We must raise the bar for future trials by requiring greater therapeutic efficacy, minimizing use of placebo, avoiding artificial disease contexts, developing multitargeted treatment strategies, and evaluating and maximizing cost-effectiveness.
—Maha Hussain, MD, FACP, FASCO
We are witnessing unprecedented progress in the development of therapy for patients with metastatic castration-resistant prostate cancer. The U.S. Food and Drug Administration (FDA) has issued 13 approvals since 1996 for agents that have demonstrated an impact on overall survival, pain, or skeletal-related events—all very clearly clinical benefit outcomes relevant for managing this group of patients. In a similar time period, more phase III trials proved negative despite some very promising biologic, preclinical, and randomized phase II trials data. In the previous era, when there were no established effective therapies to manage metastatic castration-resistant prostate cancer, oncologists based their decision on judgment, prior experience, and phase II clinical trials data.
The need to reduce the morbidity of bone metastasis resulted in the early FDA approvals for agents that reduce pain or minimize skeletal-related events, beginning with the approval of mitoxantrone/prednisone in 1996, followed by strontium, samarium-153 (Quadramet), and zoledronic acid. However, the major landmark occurred in 2004 with the approval of docetaxel, which is the first agent to demonstrate a survival impact in this disease setting. With the limited number of agents available then, clinical decisions as to what to use first were relatively simple. Now, the great news is that we have several agents with impact on survival in both docetaxel-naive patients (sipuleucel-T [Provenge], abiraterone [Zytiga]/prednisone, radium-223 [Xofigo], enzalutamide [Xtandi]) and docetaxel-treated patients (cabazitaxel [Jevtana]/prednisone, abiraterone, enzalutamide, radium-223).
Need for Guidelines?
Now that we have level 1 evidence for these approaches, one may ask: Why do we need clinical practice guidelines?
The fact that oncologists now have many treatment options to offer their patients is a wonderful development. However, the contexts in which these agents were tested creates clinical decision dilemmas as to what to pick first, how to sequence therapies, and how best to counsel patients on what to expect from individual treatments—since, in practice, patients’ prior therapy profiles are increasingly different from those of the patients included in the phase III trials.
It is within this context that the ASCO Clinical Practice Guidelines Committee and the Cancer Care Ontario (CCO) program in evidence-based care have released a clinical practice guideline on systemic therapy in men with metastatic castration-resistant prostate cancer,1 published in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post. The evidentiary foundation of the guideline consists of 26 randomized controlled trials identified through a 2012 CCO systematic review and an updated literature search through June 2014.
With regard to the specific recommendations of the guideline, the data regarding the continued importance of androgen receptor signaling in prostate cancer progression are the foundation for the guidance to continue primary gonadal suppression in patients with metastatic castration-resistant prostate cancer. While luteinizing hormone-releasing hormone–based therapy has pretty much replaced bilateral orchiectomy, patients should be informed of the option for orchiectomy, which, in addition to convenience, will minimize the cost of care.
Important Decision Factors
The guidelines recommend offering abiraterone/prednisone, enzalutamide, and radium-223, with docetaxel/prednisone also being offered with accompanying discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men, whereas cabazitaxel can be offered to patients experiencing disease progression on docetaxel. The recommendations do not provide guidance on sequencing of therapy for obvious reasons—lack of data—yet, this is one of the key clinical needs in recommending therapy to patients.
In the absence of definitive data on proper sequencing, clinical decisions should take into account patient performance status, comorbidities, presence or absence of symptoms, disease extent and location, nature of prior response to therapy, and cost. When all is equal and feasible, treating physician recommendation/judgment, patient preferences, and cost/logistics of therapy are very important decision factors. While tempting, it is important not to assume that combining treatments, because it’s possible, will have a better outcome than sequencing therapy.
The guideline does include mitoxantrone/prednisone, and this combination is certainly an option when all life-prolonging therapies have been exhausted and when the patient has no experimental options, is in need of pain palliation, and is fit enough to undergo chemotherapy. However, it is not clear that the recommendations for ketoconazole or antiandrogens (eg, bicalutamide, flutamide, and nilutamide [Nilandron]) are justified by today’s standards, considering the lack of meaningful clinical benefits with these agents in this disease context.
The recent data from the CHAARTED intergroup trial comparing androgen-deprivation therapy vs androgen-deprivation therapy plus docetaxel in patients with hormone-sensitive metastatic prostate cancer demonstrated an unprecedented survival advantage with the addition of docetaxel in this setting. Although the bulk of the benefit seems to be in patients with high-volume disease (visceral disease or at least four bone metastatic lesions with at least one involving the appendicular skeleton), the data are practice-changing and will likely have an impact on the role of docetaxel in the setting of metastatic castration-resistant prostate cancer—that is, it is unclear whether patients receiving docetaxel for hormone-sensitive disease will respond to it when their disease is castration resistant.
At this time, there are no data on subsequent sensitivity or resistance to docetaxel and other therapies. Hence, there is a need for at least broad outcomes-based data to help inform treatment decisions, since it is unlikely that a prospective trial will address this question in the United States.
The authors should be congratulated on their effort and a very balanced discussion. As a practicing oncologist, however, I am not clear that the content and the guidance change what we are currently doing in practice. It is also important that we streamline the different practice and consensus guidelines through collaboration between representative societies and groups (eg, ASCO, American Urological Association, National Comprehensive Cancer Network) to create one unified guideline in this disease setting that is practical to use.
Short of cure, patients wish to know in the short term if their cancer is responding (a potential surrogate for clinical benefit), and in the long term whether they are likely to live longer and (as much as possible) “live better.” Despite the tremendous progress in metastatic castration-resistant prostate cancer, there are several glaring limitations to the current portfolio of agents. The impact on survival continues to be modest, we use a “one size fits all” approach despite the fact that a significant percentage of patients will not respond to or will have a suboptimal response to therapy, and the cost of therapy is escalating.
That said, the past decade has demonstrated that investment in research will produce significant returns and progress in treating this deadly disease is possible. The need for greater therapeutic impact necessitates significantly more investment and commitment to high-quality research. Patients should be offered opportunities for clinical trials. Finally, we must raise the bar for future trials by requiring greater therapeutic efficacy, minimizing use of placebo, avoiding artificial disease contexts, developing multitargeted treatment strategies aiming at a maximum cytotoxic impact, and evaluating and maximizing cost-effectiveness. ■
Disclosure: Dr. Hussain has received funding from the National Cancer Institute and the Prostate Cancer Foundation, research support from Astellas/Medivation, Pfizer, Genentech, and Bayer, and is a consultant for Synthon and Johnson & Johnson.
1. Basch E, Loblaw DA, Oliver, TK, et al: Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline. J Clin Oncol 32:3436-3448, 2014.
Dr. Hussain is Associate Director for Clinical Research and Co-Leader of the Prostate Cancer Program at University of Michigan Comprehensive Cancer Center, Ann Arbor.