Latest on metastatic castration resistant prostate cancer from ASCO 2013
MD: Professor Maria De Santis – Vienna Hospital, Austria
KM: Dr Kurt Miller – University of Berlin, Germany
DR: Dr Dana Rathkopf – Memorial Sloan-Kettering Cancer Center, New York, USA
CR: Dr Charles Ryan – UCSF Cancer Center, San Francisco, California, USA
MD: Good afternoon. We are at the ASCO 2013 meeting in Chicago and I am Dr Maria De Santis, medical oncologist from Vienna, Austria. And with my are my fellow colleagues, Dr Diana Rathkopf, Dr Charles Ryan and Dr Kurt Miller. So the landscape of treatment options for castration resistant prostate cancer in the metastatic setting has been evolving dramatically within the last ten years. Dr Miller, what are the most important new therapies that have been developed recently?
KM: Well, until 2004 there was no therapy at all that had an influence of overall survival, as we know. And now, during the last two years and in the years to come, there are a lot of new therapies coming in, particularly those therapies targeting the androgen receptor like abiraterone and recently enzalutamide and also new therapies like RAD-223 that is actually targeting the bone and is an alpha emitter, in contrast to the beta emitter we had so far. And there is a lot of new therapies round the corner, I just mentioned cabozantinib which is a VEGF and MET inhibitor that has in the phase II studies shown very dramatic with cells on bone scans and other drugs to come. So really the landscape in CRPC, metastatic CRPC, in 2015 or 2016 should look totally different from that we had two years ago.
MD: For example, abiraterone acetate has shown to double our PFS in the 302 study. So Dr Rathkopf, would you like to comment on the long-term safety data you have presented at this meeting? What about cumulative toxicity or additional side effects, is there any news with the new data?
DR: Yes, sure. So I’m Dana Rathkopf from Memorial Sloan-Kettering and we did present the long-term data on the abiraterone 302 study which was looking at abiraterone acetate which is a Cyp17 lyase inhibitor for patients who had not yet received chemotherapy and were minimally symptomatic or even asymptomatic. And what we saw, interestingly, not only was there a prolongation in the time to progression but there was also a prolongation in the time to death and we saw that there were no new signals for these patients, even on treatment more than two years, in terms of safety and adverse events. The per cent incidence of grade 3 and 4 adverse events at 3 months versus 12-15 months versus greater than 24 months was all pretty much the same and the cumulative incidence over time didn’t differ between the two arms so that was very exciting.
MD: But those patients who live long enough to have treatment for 24 months or more, aren’t those the patients who don’t suffer from side effects? Is there a confounding factor here?
DR: Well sure, the patients that are on study for more than 24 months by definition will be patients that are doing better on treatment and so those patients you wouldn’t necessarily expect them to have long-term effects. But certainly being on prednisone for more than 24 months and not seeing any new signals of toxicity in either arm is important and it should be noted.
MD: Let’s turn to PSA, Dr Ryan. What about PSA in these patients, how do you use PSA for counselling your patients during treatment with abiraterone acetate or enzalutamide, for example?
CR: Well thank you Maria. There’s a couple of issues related to PSA in the management of patients right now. One has to do with the use of PSA as an outcome measure in a clinical trial. So, as you know, we report frequently clinical trial data in terms of PSA response and that type of thing. But the purpose of the data that we presented today was really to help clinicians think about the efficacy of abiraterone across different subgroups of patients when one looks at PSA. We found a couple of different things: one is that the lower the PSA at the time that a patient started abiraterone, the better, the longer the radiographic progression free survival and the longer the overall survival were. The other issue we found was something that has been shown in multiple previous studies which was that the degree to which the PSA declined on therapy corresponded to the significant improvement compared to patients who had less decline in PSA. So patients who had a 90% decline in PSA, for example, had a tremendously improved survival when compared to those who had a less than 50% decline.
MD: OK, and what about complete remissions?
CR: There were a few, around 5% or so of patients who took abiraterone on this trial experienced a PSA that went down to 0.1 or lower. Many of those remained durable while they are on therapy. I don’t go so far as to call that a complete remission but I think an undetectable PSA is something that is an interesting outcome measure and is something that appears to correspond to a very good survival and a very good time to progression.
MD: What about those other patients who don’t respond and who do not show a PSA decline? Would you recommend those patients to stop treatment or how do you manage them?
