Welcome to The GU Cancer Sessions with the Video Journal of Oncology (VJOncology).
This roundtable discussion features Giulia Baciarello(Istituto Nazionale dei Tumori, Milano, Italy) and Anna Patrikidou(Institut Gustave Roussy, Villejuif, France).
The panel examines the practice-changing prostate cancer data presented at the ESMO 2021 Annual Meeting, including a combined analysis from two comparisons in the STAMPEDE platform protocol in high risk MO prostate cancer, as well as overall survival data from PEACE-1 evaluating abiraterone acetate plus prednisone in de novo mCSPC. In addition, the experts discuss updated results from Cohort 6 of COSMIC-021 evaluating cabozantinib in combination with atezolizumab in mCRPC.
“The STAMPEDE trial needs no introduction. It is quite simply a magnificent pivotal trial. It has provided us with important data and it is a gift that keeps giving, it seems. So this year Gerhardt Attard presented to us some pretty mind-blowing data on the high-risk M0 patients.”
– Anna Patrikidou
“Actually this is a non-metastatic population, so we need to pay really attention on, on toxicities. However, the results presented were quite reassuring and in fact, the toxicity didn’t differ a lot between the two arms. Plus the number of deaths from any cause and the number of prostate cancer-specific deaths, were not so different. So I actually, will feel comfortable in prescribing abiraterone even tomorrow in this setting.”
– Giulia Baciarello
“I can say sincerely that for me, it is actually a real practice changing. However, we need to make a distinction between de novo and relapsed disease. Since in the PEACE-1 trial, only men with a de novo metastatic disease were included. So we do not have any data concerning the relapsed hormone-sensitive disease. Plus we need also to make a distinction between high- and low-volume because we have solid results, at least until now, just for high-volume disease.”
– Giulia Baciarello
“So the first message is that the combination has encouraging clinical activity, maybe more than the respective mono-therapies. The second interesting feature is that this activity seem to be maintained in their subgroup of visceral metastases, extra pelvic lymphadenopathy patients.”
“The one thing that I would like to see and definitely would like to see that in the Phase III trial, is a better dissection of this poor-risk feature group, in the results that we saw this year, the group accounted for 77% of the overall cohort.”
– Anna Patrikidou
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SECTION 1: STAMPEDE
Giulia Baciarello: So welcome to the post-ESMO discussion on VJOncology. My name is Giulia Baciarello. I’m a medical oncologist at Istituto Nazionale dei Tumori in Milan, Italy, and I’m very happy to discuss the most important studies presented on prostate cancer at the ESMO 2021 with my colleague and close friend, Anna Patrikidou.
Anna Patrikidou: Thank you, Giulia. It’s such a great pleasure to share this discussion with you. I am Anna Patrikidou, I’m a medical oncologist in Gustave Roussy Institut in Villejuif, France. Thank you everyone for joining.
Giulia Baciarello: So Anna, the most important data on prostate cancer were presented in a presidential symposium and actually both trials were academic and both trials were practice changing. So I’m speaking about the STAMPEDE and PEACE-1 trial. But first of all, would you like to present us the STAMPEDE data?
Anna Patrikidou: Indeed, this conference gave us strong, clear data that I find did better shape the two edges of the spectrum of castration-sensitive disease. The STAMPEDE trial needs no introduction. It is quite simply a magnificent pivotal trial. It has provided us with important data and it is a gift that keeps giving, it seems. So this year Gerhardt Attard presented to us some pretty mind-blowing data on the high-risk M0 patients. He reminded us that the first analysis on this population, back in 2017, was of uncertain benefit for overall survival as there were too few events in either arm. And he now showed us a 13% improvement for the six-year metastasis free survival with a HR of 0.53 and a very strong p-value. But most importantly, this benefit was well reflected on overall survival with an absolute improvement of 9% at six years from 77% to 86%. And this with a HR of 0.6. So a 40% reduction in the risk of death and a very significant p also here, 12-zeros, we hear. And the benefit was of course seen across outcome indices, the prostate cancer-specific survival has now reached 93% at six years, compared to 85% with a HR of 0.49. PFS has an HR of 0.44, and that includes local progression and even better for failure-free survival. That includes PSA progression. Very impressive data, indeed.
Giulia Baciarello: Yeah. Thank you. I know, these are really, really terrific data. And so you were, in the UK at that point. So what’s your point of view on these results?
