Treatment Pathways and Sequencing Strategies in CRPC
Published Online: Oct 25,2013
James Mohler, MD
Targeted Oncology: How would you characterize the changing therapeutic landscape for castration-resistant prostate cancer (CRPC)?
Dr. Mohler: Hormonal therapy remained mostly unchanged for over six decades after Charles Huggins demonstrated in the 1940s that prostate cancer responded to castration. There were a couple of blips, including the development of chemical castration delivered using LHRH agonist depot injections and the introduction of antiandrogens by Fernand Labrie, both in the 1980s. Over the last three years, five new agents have been approved by the FDA: the hormonal therapies abiraterone and enzalutamide; a new chemotherapy, cabazitaxel; an immunotherapy, sipuleucel-T; and a new form of radiation, radium-223 chloride. With so many new agents, it is easy for men--many of whom have already failed treatment--to become confused about their course of treatment and prospects. We're extending life in clinical trials by 3-5 months on average, and you can get excited about that, especially if the benefits are additive, or remain unexcited that we still need a curative therapy. We know we have to do much better.
Is there a consensus sequencing paradigm?
No. In the early space, some clinicians start hormonal therapy early, but there are increased side effects associated with that. I start hormonal therapy later, and prefer to use it intermittently, a strategy that has demonstrated equivalent survival but improved quality of life and reduced costs. In the castration-resistant space, chemotherapy has been shown to extend survival for about 2 months and is used only in men who are symptomatic because of the side effects. Newer agents extend survival 3-5 months after chemotherapy and they are less toxic than chemotherapy. Abiraterone has some side effects and must be administered with prednisone, while enzalutamide does not, and so some doctors favor it. That is a decision based on convenience. The new thinking is that if we can extend life later in the disease with these new treatments, they should be used earlier, but there are no data on that yet. A pessimist might say, “Do no harm,” as there are side effects associated with the new treatments, but an optimist would say, “Go ahead and use them earlier.”
How is the crop of new drugs changing clinical practice for CRPC?
Many clinicians, including me, are looking at the question of earlier use of agents, as well as how to better sequence them and whether they are effective in combinations. We don't have these answers yet. They are answered most quickly in preclinical trials, but unfortunately in the case of abiraterone, for example, lab mice don't have abiraterone targets; they don't make adrenal androgens, and so this has been a limitation for these drugs. They can be tested in chimpanzees, but there are ongoing controversies over that, and perhaps the only alternative is to study them in humans.
With so many new therapeutic options, what guides decision making in sequencing?
The only definitive information available about the new agents comes from trials in which they've been used singly after chemotherapy failure. To date, most decisions are made on the basis of side effects and not on relative efficacy. There is no information comparing one to another, nor about combinations, which can be beneficial or detrimental. We don't know yet. Under the old medication regimes, combining Lupron with antiandrogens had a small benefit, but then combining orchiectomy with antiandrogens showed no benefit. We don't want to repeat the mistakes of the past and spend millions on untested sequences and combinations that don't end up adding anything. The earlier antiandrogen receptors don't compete with dihydrotestosterone (DHT) for the androgen receptor ligand-binding domain, the pocket in which DHT binds to activate the androgen receptor.
The new antiandrogens are better but still compete poorly with DHT at the ligand-binding domain, and there is still room for improvement in my opinion. My hope is for better antiandrogens, and there are some small-molecule drugs in development as well as some antiandrogen receptor drugs that act at areas different from the available antiandrogens The problem is that it takes a long time to test whether the benefits exceed the side effects, and then we also have to think about expense.
How do we determine which patients will benefit from a particular sequence?
We still know very little about this right now, and we'll have to be patient and wait for results from clinical trials.
What do we know about the efficacy and safety of the new drugs?
There is a smorgasbord of new treatments, and the hope is that each agent associated with extension of survival is additive, but we don't know that yet. We hope to turn prostate cancer into a chronic disease, but we're not there yet. Again, the hope is that these agents truly are additive.
Abitaterone requires co-administration with prednisone and is fairly well tolerated. It extends survival about 4 months on average.