CR: That’s a good question. So, one of the issues that came up was what is the outcome of a person who does not have a PSA decline? And it looks like their outcome is not that much different from patients who, for example, are taking placebo. So I’m less inclined than I was previously to maintain a patient on abiraterone even if the PSA has not gone down. In particular, now that we have so many other therapies, I think that it’s reasonable for a patient to receive, for example, twelve weeks of therapy and if there is no sign of clinical benefit after twelve weeks, if there is no PSA decline or if there is an overt rise in the PSA, then I think one has to consider that this patient is probably in that 15-20% of patients who simply don’t benefit from this drug.
MD: So we have heard that patients live significantly longer now with the new treatments in the post-chemotherapy setting. Has the proportion of patients with, for example, bone only disease or the proportion of patients with visceral metastases changed with the longer survival of the patients?
KM: There’s some evidence that indeed self-tissue metastases have increased over time which might be a function of that what you just said, that the patients have a better prognosis, live longer. This is mostly, however, lymph node metastasis so on the other hand probably the relationship… liver metastasis which have the worst prognosis and lung metastasis did not really change over time.
MD: So, for patients with soft tissue metastases only, for example, or for those with visceral metastases, would you tend to use more chemotherapy or more of the hormonal agents?
KM: Actually the patient who has liver metastasis, let’s just make an example, only with no bone metastasis, this is still a rare patient in prostate cancer. But to date we have no real evidence that one therapy is superior to the other. People tend to think that cytotoxic treatment might be better in these patients who do have the worse prognosis but this is rather thinking that that is based on studies or on evidence or on any data we have to date.
MD: So this is more speculative?
KM: It’s more speculative, right.
CR: I would just add that the first thing I would do in a patient who has visceral metastases without bone metastasis is do a biopsy because we’re finding that there’s a lot of heterogeneity in that and that’s probably driving some of that differences in outcome.
MD: These are those patients who often have a low PSA, for example, and those newer endocrine features.
MD: So this might be the patients who benefit more from chemotherapy although they might benefit also from abiraterone acetate because this is the low PSA patients. So actually I think it’s still not so clear who would benefit from which treatment. This brings us back to the next question, Dr Rathkopf, which treatment for which patient? What options would you, for example, consider for patients who are more unfit, for those with ECOG performance status 2 or 3 or with multimorbid conditions?
DR: So I think that that patient population is really challenging because you want to make sure that you’re treating the patients in such a way that you’re not having the treatment be worse than the disease itself. And so, depending on how symptomatic a patient is, I think, is how I tend to look at what the risk of the treatment should be. Certainly for the unfit patients, unfit patients meaning patients who probably aren’t good candidates for chemotherapy, in the past what we have thought about using are drugs like abiraterone or enzalutamide and more recently alpharadin now that it’s more widely available for these patients; I think those are all very good options.
MD: Also those patients have not been included in the clinical trials because ECOG performance status 3, for example, was not included and many patients with comorbid conditions also were excluded from the trials. So we do not have a lot of data for this patient population.
DR: It’s similar to your question about how to treat visceral metastases. I mean there were very low numbers of patients with visceral metastases on the post-chemotherapy abiraterone trial, for example, I think it was somewhere between 10-20%. So we don’t have a lot of data for the sicker patient population because those aren’t usually the patients that we put on these type of clinical trials. But certainly in practice when you have a patient who is unfit for, say, a cytotoxic treatment and yet they have a disease that’s rapidly progressing, that it’s worth trying drugs such as abiraterone acetate or alpharadin or enzalutamide. And we certainly do know from the studies that, at least in more fit populations, that the toxicity is, as we alluded to earlier, the long-term toxicities of some of these agents are very well tolerated and safe.
MD: At the other spectrum of patients, those patients who are minimally symptomatic or asymptomatic, which treatment would you consider first, Dr Ryan?
CR: A minimally symptomatic patient or an asymptomatic patient?
CR: Well, that’s a situation where here in the United States, we have sipuleucel-T available and this is the setting in which I do use it, I don’t use it in every patient in that situation but this is the situation where I say if this patient has a good prognosis and relatively indolent disease, I will do it. Typically after using sipuleucel-T one wants to initiate a treatment with more remission potential, such as abiraterone, enzalutamide or chemotherapy and there has been a lot of concern about, for example, the prednisone which is given concurrently with the abiraterone as that may be something that would impair the immune response to the sipuleucel. We now have some early data that suggests that that’s probably not the case and that is actually reassuring to us in so far as we might be able to treat a patient with abiraterone shortly after they receive sipuleucel. It doesn’t tell us that we have to do that, it just tells us that we can do that and that we’re probably not undoing the immunotherapy. In the absence of the use of immunotherapy, however, our standard of care right now is to use abiraterone in that setting, that’s what has received FDA approval. And we continue to study new combinations of drugs in that setting and entirely new agents of different classes too.
