an ATM mutation, this is where perhaps one consideration might be to say, maybe Taxotere first, then go to this drug.

The other cohorts that I think were interesting to see are the different other genes like the CHEK2, there was some suggestion of benefit. Rad, some suggestion of benefit there. And so I think that all in all, there is a trend and I would encourage the audience basically to look at the paper and at the data and then use that as a potential gauge for when they would like to offer their patients the potential for a PARP inhibitor.

Alicia Morgans:  I think that's a great message because the label is actually broader, certainly than BRCA1 and BRCA2. And also, it can be sort of not the right thing to do to necessarily rely 100% on exploratory analyses that are not powered. But if we have a patient in front of us and we go back to the data, we can at least get a sense of what we might try because there aren't any 100% answers in this.

Maha Hussain:  Exactly, exactly. And I think that the point here is some judgment has to be used with regard to how best to tackle the management of these patients. And at the end of the day, the vast majority of patients, once you put in the NGS testing for these patients, the bulk of these patients are going to be the BRCA1, BRCA2, and ATM. I think there's going to be a handful at best in our daily practice, patients who have alternative mutations. I would say the biggest one is the CHEK2. Certainly based again, on the CHEK2 and then the CDK12. This is based on obviously the PROfound data, but I have to say in my daily practice, this is something that we see.

The other thing I want to point out is that the FDA approval actually covered all genes, including cohort B genes, except for a gene that has a long name. I'm sorry. The mutations in the gene are the PPP2R2A. That one actually was allowed in terms of an eligibility criteria.  At the end of the day as more data accumulated and more pre-clinical data accumulated and so on. This is not an HRR gene, and so, a mutation gene. So this is out of the approval panel from the FDA perspective.

Alicia Morgans:  Thank you for pointing that out. Because I think anytime we have more information coming out particularly regarding whether patients are going to respond to a treatment or not, updates on the label and clarification, it's so important. One thing that folks have talked about as they are thinking about using these drugs, particularly from experience in ovarian cancer and other settings is the development of leukemias and things.

And I know that you were watching very closely at all of these patients. There was one patient who developed AML. I think this was after essentially, the study follow-up was planned to have ended, but you still included and reported that which I think is very helpful.

Maha Hussain:  Absolutely. Yeah. And I think safety trumps, in the business we are in. As physicians, safety trumps everything else. And I think you have to report it. There are obviously different reports; however, just by sheer accident, this could have happened. I mean, this is a population, 4,000 patients were screened for this particular trial, albeit, obviously the majority were not included. But I do think that it's important to be mindful of that.

The other thing I want to highlight is this, is the observation we made on tolerance. And what I think is fascinating is, the patient population and I would really encourage the audience to go look at the eligibility criteria and then look at the patient characteristics. A large number of these patients really had bad disease. They had visceral involvement, they had very high PSAs. The interesting thing is that the age group actually, some of these patients were in the late 80s and early 90s.

And again, it highlights the feasibility of actually treating those patients in our practice. And so age, again, age is to be respected, but it's not an exclusion factor in terms of offering this. Whereas, if you want to give chemo, you are to really worry a little bit when you have a 92-year-old, for example. So some of these subtleties are I think, important.

Alicia Morgans:  They are. And also recognizing that so many of these patients were actually exposed to chemo in the past are still being able to tolerate this. That's important as well. So if you had to sum up the data that you've newly presented and now published in the New England Journal, what would your summary be?

Maha Hussain:  I think the summary would be, as the first thing, the big picture is that precision medicine and targeted therapy are possible in prostate cancer. And that I would encourage all investigators, sponsors, pharma, whomever, to actually look at prostate cancer and look at PROfound and certainly the TRITON trial. It is feasible to do these trials and demonstrate benefits, in fact, if the drug is going to work, but that would be one.

The second part is, that obviously an exciting part now that we have another drug in the pipeline for managing patients and managing them in a much more personalized matter, similar to, again, the benefit is similar to what is seen in breast cancer, ovarian cancer, and pancreatic cancer. Is it a cure? Of course not. However, I would say that it is remarkable that some of our patients, you may have similar patients on olaparib that have been on treatment for over a year and these are patients that have been heavily pre-treated. So from that perspective, I think it's very exciting.

I do think that the sky is the limit as to what we can do. And I would love to see us begin to develop combination treatments, investigate additional agents to better personalize the care. And I think from the big picture perspective, understanding even when you're pre-selecting for the HRR mutations, even in the context of the BRACA situation, not everybody responds and the question is why? And so clearly investing in research in this area to better understand collaborative and sort of resistance mechanisms becomes very important.

