COMMENTARY

Confirmed: Abiraterone Ups Overall Survival in mCRPC

Stéphane Oudard, MD, PhD; Cora Sternberg, MD

Disclosures

October 13, 2014

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17-Month Improvement in Survival for Hormone-Sensitive CRPC

Stéphane Oudard, MD, PhD: Hello. I am Stéphane Oudard, professor of medicine at the Paris Descartes University and chief of the Department of Oncology at the George Pompidou Hospital in Paris, France. Welcome to this edition of Medscape Oncology Insights in prostate cancer, coming to you from the 2014 Congress of the European Society for Medical Oncology (ESMO). Joining me today is Dr Cora Sternberg, chief of the Department of Medical Oncology at the San Camillo Forlanini Hospital in Rome, Italy.

A number of studies have been presented in the prostate cancer session of the ESMO meeting so far. What do you see as the most significant, interesting phase 3 studies so far?

Cora Sternberg, MD: A few studies have been practicing-changing. A study presented by Christopher Sweeney[1] was first presented at the American Society of Clinical Oncology meeting.[2] An update was given at this ESMO meeting focusing primarily on patients with high-risk disease. In the past we have used docetaxel chemotherapy only for patients with castration-resistant prostate cancer (CRPC). But there has always been a debate, when patients first develop metastatic disease, about whether there could be metastatic cell clones, and if we give hormonal therapy, we allow these resistant clones to grow. Or if we wait longer, patients could perhaps become too debilitated to receive chemotherapy, and these clones could then grow and take over. There has been this pro/con debate over whether it would be better to give them chemotherapy up front the moment they develop hormone-sensitive metastatic disease.

ECOG has conducted a randomized study[1] of more than 700 patients who were randomly assigned to receive either standard androgen deprivation therapy for metastatic disease or androgen deprivation therapy plus six cycles of docetaxel chemotherapy. Docetaxel was given without the prednisone in this study. What they found was remarkable. They focused on patients with high-risk disease, defined as at least four bone metastases (at least one of which was outside of the axial skeleton) or visceral disease. They had found in previous studies that this was the worst group of patients, and that these patients did very poorly.

In the patients who were given chemotherapy, there was a difference in overall survival of 17 months in favor of the combination arm. A 17-month improvement in overall survival is the biggest difference we have seen in any study in oncology lately. In the entire group of patients, the difference in overall survival was 14 months, but it was really driven by these high-risk patients. The low-risk patients don't have a difference in survival, or more follow-up is needed.

Dr Oudard: You are convinced about these data, so what are you going to do on Monday, or next week, for your patients?

Dr Sternberg: In my institution, docetaxel is not approved for patients with hormone-sensitive disease, but we need to speak to our authorities about this study, and to our patients, particularly our younger patients who present with extensive or visceral disease. We are obligated to tell them about this study and to seriously consider giving these patients chemotherapy. There was not a lot of toxicity with the chemotherapy, but this was a group of patients who had not been on hormone therapy or various other therapies for years and years. I would discuss this with my patients and try to convince our institution to consider giving chemotherapy to certain patients. For elderly men in their 80s, we should think twice about that.

Dr Oudard: Are you concerned about the quality of life of these patients? So far we don't have any data on quality of life. Will you start right away with docetaxel, chemotherapy, and hormonal therapy, or do you think we should wait for the final publication and the quality-of-life data?

Dr Sternberg: It would be very interesting to see. From what I have seen of the toxicity of docetaxel, it didn't look as though it was very toxic in this patient population. They even tried to keep the toxicity down by not giving the twice-daily prednisone that we often give with docetaxel to patients with CRPC. This was intended to improve quality of life, but I don't know those results yet.

Abiraterone Improves Overall Survival in CRPC

Dr Oudard: Another very interesting study in CRPC patients looked at the efficacy of giving abiraterone prior to docetaxel, the COU-AA-302 study (previously called Cougar-302).[3] The investigators gave an update of the overall survival data. What do you think about these results so far?

Dr Sternberg: These results are very important and also practice-changing. After 2004, docetaxel became the fulcrum of the chemotherapy[4] that we used for CRPC, and now we see that even though patients are castrated and have low levels of testosterone, they can still respond to such new therapies as abiraterone and enzalutamide. We first tested these agents in patients after chemotherapy,[5,6] and because they were so effective we began to test them in patients pre-chemotherapy.[7,8]

This study[3] was done in patients with metastatic CRPC who were relatively asymptomatic or had few symptoms and no visceral disease. More than 1000 patients were randomly assigned 1:1 between abiraterone acetate and prednisone vs placebo and prednisone. We could do that 1:1 randomization because the patients were not very sick.

The study was stopped at the first interim analysis when they saw a 57% reduction in the risk for progression. The Independent Data Monitoring Committee said we needed to stop the study, that it's not ethical to continue, that we must cross over patients right away. So what happened was, the overall survival was not statistically significant in favor of abiraterone, because patents crossed over to the abiraterone arm. They have subsequently done several other analyses that were preplanned, and always the overall analysis never reached statistical significance.

What Chuck Ryan[3] presented the other day was a follow-up of the last planned interim analysis of 49 months (4 years), and now the overall survival data have also become positive with longer follow-up. This is very important because many of our regulatory authorities have not wanted to approve this drug without the overall survival data, even though patients were living longer (with a much longer progression-free survival) and waiting longer until starting chemotherapy.