MD: So, Dr Millar, what would you suggest for patients who are asymptomatic or minimally symptomatic, more going for abiraterone acetate as in the 302 trial or more going for chemotherapy because are the patients who might tolerate chemotherapy best?
KM: Well I think we’re in Europe in about the same situation as Charles just mentioned, the only difference is that we don’t have sip-T. And so abiraterone clearly is the first line treatment of choice. Why? Because in asymptomatic patients in the past, most of the urologists and the oncologists have been reluctant to go to chemotherapy because offering chemotherapy to an asymptomatic patient is always a hurdle to take, psychological, for the doctor and the patient. So it’s having a drug that has much less toxicity is really a step forward. It’s easier to offer it to a patient who is not symptomatic. So I think the current sequence we have is really starting with abiraterone in these patients, asymptomatic or minimal symptomatic, and then going to cytotoxic treatment.
MD: And the symptomatic patients, then, would be treated with chemotherapy?
KM: Not necessarily because when you look at the palliation data of abiraterone and if you look at the palliation data of, let’s say, docetaxel or cabazitaxel, also in that setting abiraterone looks better to me than chemotherapy. That’s also a feeling that people think if the patient is symptomatic better give him cytotoxic treatment, which is actually not the case. I mean this is cross-study evaluation which is always difficult but if you look at the study itself, for me, I would start with abiraterone even in symptomatic patients.
MD: Do we have biomarkers for patients in the metastatic castration resistant prostate cancer setting and can we predict response to treatment? Is there any new data, Dr Rathkopf?
DR: Such an easy, simple question.
KM: Just say no.
DR: I guess yes, you could just say no but we’re exploring a lot of different avenues. There are none that have been validated but certainly a lot that look promising and so at ASCO this year there was some data on looking at ERG rearrangements in patient samples for the 302 study or the study of abiraterone for patients who haven’t yet received chemotherapy and seeing if that predicts response. Looking at CTCs, there are a lot of abstracts about circulating tumour cells and different ways of analysing these, looking at circulating mRNA. So I think that as we develop more drugs that show a survival benefit, that patients are going to be living longer and showing a survival benefit as a means by which to approve drugs going forward is going to be difficult. So the onus is on us and the community to develop biomarkers that can be intermediate endpoints as a read-out for how drugs will behave going forward and maybe even the dream would be for these to be rapid read-outs and allow drug approval earlier. So there are a lot of exciting things on the horizon but nothing yet that’s validated.
MD: There might be other biomarkers like hormone levels. Dr Ryan, any comments about hormones in the serum and correlation to hormonal treatment?
CR: Sure. Well this has been an area that I’ve spent a lot of time thinking about in the last few years. We did a subset analysis of a group of patients who were on the post-chemotherapy abiraterone study; actually it wasn’t much of a subset analysis, it was almost every patient enrolled in the trial. And we looked at serum androgen levels determined through a liquid chromatography mass spectroscopy-type assay that gave us a much greater sensitivity than the standard assays. And what we found were two interesting components. One was when you look at patients who have higher levels of androgens in the serum they actually had a better prognosis overall, and this applied to both the prednisone treated patients as well as the abiraterone treated patients. The other facet that was interesting were two things: one is that even the patients with the lowest levels of androgens appeared to benefit from abiraterone over prednisone alone, suggesting that even low levels of androgens are important to reduce. It might mean that those patients with low levels of androgens in the serum may have a propensity to have tumours that have intracrine androgen production, we don’t know that, that’s just a speculation. But the other thing that was interesting about that study was the average testosterone level in men we enrolled in that study was about 5 or 6, 5.6 I think it was, and the cut-off for eligibility based on testosterone is 50ng/dl. So we have been probably a little bit off the mark over the past few years in requiring a testosterone level be less than 50 when actually the testosterone levels are quite low when one looks at them with these very sensitive assays.
MD: So we had a lively discussion about the use of the novel agents in the treatment of metastatic castration resistant prostate cancer. We talked about long-term use of abiraterone acetate and the lack of additional toxicity in these patients. Furthermore we discussed the clinical presentation of the patients in view of a longer survival. We tried to answer the question, which patient would benefit from which treatment, which is important for daily clinical practice. And finally we asked the question how to use PSA for counselling patients with all the new treatments. I wish to thank my fellow colleagues for joining us today at this discussion at the ASCO 2013 meeting in Chicago. Thank you.