Anna Patrikidou: Yes. Indeed I was involved with the trial when the abiraterone arm patients were in the treatment or the follow-up phase and the abiraterone enza arm was recruiting in the arm J. At that time, the first STAMPEDE docetaxel results had come out. And I remember being rather skeptical of the tendency to generalize the use of docetaxel for the entire spectrum, from high-risk M0 to heavily metastatic disease. Despite the fact that the trial was indeed designed and powered for all, yet there was some evidence from the forest plot that it might not work as well in the M0 patients. And this was indeed subsequently demonstrated to be so, both from the STAMPEDE comparison, but also in the French GETUG 12 trial, in regards with overall survival, they were positive for PFS. The story is different for AR signal inhibition. We now have consolidated data from several trials that show that the earlier in the disease, we target the androgen receptor, the better it is. The more we gain and this, this year, at this ESMO, is the first report for non-metastatic patients. So even there we have benefit and the magnitude of benefit in this high-risk population with just two years of abiraterone is such that it cannot be ignored in my opinion. So I think it ought to be indeed considered as the new standard of care. But what do you think Giulia, about treatment safety in these patients that have a long expectancy, life expectancy ahead of them. And it is also of major concern, toxicity data beyond two years were not presented.
Giulia Baciarello: Yeah, you’re totally right. Actually this is a non-metastatic population, so we need to pay really attention on, on toxicities. However, the results presented were quite reassuring and in fact, the toxicity didn’t differ a lot between the two arms. Plus the number of deaths from any cause and the number of prostate cancer-specific deaths, were not so different. So I actually, will feel comfortable in prescribing abiraterone even tomorrow in this setting. Given also the fact that we are now experts in managing side effects, side effects of abiraterone. However, one concern, the safety, we need to wait for more safety data, especially for what comes in the long term data. So Anna, we’ve seen in the patient characteristics that this population was quite heterogeneous. However, only 3% of them had a relapsed M0 disease. So would you be confident to use abiraterone in this population?
Anna Patrikidou: Yes, this is a very good point and it is true that we have more data for de novo setting, and it is the same for metastatic disease, and we’ll discuss this with PEACE-1. If we see the criteria of STAMPEDE for the high-risk M0 patients, firstly, they’re different to the D’Amico classification, and they also differ for newly diagnosed versus relapsed patients. So the answer is that for the relapsed patients, given the very low number, I will probably discuss case by case if we’re talking about a node positive relapse, for example, or a very rapid PSA doubling time, I would be inclined to use it, especially if we cannot use local salvage treatment. But also probably together with it. But this needs to be a multidisciplinary decision, really.
Giulia Baciarello: Yeah, I totally agree. I think that we should pay attention in the subgroups of patients which were under represented in the study and we need to discuss it case by case, as you said. And what do you think about the combination with abiraterone and enzalutamide?
Anna Patrikidou: Well, this seems to be, or it seems to be from the results we had, that there was no added benefit from the addition of enzalutamide either for metastasis-free survival or for overall survival. Which is consistent with results we had in the mCRPC setting for combined use of ARSIs, like the ACIS trial for the abiraterone apalutamide combination. So I personally see no reason really for the added toxicity, even if small, or for the enhanced cost of treatment, with the data that we have so far. But let me ask you, after this ESMO in which way will this data impact your daily practice?
Giulia Baciarello: Well, actually I really think that these data are practice-changing. As you know, in the last year, we have assisted to a real revolution for what concerns the earlier phases of the disease. So metastatic hormone-sensitive and M0 CRPC as well. And now of course, the M0 high-risk population. So to treat these patients, according to the guidelines and, especially the future guidelines, we really need to communicate more with our colleagues and I’m talking about urologists and radiotherapists, of course. So when need to, to learn and to discuss, on the tumor board, every patient with a higher risk M0 disease. Because we have to stress again, to our colleagues that actually, adding a systemic treatment to a local therapy in this setting can likely cure 10% more patients. We also need to remember that these are similar numbers to those of some solid tumors for which neoadjuvant and adjuvant chemotherapy are actually standard of care.
Anna Patrikidou: Indeed. And you know, it is, it is really a pleasure to, to have the discussion about a successful adjuvant treatment in prostate cancer other than ADT. So thank you, Giulia.
SECTION 2: PEACE-1
Anna Patrikidou: Now let’s talk about the PEACE-1 study. Another plenary trial, and one we both know very well.