Alicia Morgans:  Well, I always appreciate your overarching messages because they're not just summaries of what you found, but where you want to go in the future and certainly encouraging all of us to take those next steps. So thank you again for sharing your take on this fantastic work. Congratulations to you and everyone involved, including the patients for getting this personalized medicine treatment study Phase 3 in prostate cancer actually finished and showing a positive result. Thank you again.

Maha Hussain:  Thank you very much. And it takes a village as they say. So keep working.

Zachary Klaassen: Welcome to this UroToday Journal Club. We'll be discussing enzalutamide and survival in non-metastatic castration-resistant prostate cancer. My name is Zach Klaassen. I'm an Assistant Professor in the Division of Urology at the Medical College of Georgia, and joining me is Chris Wallis, he's a Fellow in Urological Oncology at Vanderbilt University in Nashville.

As I mentioned, we'll be discussing this paper that was recently published in the New England Journal of Medicine following presentation at the 2020 ASCO Virtual Meeting. The first author is Cora Sternberg for the PROSPER investigators.

By way of background, enzalutamide is an oral androgen receptor inhibitor, and it's been approved in men with metastatic castration-resistant prostate cancer in both the pre-chemo and post-chemo state based on the AFFIRM and PREVAIL trials. It was also recently approved in men with metastatic castration-sensitive prostate cancer based on ENZAMET and the ARCHES trial.

Enzalutamide was first approved by the FDA in 2018 in this disease space of non-metastatic CRPC on the basis of improved metastasis-free survival compared to ADT alone. You can see here that the hazard ratio for metastasis or death was 0.29 with a 95% confidence interval of .24 to .35, and this was published by Hussain and colleagues in the New England Journal of Medicine in 2018.

Subsequent to this publication was a quality of life study from this data, which was published in Lancet Oncology in 2019, looking at several factors that showed that enzalutamide compared to ADT alone improved health-related quality of life, including the BPI-sf item 3 tool, the EORTC QLQ-PR25 urinary symptoms metric, as well as that same metric for bowel symptoms, the FACT-P total score, and finally the European quality of life visual analog scale. So, you can see an early separation of the curves for all of these quality of life metrics favoring enzalutamide.

In the initial publication in 2018, which was the primary analysis of PROSPER, there were 23 months of follow-up, but the OS data was immature and the median OS was not reached. At this point in time, they had 165 deaths, which was 28% of the pre-specified survival events for the final analysis. The publication that was published in June of 2020 is the survival analysis with longer follow-up in the PROSPER trial, which we'll be discussing today.

This was a multinational, double-blind, randomized, placebo-controlled, Phase III trial of 300 sites and 32 countries. The key inclusion criteria were confirmed prostate adenocarcinoma with an increasing PSA despite a castrate level of testosterone, a baseline PSA level of greater than two nanograms per milliliter, a PSA doubling time of less than 10 months, and no evidence of metastatic disease.

In terms of their methods, stratification was based on PSA doubling time of less than or greater than six months. They also stratified based on previous or current use of bone-targeting agents, and randomization was two to one for ADT plus enzalutamide versus ADT plus placebo. Their primary endpoint was MFS or death, which, as I mentioned before, was reported in their 2018 New England Journal of Medicine article, and there were several secondary endpoints as you can see here, one of which was overall survival, which was the key endpoint discussed in their 2020 update.

Their efficacy endpoint was in the ITT population. They evaluated safety, which was described as time from the first dose to 30 days after the last dose or to the day before initiation of a new antineoplastic therapy. For their final analysis of overall survival, they needed 590 deaths to provide 85% power to detect a hazard ratio of 0.77 with a two-sided significance level of 0.05. This was the third preplan analysis for overall survival. After adjusting for multiplicity, they detected if there was a P value of less than or equal to 0.021, this indicated statistical significance.

Christopher Wallis: Thanks for the setup, Zach. I'll talk now about the results of the updated overall survival analysis and help put these in a little bit of context.

The original publication of the PROSPER trial described some of these initial background features, but we'll just review them quickly. Patients were screened and accrued between 2013 and 2017, with enrollment stopped after about 450 MFS events, giving adequate power for the primary outcome. There was two to one randomization schema to enzalutamide versus placebo and, as Zach described before, this was stratified on the basis of receipt of prior bone-targeting agents and PSA doubling time. As we might expect from the fact that enzalutamide prolonged metastasis-free survival, the median duration of treatment was longer for patients who were on therapy than on placebo.

