Treatment of Castration-Resistant Prostate Cancer: Current Options and Novel Therapies

Andrew J. Armstrong, MD, MSc

Tomasz M. Beer, MD, FACP

Even though prostate cancer is generally a slow-developing disease, up to 40% of men diagnosed with the disease will eventually develop metastatic disease. Despite surgical castration and initial treatment, progression to castration-resistant prostate cancer may be inevitable.

In this interview, CancerNetwork speaks with two prostate cancer experts-both are actively involved in the research and clinical trials of novel agents-on the topic of newly available and upcoming treatment options for patients with castration-resistant prostate cancer. Dr. Tomasz M. Beer, Oregon Health & Science University Knight Cancer Institute, and Dr. Andrew Armstrong, Duke Cancer Institute in North Carolina, are invited speakers at the 2012 Annual Meeting of the American Society of Clinical Oncology in Chicago this June, where they will discuss this topic.

-Interviewed by Anna Azvolinsky, PhD

CancerNetwork: Over the last year or so, there has been a lot of progress with new systemic therapies showing a benefit for patients with castration-resistant prostate cancer. Let’s start with the new hormonal therapies. Dr. Armstrong, can you describe both abiraterone, which was approved last April, and also MDV3100, which is a novel androgen receptor signaling inhibitor that has actually rapidly moved from early stage trials to phase III?

Dr. Armstrong: I want to highlight here that over the past 10 years, one of the major paradigm changes in our field has been the recognition that our hormonal therapies are what have been failing our patients, and not that patients are truly hormonal refractory. Several of the resistance mechanisms that emerged during castration-resistant progression has been still involving hormonal signaling.

So we have learned over the past few years that prostate cancer can generate androgenic precursors as a resistance mechanism, they can amplify the androgen receptor, and they can develop mutations or splice variants in these receptors. They really adapt to these hormonal therapies over time and in the past our older hormonal therapies simply were not as effective at controlling that disease state. So the term actually changed from hormone-refractory disease to that of castration-resistant based on many of these new therapies demonstrating greater efficacy and still some sensitivity to hormonal therapies.

Abiraterone is one of the first. It is a modification, essentially, of a drug that we used for many decades called ketoconazole. It is really an androgen precursor synthesis inhibitor. It blocks the synthesis from cholesterol to dihydrotestosterone (by being a cytochrome P450 CYP17 inhibitor), which is one of the key enzymes that builds testosterone from scratch. That works both in the adrenal gland to block one of the remaining sources of testosterone, but also in a paracrine/autocrine fashion given that prostate cancer can synthesize its own or use these to make testosterone from the serum. The Medivation drug is quite different. The MDV3100 compound is a second-generation antiandrogen, so it blocks the receptor-particularly the amplified receptor in ways that older androgens did not. So they are really different mechanisms. But they are both hormonal agents.

Abiraterone was the first to demonstrate an overall survival benefit. The first trial that reported this, and is now published in the New England Journal of Medicine, was in men with castration-resistant disease who progressed after docetaxel. This showed a nearly 4-month improvement in overall survival compared to prednisone alone. Abiraterone is given with prednisone to maximize the efficacy and reduce the toxicity of that drug. The Medivation compound recently reported its results at the 2012 ASCO Genitourinary Symposium and will also be shown at ASCO this year. It demonstrated a survival benefit of nearly 5 months in the same kind of setting-post-docetaxel, castration-resistant metastatic patients were in that trial. The trial is called the AFFIRM trial. While this is not published yet, the data is compelling and that drug is currently under FDA review for approval in that disease state. There are many other drugs that are coming that are very similar to both of these original compounds-TAK-700 is fairly similar to abiraterone, and second-generation antiandrogens are in development as well.

CancerNetwork: What do both of you think are the next important steps specifically for these agents-combination, better search for predictive biomarkers, earlier delivery? Dr. Beer let’s start with you.

