Sequencing of Medical Therapy in Advanced Prostate Cancer
The typical sequencing of medical therapy in advanced prostate cancer has been well defined in recent times, but the existing paradigm is being rewritten with the advent of these new therapies. The development and approval of these agents has generated an unprecedented excitement in prostate oncology.
Systemic therapy has generally been initiated with GnRH agonists/antagonists as monotherapy or in conjunction with an anti-androgen. With progressive disease, the anti-androgen was withdrawn, to assess for a therapeutic response, known as the anti-androgen withdrawal syndrome. At that point additional, secondary hormonal agents such as ketoconazole(Drug information on ketoconazole) could be utilized, with modest data to support this approach. For those with aggressive or symptomatic disease and a good performance status, docetaxel(Drug information on docetaxel) chemotherapy was given (Figure 1).
This traditional schema for the medical management of prostate cancer has now changed. Rather than utilizing generally poorly studied secondary hormonal therapies for patients with CRPC, we now have sipuleucel-T available, which has a proven survival advantage in men with metastatic CRPC with minimal or no symptomatology. Additionally, for patients with CRPC after treatment with docetaxel, both abiraterone acetate and cabazitaxel are available. While there are no head-to-head trials to guide us, the side-effect profile of these agents, as outlined, is different and will in large measure dictate patient selection for these therapies. Thus, in the course of 2 years, we have four medical therapies rather than one for CRPC, approved based on a survival advantage.
In additional to the agents highlighted above, there are other novel drugs in late-stage development, several of which are likely to change our treatment approach in prostate cancer in the coming years (Figure 2).
• MDV3100, a new-generation anti-androgen, is more potent and selective in targeting the androgen receptor (AR), impairing both nuclear translocation of the AR and its nuclear binding. In a phase I/II study, 140 men with metastatic CRPC were treated with 30 mg to 600 mg of MDV3100, with PSA reductions of ≥ 50% observed in 56%. Randomized phase III clinical trials of this agent are underway (clinicaltrials.gov identifier: NCT00974311 and NCT01212991). The AFFIRM (A study evaluating the eFFicacy and safety of Investigational dRug MDV3100 in men with advanced prostate cancer) post-docetaxel clinical trial was just reported to show a survival benefit for the agent. Initial reports of the post-docetaxel AFFIRM study from an interim analysis by the Independent Data Monitoring Committee (IDMC) indicate a 4.8-month survival advantage with use of MDV3100 vs placebo (13.6 vs 18.4 months; hazard ratio [HR] = 0.631). The study was stopped on this basis, with subjects in the placebo arm to be offered MDV3100 therapy. Additionally, the IDMC indicated that the unblinded safety analysis yielded a favorable risk-to-benefit ratio for MDV3100.
• PROSTVAC-VF (Prostvac) is a PSA-targeted immunotherapy that utilizes a vaccinia vector for priming, followed by six fowlpox vector boosts.[22,23] A phase II study of PROSTVAC-VF with 125 patients randomized in 2:1 fashion to the vaccine vs control vectors has been reported. There was no difference in the PFS, but the median overall survival was longer in the PROSTVAC-VF arm (25.1 months vs 16.6 months; P = .0061). This is in concordance with the sipuleucel-T phase III trials, in which immunotherapy improved overall survival but not PFS. A phase III study of PROSTVAC-VF is planned in men with metastatic CRPC who have minimal or no symptoms (clinicaltrials.gov identifier: NCT01322490).
• Orteronel (TAK-700) is a selective 17,20-lyase inhibitor, similar to abiraterone, which allows for a more targeted inhibition of the CYP17. This selectivity may be associated with less mineralocorticoid excess, potentially leading to an improved side-effect profile. Phase III studies in CRPC are underway (clinicaltrials.gov identifier: NCT01193257 and NCT01193244).
• Alpharadin is an alpha-emitting radiopharmaceutical for the treatment of bone metastases (223RACl2).Compared with currently available radiopharmaceuticals such as strontium-89, Alpharadin utilizes alpha, not beta, particles, which have the advantage of more localized delivery of radiation, with the potential for less bone marrow toxicity. Preliminary reports of a randomized, phase III trial (ALSYMPCA [ALpharadin in SYMptomatic Prostate Cancer]) have been reported at the 2011 European Cancer Organisation (ECCO)-European Society for Medical Oncology (ESMO) meetings in patients with CRPC and symptomatic bone involvement. The overall survival was improved, reported as 14.0 months with Alpharadin vs 11.2 months with placebo.