Now, these baseline characteristics come from the initial publication, but as we would expect, they ought to be the same in the updated analysis, and so we see a fairly typical prostate cancer population, the median age in the mid-70s, good performance status, median PSAs in the range of 10, and a doubling time in the range of four months. Bone-targeted therapy was used infrequently in only about 10% of the population at baseline.

Now, following primary analysis of the metastasis-free survival endpoint, trial data were unblinded. And at that time, given that it demonstrated benefits of enzalutamide in prolonging metastasis-free survival, patients who were receiving placebo who hadn't yet progressed, that is who were still nmCRPC, were allowed to cross over. So, among 114 eligible patients randomized to placebo who had not progressed, 87 of those crossed over to enzalutamide. And this, as you might imagine, affects our ability to detect overall survival differences in an ITT analysis.

Despite the crossover, as we see here, overall survival was significantly improved for patients receiving enzalutamide compared to placebo. With a median follow-up of 48 months, we see a median survival of 67 months in those patients on therapy and 56 months in those initially randomized to placebo. As a result, the hazard ratio is 0.73 and a P-value of 0.001. As Zach alluded to before, due to multiplicity, the threshold for statistical significance here was 0.021, so this reaches statistical significance.

In subgroup analyses, we see a relatively consistent effect across subgroups defined based on geographic region, patient age, performance status, PSA doubling time, as well as absolute PSA values, the use of bone-targeting agents, Gleason Score, LDH values, and hemoglobin values, indicating that there are no specific subgroups for whom a greater or lesser benefit would be expected.

As of the data cutoff of October 15, 2019, about 60% of patients who were randomized to enzalutamide had subsequently stopped therapy, and a reasonable portion of those who had crossed over later had also stopped. Treatment was stopped for both disease progression and adverse events, and we'll talk about that a little bit here.

So, the next lines of therapy, following progression or discontinuation for toxicity, subsequent therapy was used in about one-third of the patients randomized to enzalutamide and about two-thirds of those randomized to placebo. Abiraterone was the most commonly used agent in patients who were initially randomized to placebo, where docetaxel was the most commonly used agent in those initially randomized to enzalutamide. And this makes sense given what we know from other work from Kim Chi's group as well as the CARD study, suggesting that failure on one androgen receptor-targeting agent should lead us to consider cytotoxic chemotherapy rather than an androgen receptor-targeting switch.

In terms of adverse events, this is a summary of overall any adverse events and serious adverse events. We see that these are quite common in both groups, although somewhat higher in the enzalutamide-treated population with a 94% rate of any adverse events versus 82% in the placebo group. Serious events, again, were more common in the enzalutamide group at 48% as compared to 27% in the placebo group, and adverse events leading to treatment discontinuation occurred in 17% of those in the enzalutamide group and only nine in the placebo group. Deaths were uncommon in both, but slightly more prevalent in the enzalutamide group.

Based on data from the use of enzalutamide in other disease states, including metastatic castration-resistant prostate cancer, there are specific adverse events of interest, including fatigue or asthenia and seizures, and these are summarized here. Fatigue is somewhat more common in the enzalutamide group with a proportion of 46% as compared to 22 in the placebo group. However, very few seizures were noted in the study population.

Now, despite the fact that we've been able to demonstrate a statistically significant difference in overall survival, these data are still relatively immature. And as we see from data on the use of enzalutamide in early metastatic castration-resistant prostate cancer, as data matures, we may expect changing effect estimates. And so, these show that from the initial analysis in 2014, 22 months through extended analysis published in 2017 of 31 months, and now onto 70-month median follow-up, the hazard ratio of the benefit of enzalutamide in early metastatic disease has moved towards one, although remains statistically significant, so Dr. Beer highlighted that this may occur in the non-metastatic space as well when he was discussing this paper at the ASCO 2020 virtual meeting.

In conclusion, an updated analysis of the PROSPER trial shows improved overall survival for patients with nmCRPC who receive enzalutamide as compared to placebo. There are now three agents approved for non-metastatic CRPC on the basis of metastasis-free survival improvements, and each of these has now demonstrated subsequent proven benefits in overall survival. The specific magnitude of benefit is likely to change as the data matures, but these data provide encouraging information for our patients, suggesting that early use of androgen-targeting agents in patients with castration-resistant disease is likely to provide a survival benefit.

I'd like to thank you for your time and hope that this session has proved both interesting and informative for you.