Dr. Beer: I just want to point out that the level of benefit that we are seeing with these patients is really quite impressive relative to what we know about chemotherapy. These are oral agents with relatively modest toxicity in comparison to conventional chemotherapy drugs. These are real and substantial advances for patients. But getting to your question, I do think that in many cancers the full potential of systemic therapy is really only understood once the therapy has been tested across the continuum of the entire disease. I would be very interested in seeing these agents move into earlier stages of disease, where a 30% to 40% benefit, for example, in a situation where men live many years, could really be a transformative benefit if it holds up. I think earlier stage of the disease, up to and including combinations with radiation for locally advanced high-risk disease, where we know conventional hormonal therapy has a big impact on survival and improves the results of radiation. One would certainly wonder if better hormonal therapy could make an even bigger difference. Certainly combination versus sequence is an important question in the field. We don’t, at this point, really have a lot of insight into whether these drugs could do even better if we maximally suppress all elements of androgen signaling including ligand production and the receptor at the same time. I think that is an important question that needs to be asked.

Dr. Armstrong: I would just echo that and say that the phase III trials, pre-docetaxel for abiraterone, for example-we already know that that is essentially a positive study and will be presented shortly. But, other trials looking at abiraterone with radiation or in earlier disease setting makes sense. Our goal is obviously to improve cure rates as well as to improve survival with the earlier use of these drugs. For Medivation, the PREVAIL study, for example is a pre-docetaxel trial that is still ongoing. The use of these drugs adjuvantly, after surgery or with radiation in combination or sequence does make sense. The longer you have men on these studies-obviously these are very potent hormonal therapies-we do also have to pay attention to the long-term safety.

CancerNetwork: Two other drugs that have recently been approved are the immunotherapy-Provenge, as well as the chemotherapy cabazitaxel (Jevtana). Could both of you describe your view on the role of these agents in treatment?

Dr. Armstrong: Provenge or sipuleucel-T was FDA-approved over a year ago now based on a survival advantage in men with castration-resistant disease that was metastatic. It was the first drug to really have a label based on symptoms-it is particularly indicated for men with asymptomatic or minimally symptomatic disease similar to the IMPACT trial, a phase III trial that enrolled these types of men. These men did not generally have liver or lung metastases and generally had not had prior chemotherapy, although there were some exceptions to that. The trial showed a 4.1-month improvement in survival. It did not have other effects like the hormonal therapies we just described, such as PSA declines or delay in progression or radiographic responses.

With an immunotherapy-quite a different mechanism of action-you may expect different end points or a delayed end point. We are still trying to work out which patients might benefit more from this therapy, or find biomarkers that can help interpret patients who are responding or not, and how best to combine this or sequence it with all of these new agents. These are some of the active questions.

Dr. Beer: I will comment on cabazitaxel. It is the second chemotherapy drug after docetaxel shown to be effective in extending survival in advanced prostate cancer. It has become a standard tool in the management of patients who have metastatic castration-resistant prostate cancer following docetaxel therapy. Of course now with abiraterone in use after chemotherapy this is a crowded area and I think many of us are currently approaching the treatment with docetaxel first, abiraterone next, and cabazitaxel third. I do expect this to evolve. I think that it is reasonably likely that the hormonal drugs will continue to be moved earlier in disease. Cabazitaxel is being tested against docetaxel in the front-line setting. We are going to see continued evolution of the treatment paradigm. I do think cabazitaxel offers an important option especially for those patients where hormonally active agents are no longer useful. Even though we have extended the range of those agents, eventually, most patients find themselves in a situation where the cancer is resistant to all of the various hormonal agents that are available.

CancerNetwork: Another set of agents, that aim to prevent bone metastases, such as denosumab (Xgeva), which is approved, and also radium-223 (Alpharadin) which has shown an overall survival benefit in advanced prostate cancer patients. What is the difference between the two agents and what are their roles?

Dr. Beer: Alpharadin is an alpha-emitting radiopharmaceutical, a relatively unique agent. It is, I suppose, similar to denosumab in that it targets disease in the bone but how it does so and what it does is dramatically different. It essentially delivers radiation therapy to sites of bone metastases. It is the first radiopharmaceutical to show, convincingly, real antitumor effect as measured by PSA decline and pain control. But also survival advantage, and I think that is very exciting. The drug is not yet available in the marketplace, we are not using it routinely. I do expect it to become another tool in the toolbox. It is likely to be a drug that we use after chemotherapy but we are going to have to learn more about this drug and gain more experience with it. It is important to have drugs of different classes available and this is clearly a unique class.