Cabazitaxel is sometimes used when docetaxel fails, although treatment with docetaxel can be repeated, and some patients respond to that. The main toxicity with cabazitaxel is bone marrow suppression and other side effects associated with chemotherapy. It extends survival for about 3 months on average.
Sipuleucel-T is well tolerated, but its efficacy is hindered by our inability to assess response; it doesn't affect prostate-specific antigen (PSA) but it does extend survival. It appears to stabilize the disease, and the field has been so surprised that it works that the science behind the why has lagged behind its use. The fact that immunotherapy works in CRPC surprises me, as there is a large disease burden at this stage of the cancer, and it therefore should have a poor immunological response. It should be tested in patients with relatively small burdens of disease, but no one can afford to test in the early space because these patients are going to live so long, as many as 20 years and more.
Radium-223 chloride, a new approach to radiation, carries radiation to areas where bone is being repaired through new cell growth near metastases, and its short-range tissue penetration allows it to kill the metastatic prostate cancer and not the surrounding tissue, including bone marrow. The safety profile is better than standard radiation, but you can't give it simultaneously with chemotherapy. This is a nuclear medicine-based treatment that is helpful at the end of life when the disease is painful.
What are we still learning about sequencing in CRPC?
The major unanswered questions from a therapeutic standpoint are whether these agents will work better if they're given earlier in the course of disease--or if they're given together, whether they will achieve synergies or make the situation worse. We have no idea. The third is a societal question. We can add a half million dollars to the treatment of every man, but should we? This is a moral and ethical question that is not being addressed largely because of its difficulty. It is easy to understand why doctors do not want to deny treatment to any individual, because many men do have a 1- to 2-year response to treatment, but it would be much more cost-effective if we could learn which patients are the good responders and which are not. But these studies have been difficult to fund. We need biorepositories of tissue and greater investment in longer but more important clinical trials. The amount of resources we dedicate to these studies remains too low.
What are some noteworthy clinical trials to determine optimal sequencing, and what do we hope to learn from them?
There are a couple of trials that particularly interest me. There is a study at MD Anderson that evaluates the effect of either abiraterone or enzalutamide on bone marrow metastases. One study has been published in the Journal of Clinical Oncology, and another is under review. These studies look directly at what happens to the bone marrow metastases to see who responded and who did not, and hence does not wait for survival data to answer this question.
There is another study at Dana-Farber that uses the time between diagnosis and radical prostatectomy. It asks questions about whether it's possible to eradicate the disease by treating men upfront before prostatectomy as an attempt to evaluate these new treatments faster and provide a rationale for their earlier use. Other studies at the Vancouver Prostate Centre evaluate tissue samples from radical prostatectomy specimens to search for biomarker predictors of sensitivity to specific therapies as well as resistance. These trials in men with localized and advanced disease may inform our use of these new agents at the end of life and early on.
What are some of the new investigational therapies to watch?
New drugs include TAK-700, a CYP17 inhibitor that does not usually require co-administration of prednisone, and ARN-509, another new antiandrogen that may also keep the androgen receptor from entering the nucleus. There is also a new small-molecule drug, EPI-001, that targets the amino terminal of the androgen receptor, while all others target the C-terminal. It may do a better job of blocking androgen receptor signaling and block the effect of splice variants, fragments of the androgen receptor that don't require DHT for activation. Lots of investigators at universities and pharmaceutical companies are searching for better agents that should provide hope to all men with advanced prostate cancer.
What challenges remain in treating patients with CRPC?
In spite of advances, men continue to die of prostate cancer, and so this is a significant unmet need. What we need are agents to cure advanced prostate cancer. We must also do a better job at earlier detection of potentially fatal prostate cancer. However, it's important to keep in mind that when we find prostate cancer earlier, we are also finding disease that doesn't need to be treated. We need to be more intelligent about dealing with these early cancers and avoid overtreatment. Prostate cancer is a fascinating disease, but very frustrating for patients seeking treatment because everything about it is controversial. We need better treatments, but we also must develop better medical and public health policies that allow application of these treatments to men who need them.