Without those overall survival data, it provided an excuse for regulatory authorities in some countries to not reimburse the drug. With these new data, the regulatory authorities will be forced to approve the drug. Patients will feel more comfortable and their doctors will feel more comfortable that they know they are also increasing overall survival. What happens in these studies is that after the study is stopped, many patients cross over, and in this case, many crossed over to abiraterone and many received docetaxel or enzalutamide afterwards, so it's harder to prove that an overall survival benefit is associated with any particular upfront drug. Still, it's a very important study.

Dr Oudard: It's a study where abiraterone was given either earlier or later, due to the crossover, and half of the patients received abiraterone at relapse. What do you think about that? Do you prefer to use abiraterone early or to reserve it for later on?

Dr Sternberg: In patients who are asymptomatic or relatively asymptomatic, I prefer to give abiraterone early. We have participated in this study and similar studies. Patients prefer to delay chemotherapy as long as possible, so it is something that patients are very happy to do. They are used to being on hormonal therapy. If you continue them on hormonal therapy, they are very happy to do that, and if there is an overall survival advantage patients can still benefit from other chemotherapy and other therapies afterwards. It raises the question of the right sequence of drugs that we should be giving. We don't know.

We have never had a head-to-head study of docetaxel vs abiraterone or abiraterone vs enzalutamide, so we don't know the best sequence in which to give the drugs. We know that there is some cross-resistance between the agents and that the taxanes also affect the androgen receptor in translocation to the androgen receptor, so we expect some cross-resistance. Whatever drug you give second or third may not work as well as the one you give first. There could be different reasons for this. Perhaps the patients have more bulky disease or they are sicker as well. There are many issues, and we need to sort this out in future trials.

Androgen Receptor Variant: 'Most Exciting' Marker to Date

Dr Oudard: In the metastatic setting we have plenty of drugs so far—chemotherapy, immunotherapy, hormonal therapy—and now we have very interesting data from Antonarakis[9] with the AR-V7. What do you think about this variant? Is it a predictor of resistance to therapy with abiraterone and enzalutamide? How do you use this?

Dr Sternberg: We don't know the right sequence of drugs. We have a problem with this. We know that up to one third or one fourth of patients do not respond to abiraterone or enzalutamide, so what we would like to know is which patients will respond and which will not respond. We have some data from MD Anderson[10] using bone marrow biopsies, suggesting that men with high testosterone and high CYP17 have a better chance of responding.

What the group from Johns Hopkins has done is very interesting.[9] They have looked at this splice variant in circulating tumor cells. At least 20 splice variants have been described; the AR-V7 is perhaps the most frequent one, and they have measured the AR-V7 splice variant. "Splice variant" means that you have the androgen receptor, which is cut at the hinge region at the C terminal, so there is no ligand binding domain. You have a constitutively active androgen receptor that doesn't need to be bound to testosterone and can be active on its own to produce downstream growth and proliferation. To measure the AR-V7 splice variant in the circulating tumor cells, they took three samples of blood during the study. There were only 62 patients in the study—31 on abiraterone and 31 on enzalutamide. At Johns Hopkins they usually use abiraterone first, so most of the patients on enzalutamide had received abiraterone.

The first data were published in the New England Journal of Medicine[11] in September. They looked at prostate-specific antigen (PSA), radiologic progression, and clinical progression. Patients who bore the splice variant had no PSA responses—none whatsoever—and their radiologic progression-free survival was about eight times worse in the enzalutamide arm and 16 times worse in the abiraterone arm [than those who did not have the splice variant].

The data presented at ESMO were an updated analysis of overall survival. Looking at overall survival in just 62 patients, they found that among patients who received enzalutamide (and these are patients who had already received abiraterone) those patients who bore the splice variant had four times less chance of surviving. Patients who bore the splice variant and were treated with abiraterone had a 10-times-less chance of surviving, which is a big difference.

This study was done in one hospital only, and it is not a CLIA [Clinical Laboratory Improvement Amendments]-validated test. We can't just send our circulating blood cells off to the lab for this test yet. It clearly needs to be validated. I don't know whether the splice variant is a prognostic marker for overall survival or just a predictive marker for whether a patient will survive. However, of all the different markers that I have heard of so far, this is perhaps the most exciting. I am sure that many people will be studying this and trying to validate it to see whether we can predict who will and who will not benefit from these therapies.

End of the Line for 'Docetaxel Plus Something'

Dr Oudard: Could you say a word about the negative SYNERGY study looking at the addition of custirsen to docetaxel/prednisone?[12]

Dr Sternberg: Since 2004 when we first saw the addition of docetaxel to chemotherapy, we have all participated in perhaps 10 different studies trying to improve overall survival with docetaxel. This has been very difficult. First of all, in prostate cancer, most patients have disease in the bone, so it's very difficult to measure by RECIST criteria whether they have a response. The only thing that has been accepted by the authorities is overall survival. Whereas we may see wonderful responses and patients do well in terms of progression-free survival, when it comes to overall survival, all of the studies have been negative.

I don't think we are going to do any more studies of docetaxel plus another agent, unfortunately. This was our last hope. This was a study with custirsen, which is a second-generation, anti-SNS, oligonucleotide that works against clusterin. Clusterin has something to do with resistance, so the idea was to decrease the resistance that might occur with chemotherapy. We hoped that by using custirsen we could make the docetaxel work better and reduce the resistance mechanisms that might be occurring within the patient. Unfortunately, the results, in terms of overall survival, were not positive and the only patients who seemed to benefit were those who had poor prognostic factors and were rather sick. I am afraid, even though there is another study going on in second-line, that this SYNERGY study was a negative.

Dr Oudard: Thank you, Cora. You provided a very clear overview of the highlights in prostate cancer so far. See you next year for the ESMO meeting 2015.

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