Denosumab is a drug that inhibits bone turnover and has been studied, as you indicated, to prevent bone metastases, to treat osteoporosis and to reduce the risk of skeletal-related complications from prostate cancer. So it is really a bone-targeted drug that targets the bone directly and does not directly target the cancer like Alpharadin or chemotherapy. At the moment, I think it is most widely used in prostate cancer to prevent skeletal-related complications or to delay them in metastatic castration-resistant disease. As a tool to prevent metastases, it did not gain FDA approval. There was a delay in metastases but not an overall survival advantage. Earlier use of this drug necessarily resulted in a higher risk of side effects particularly osteonecrosis of the jaw. I view this drug as an important tool in the supportive care management of patients. But like all tools, one that needs to be evaluated on a risk-benefit analysis, being mindful that we want to be careful about causing one side effect while preventing another. In general, I think it is used to reduce skeletal complications in high-risk patients and is certainly an exciting option. Its use to prevent metastases is probably not justified by the current data but that is a controversial point and I wonder what Andrew will say about it.

Dr. Armstrong: I agree with you Tom. I think the ODAC committees agree with you as well. Delaying an event that is just a pure radiologic event by just a few months did not seem to be a reason to change or expand the label based on a single trial without evidence for improved survival or longer term outcomes, particularly given the toxicities with years of denosumab use and the cost. But I would just say that these agents, like zoledronic acid and denosumab can compliment drugs like radium. In fact, the radium data suggest that if patients are on these bone drugs, particularly zoledronic acid, the benefits seem to be even greater for preventing skeletal-related events. So they can really help each other out. Many of these drugs are given at the same time as other therapies like chemotherapy or hormonal therapies-not the radium necessarily. Radium was an interesting trial design. In essence, they were able to deliver hormonal therapies to the patients at the same time as the radium. They did not mix it yet with chemotherapy. Many of the patients did receive second-line or third-line hormonal therapies as part of that trial on both sides of the trial. It will be interesting, obviously, to eventually combine some of the newer hormonal therapies that we talked about earlier with radium.

CancerNetwork: As a last question, with all of these new agents, what is the current role of clinical trials for advanced prostate cancer? Dr. Beer you have recently written a book about how to make the best-educated decision about clinical trials for cancer, so let’s start with you.

Dr. Beer: I think that the role of clinical trials hasn’t changed. We have made much progress through clinical trials but much more is necessary. When we look at, for example, testicular cancer, where 90% of patients with metastatic disease can be cured with 12 weeks of medication, it is pretty obvious that we have a long way to go. So I think our commitment to clinical trials should, in fact, be greater than ever. This is because we have now demonstrated to ourselves and to our patients, what kind of progress is possible through clinical research. I think, from a researcher perspective, it is a much more difficult universe to be in.

All of these effective agents have created many subpopulations of patients and the design of clinical trials today is PhD-level work, compared to high school level work just a few years ago. Just figuring out how to study new agents in this incredibly complicated field where, as our discussion has clearly demonstrated, we haven’t figured out exactly how to use the agents we already have. So, it is a challenge. For those of us who like those kinds of challenges, this is an exciting time. We have never had a better understanding of cancer biology that has driven a more robust effort to develop exciting new drugs, and the fact that we have gone from 1 drug that improves survival to 6 in a matter of about 2 years-it is just the tip of the iceberg as far as I am concerned.

I am very excited that I had a chance to write a book with one of my patients and clinical trial participants. The book is entitled, Cancer Clinical Trials, and we hope that those folks who are contemplating participating in a clinical trial will find that book helpful and help them think through where a clinical trial may or may not fit into their cancer care plan.

Dr. Armstrong: That’s great. I would just add to that with all of these new drugs, our prostate cancer community will likely form new questions and new control groups and new designs that will help to answer questions. I will also say that many of our colleagues in other solid tumors, particularly lung and breast cancer are moving toward predictive medicine or precision medicine where we are using tumor biomarkers to select patients for a given therapy in order to maximize benefit to those patients who are likely to respond to a therapy. That takes a well-validated, qualified biomarker-for example, estrogen receptor, progesterone receptor, HER2 in breast cancer, or EGFR mutations in lung cancer. These are the biomarkers where you can see real dramatic outcomes with drugs that really inhibit that target. I would say that prostate cancer is heading in that direction and it is still an unmet need as far as developing those biomarkers that can really select patients who will have an astounding benefit from abiraterone or Medivation's drug, or even taxanes for that matter. Ideally our field will go towards that to really maximuze benefit and minimize harms. That is my hope.

CancerNetwork: Thank you both so much for joining us!

Dr. Armstrong: Thank you.

Dr. Beer: Thank you very much, my pleasure.