Sequencing of Therapies in Advanced Prostate Cancer

After several decades with only modest changes in the therapeutic paradigm, rapid progress in understanding the biology of advanced prostate cancer has been translated into more accurate terminology, such as “castration-resistant” (as opposed to “hormone-refractory” or “androgen-independent”) prostate cancer, as well as clinically meaningful therapeutic developments.

As noted by Drs. Crawford and Flaig, developments over the past several years include the regulatory approval of sipuleucel-T (Provenge); cabazitaxel (Jevtana); denosumab (Xgeva); and, most recently, the androgen biosynthesis inhibitor, abiraterone (Zytiga). In addition there is compelling evidence in the public domain to suggest that the second-generation androgen receptor antagonist MDV3100 and radium-223 chloride (Alpharadin) may soon join the ranks of FDA-approved agents for metastatic castration-resistant prostate cancer.

Myriad questions and opportunities follow from these developments. Among the most compelling questions are how we can optimally combine/sequence/integrate these novel agents into the current treatment paradigm, whether we can we actually afford them, and whether overall survival will remain the gold standard for regulatory approval of new agents.

The compelling impact on survival that we have seen derived from novel therapies targeting the androgen receptor (abiraterone/MDV3100), along with their favorable safety profile, sets the stage for these agents to be moved into the pre-chemotherapy or “second-line hormonal therapy” setting should the results of both ongoing and completed clinical trials be supportive. Investigation of the potential utility of combining these two compounds is underway, and other smaller studies may provide some guidance regarding optimal sequencing. Among the most pressing clinical questions that practitioners are already facing is the issue of if, or when, to discontinue abiraterone in the face of disease progression, which includes diverse potential clinical settings such as prostate-specific antigen (PSA) progression, clinical/symptomatic progression, or overt radiographic progression. Although there is some suggestion from early investigational experiences that patients with PSA progression only may continue to derive clinical benefit from being maintained on therapy, it remains an undefined clinical area. This issue will have economic ramifications across the disease spectrum, and in the pre-docetaxel setting the need for long-term steroid administration will enter into the clinical decision-making process.

Should abiraterone move into the pre-chemotherapy setting, the optimal use and sequencing with sipuleucel-T administration will become another clinical dilemma, given concerns (appropriate or not) about the potential detrimental impact of low-dose steroids in combination with abiraterone to “dampen” the immune response.[1]

Projecting out over the next 5 years, one could speculate that second-line hormonal therapy following disease progression on luteinizing hormone–releasing hormone (LHRH) agonists will consist of sequencing of androgen biosynthesis inhibitors with second-generation antiandrogens. Prospective data supporting an optimal sequence (or combination) of these agents is unlikely in that time frame, and therefore pragmatic issues such as drug cost and ease of administration (ie, requirement for steroids) will likely drive decision-making in many clinical settings.

The rapid, unprecedented development of novel agents in prostate cancer that prolong survival is a major accomplishment that will have a real impact on patient outcomes. To date, however, none of these compounds leads to permanent disease control, begging the question of the emerging challenge of drug development/regulatory approval in this disease setting in the near future.

Unlike other major epithelial neoplasms, the bone tropism of prostate cancer requires the use of a variety of composite endpoints to assess progression-free survival. This has challenged investigators and regulators alike, thus the current paradigm for new drug approval is tied primarily to a survival endpoint.[2]

Following the approval of docetaxel in 2004, new agents were frequently taken into the post-docetaxel space, given the clinical unmet need, in most instances with survival endpoints. As noted, recently both cabazitaxel and abiraterone have gained FDA regulatory approval for this clinical indication, and recent data suggest the potential for both MDV3100 and radium-223 chloride to do so in the near future. With multiple agents having an impact on a variety of targets, all with the potential for survival benefit, prior strategies of “going to the end of the line” to conduct phase III studies of an active new compound vs best supportive care or other agents without demonstrated survival benefit (ie, mitoxantrone or steroids) may be increasingly problematic. Of potentially greater consequence is the impact on drug approval in the “pre-docetaxel” space, given the current (and understandable) reluctance of the FDA to consider progression-free survival as a primary approval endpoint. The potential for new biomarkers such as circulating tumor cells to inform clinical decision-making or act as surrogate endpoints remains a goal, but this will require validation from recently completed phase III trials.

Financial Disclosure:Dr. Dreicer has served as a consultant to Millennium, Janssen, sanofi-aventis, EMD Serono, and GTX.

References:

References

1. Naito M, Itoh K, Komatsu, N, et al. Dexamethasone did not suppress immune boosting by personalized peptide vaccination for advanced prostate cancer patients. Prostate. 2008;68:1753-62.

2. Scher H, Halabi S, Tannock I, et al. Design and endpoints of trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:1148-59.