Giulia Baciarello: Yeah, actually we were both involved in the PEACE-1 trial as investigators. So we are probably a little bit biased. However, the PEACE-1 was a huge academic Phase III trial, who included men with de novo metastatic disease And these patients were randomized into four arms, the standard of care alone, standard of care plus abiraterone, standard of care plus prostate radiotherapy, and standard of care plus abiraterone, plus prostate radiotherapy. So at the beginning of the study, the standard of care was defined as ADT alone. However, since in 2015, the results of the benefit of docetaxel in the setting were presented. And I’m speaking about CHAARTED and STAMPEDE trial, the use of docetaxel was permitted by an amendment at physician’s discretion. And of course the choice of docetaxel had to be made before the randomization. And later on, in 2017, when the results from LATITUDE and STAMPEDE on abiraterone were presented, the use of docetaxel became mandatory.
Anna Patrikidou: Yes. Which was indeed, I remember that, which was indeed the ethical and the correct thing to do, I find.
Giulia Baciarello: Yeah totally, totally. So actually, the real standard of care was ADT plus docetaxel for most of these men. Plus, since there was no evidence of interaction between abiraterone, and radiotherapy in the ADT plus docetaxel population, the two abiraterone arms, so the patients treated with or without prostate radiotherapy were pooled together in order to have a more power for the efficacy analysis. So actually the results presented by Karim at the ESMO were of two groups. Men treated with the ADT plus docetaxel, so standard of care, versus ADT plus docetaxel, plus abiraterone. And in the overall population, the triplet induced a 45% reduction in the risk of progression or death. The radiographic progression-free survival was improved from a medium to 2 years, to 4.5 years. So a difference of 2.5 years, incredible. And again, in the overall population, they use of the triplet, resulted in improvement of, in the reduction of 25% of the risk of death. While, and these results were more evident in the high-volume disease, for which the hazard ratio was 0.7 and the difference in terms of overall survival was about one year, and a half.
Anna Patrikidou: So thank you for the excellent outline, but let me put you on the spot. What’s your verdict about what PEACE-1 brings to us today? Does it change practice? What is the straight value of the trial for you? In my opinion, it is enormous, at least for the high-volume results we have so far.
Giulia Baciarello: Well, I can say sincerely that for me, it is actually a real practice changing. However, we need to make a distinction between de novo and relapsed disease. Since in the PEACE-1 trial, only men with a de novo metastatic disease were included. So we do not have any data concerning the relapsed hormone-sensitive disease. Plus we need also to make a distinction between high- and low-volume because we have solid results, at least until now, just for high-volume disease.
Anna Patrikidou: You are right. So I agree. The benefit here is proven even when it seems 84% of patients in the control arm subsequently used an androgen receptor signaling inhibitor. So early use seems to be better indeed. We do not have a head-to-head comparison within a single trial of abiraterone versus docetaxel versus abiraterone and docetaxel. But Karim Fizazi provided an excellent slide in the end that pulled all the currently available data and the point is indeed there, I find. We gain up to 11 months in overall survival for the high-volume patients by adding docetaxel to ADT and abiraterone. I should also probably, we should also probably add that given the PEACE-1 results we will probably have in the future, more overall survival analysis from the high-volume patients from other trials in this setting that use triplet combinations involving docetaxel and other androgen receptor targeting agents. But what do you think about the de novo low-volume disease?
Giulia Baciarello: Well, you know, the data for this type of patient on overall survival are not made sure yet. We know that in the overall population, the triplet has a benefit in terms of radiographic progression-free survival and overall survival. But we need to have stronger data on these subgroups to, to change our practice, probably. And on the other hand, what do you think about the local treatment in this population?
Anna Patrikidou: Good question. Well, the HORRAD and the STAMPEDE trials, they have clearly showed a benefit for radiotherapy to the primary for oligometastatic low-volume patients And I think this is now rather universally accepted. The PEACE-1 results presented as, as you said, the combined results for the radiotherapy and non-radiotherapy arm. So the conclusion of benefit for the triplet, for the high-volume patients, but also the lack of mature data for the low-volume is applicable irrespective of the treatment to the primary. And this is an important point. Whether or not we should do both radiotherapy to the primary and systemic treatment to the low-volume or rather what this systemic treatment ought to consist of remains to be seen. And we will probably see such analysis from PEACE-1 in the future, but for low-volume patients, I would also discuss metastasis-directed treatment. I think, that for these patients, probably, the best option would be a clinical trial that evaluates SBRT further to the standard of care. There are several ongoing trials globally, such as the PLATON, the STARPORT, but also the oligometastatic cohort of the STAMPEDE trial. And here in France, we have the PRESTO trial, which includes both de novo and relapsed low-volume metastatic patients. And the standard of care, of course, includes radiotherapy to remove the primary and pelvic lymph nodes and ADT. But it also allows for the addition of docetaxel or androgen receptor agents per multidisciplinary decision. So I think that we will have interesting data coming ahead.