The addition of these novel agents to the therapeutic armamentarium for advanced prostate cancer raises exciting and challenging questions about a future role for medical therapy in the adjuvant setting. There is controversy about the use of adjuvant hormonal and/or chemotherapy in prostate cancer. This is largely due to a paucity of data, rather than negative data. The new agents highlighted here have not been evaluated in the adjuvant setting in a meaningful way. The largest modern effort to define the use of adjuvant chemotherapy/hormonal therapy in prostate cancer was Southwest Oncology Group (SWOG) trial 9921, in which men were randomized to 2 years of ADT, with or without mitoxantrone. Unfortunately, this study was closed before completing accrual due to the observation of leukemia in the mitoxantrone arm. Notably, even though all subjects in the trial received ADT, the 5-year overall survival of the ADT-alone arm was recently reported as 95.9% and noted to be much better than predicted. The 8-year median survival is currently estimated to be 88% (with a median follow-up of only 4.4 years), even though the trial initially assumed a median survival of 10 years in the control arm. While mitoxantrone was the only approved cytotoxic agent for advanced prostate cancer when SWOG 9921 was being designed, we now know that docetaxel is more efficacious than mitoxantrone, and that cabazitaxel is active in patients progressing after docetaxel. In this light, a large-scale adjuvant trial of cabazitaxel or docetaxel would be rational, as these are more active agents than have been available in the past. Additionally, the use of immunotherapy in the adjuvant setting is theoretically advantageous, utilizing this largely nontoxic therapy at the point of lowest disease burden for those at high risk. The challenges of completing a large, randomized trial to examine the role of medical therapy in this setting include the difficulty of defining a “high-risk” group, historically poor accrual to such trials, and the long follow-up period needed to assess the survival impact of any adjuvant therapy in prostate cancer. With the favorable results of ADT-alone in SWOG 9921, a very large study or a more narrowly defined “higher” risk group would need to be identified for future adjuvant studies.
Sequencing medical therapy in prostate cancer: a future outlook
It will take many years to complete and fully report on the current studies of the agents in development reviewed here for prostate cancer. With four newly approved agents and several other promising drugs in late-stage development, future trials should be focused on defining the optimal application and timing of these therapies. Theoretically, active agents in prostate cancer with the least amount of toxicity should be used earliest in the disease process. For example, at the time of this writing, the FDA-approved indication for abiraterone acetate requires previous docetaxel therapy before its use. This is based on the patient population in the registration trial, but it raises a clinical dilemma: for a patient with metastatic CRPC who is not a good candidate for docetaxel chemotherapy, abiraterone acetate use would be off-label, but would be a clinically rational and much less toxic approach than docetaxel. A trial of abiraterone acetate in this setting has been completed and results are forthcoming. Along this same line of reasoning, there are several unresolved questions regarding the optimal future use of these agents (Table 3), namely:
• Should active agents in CRPC with less toxicity, such as abiraterone acetate, be utilized before more toxic agents, such as docetaxel?
• Is cabazitaxel more efficacious than docetaxel as first-line cytotoxic therapy in CRPC?
• Could the early or adjuvant use of immunotherapy, which is currently approved for later-stage disease, improve long-term outcomes or even cure micrometastatic disease?
• Would monotherapy with a new-generation antiandrogen such as MDV3100 be as effective as traditional ADT for front-line hormonal therapy, and would such anti-androgen monotherapy be associated with an improved side-effect profile?
• Can any of these new agents (eg, sipuleucel-T with PROSTVAC-VF or abiraterone with MDV3100) be combined for greater efficacy with acceptable toxicity?
• What are the financial implications of all these new agents in the care of men with CRPC? (Table 2 outlines the agents and costs, which do not include the costs of drug administration, laboratory analysis, and supportive care.)
In conclusion, the rapid approval of several novel agents has given prostate cancer patients and their treating physicians many new and effective therapeutic options. This is a very exciting era in the management of CRPC. These newly approved agents and those in the pipeline present the real possibility of prolonging survival and the hope of turning the disease into a chronic condition. However, the optimal timing and the potential to combine these new agents with other medical therapies is not well defined. Over the last several years, the prostate cancer community has demonstrated the ability to successfully design and complete important trials, redefining the treatment of advanced prostate cancer. Moving forward, we must focus on defining the optimal use of these agents and supporting the clinical trials needed to accomplish this task.
Financial Disclosure: Dr. Crawford serves on the advisory board, and his wife is an employee, of Ferring. Dr. Crawford also serves on the advisory boards of sanofi- aventis, Janssen, Amgen and Dendreon. Dr. Flaig serves as a consultant to sanofi-aventis and has received an honorarium from Amgen.