Giulia Baciarello: Yeah and may I add that the PRESTO trial, is another academic trial, so.
Anna Patrikidou: Indeed, indeed. So of added value for us. But you know, Giulia, one of the fears that our colleagues have or would have about the triplet, the use of triplet is what to do next. What would you prescribe to a patient that relapses after docetaxel and abiraterone and enters a castration-resistant phase?
Giulia Baciarello: Well, that’s the 1 million dollar question. And the real thing is that, we still don’t know, of course. We do not have data on subsequent treatments yet in the PEACE-1 population. However, we, we know from other cancer types that we really need to use our most powerful armamentarium as soon as possible in the disease, because it’s in the earlier disease that we will achieve the most benefits. And we need to remember that we can have very long responders on upfront using the triplets. So in case of progression, however, we have some standard treatments like cabazitaxel, alpha radium, lutetium PSMA or even PARP inhibitors in HRD positive men. We have also several drugs that are currently under investigation. And in my opinion, I think that if I start a triplet tomorrow, which I would do in an ideal world, I would probably have almost three years, you know, to find the right subsequent therapy in case of progression.
SECTION 3: COSMIC-021
Giulia Baciarello: So speaking about progression, let’s move to castration-resistant setting. Can you please tell us something about the COSMIC-313 trial?
Anna Patrikidou: Yes, of course. Firstly, I agree with you. We should not be afraid to use our combined arms upfront or for fear of lack of options in the castration-resistant setting. Prostate cancer clinical research continues to develop. We have novel smarter AR targeting agents coming up, new immunotherapy drugs, we have ADCs and even adoptive cell therapies targeting prostate-specific TAAs. And we also have combination treatments and one such was used in the COSMIC trial. The trial assessed the use of cabozantinib and atezolizumab in patients, pretreated with enzalutamide or abiraterone. Docetaxel was allowed in the castration-sensitive setting. What we saw this year was the results on the expanded mCRPC cohort in a total of 132 patients, a quite large number for a Phase IB trial. We saw results on the overall cohort and separately for a cohort of visceral metastasis and extra pelvic lymphadenopathy patients. For the overall cohort, they showed an overall independently-assessed ORR of 15% with a disease control rate of 81%. The toxicity was acceptable albeit with a 43% dose reduction rate for cabozantinib. A similar percentage of dose delays for atezolizumab, and then an overall 21% discontinuation rate for toxicity. So the first message is that the combination has encouraging clinical activity, maybe more than the respective mono-therapies. The second interesting feature is that this activity seem to be maintained in their subgroup of visceral metastases, extra pelvic lymphadenopathy patients. Who are really poor-risk patients. They had an 18% ORR and an 84% disease control rate numerically similar, if not slightly better than the overall cohort.
Giulia Baciarello: Well, that’s true. You know, these preliminary results are really interesting and the the combination seems to be effective. And especially as you’ve said, on patients with visceral metastasis and the extra pelvic lymph nodes as well. So what’s your idea concerning this population?
Anna Patrikidou: Yes, that’s, that was really very interesting. The study required soft tissue progression at the study entry, with measurable disease. So it indirectly enriched for these patients and indeed they constituted some 77% of the total cohort and the activity, as we said, is as good in these patients as in the overall cohort. In fact, the Phase III trial now focuses on this group of patients, in my opinion, very correctly, as it is important to find a solution for this niche of poor-risk patients. The one thing that I would like to see and definitely would like to see that in the Phase III trial, is a better dissection of this poor-risk feature group, in the results that we saw this year, the group accounted for 77% of the overall cohort. 32% of the overall cohort had visceral mets. So from the remaining 40 odd percent of patients that had extra pelvic lymphadenopathy without visceral metastasis, it would be interesting to know how many there were, maybe oligometastatic, they had one or two small lymph nodes that were just above the pelvis and maybe no, or minimal bone mets because the prognosis of such patients, as we know, would be different to the pure poor-risk feature of patients with liver metastasis. But assuming that these were not many and they did not significantly skew the results, these are very helpful, but we are indeed looking forward to the Phase III trial results.
Giulia Baciarello: Well, I totally I agree with you. Thank you. And unfortunately, we’ve run out of the time but we will probably continue our discussion over a glass of wine. I would like to thank VJOncology for this invitation. And to thank of course, Anna, for sharing this discussion with me. And we would like to thank you all for your kind attention. Thank you.