Is This a True Renaissance for the Treatment of Prostate Cancer?

The article by Rove et al represents a comprehensive review of the recent clinical advances in the treatment of metastatic, castrate-refractory prostate cancer. The therapeutic armamentarium for the treatment of prostate cancer remains limited compared to other malignancies, such as breast cancer. It took approximately 14 years after mitoxantrone data emerged for us to see the approval of another chemotherapy agent, docetaxel. The successful outcome of recent clinical trials confirms that true advancement in prostate cancer treatment can be achieved by rational and rigorous clinical testing, but participation in prostate cancer clinical trials remains low, especially participation by African-American patients. Research study enrollment should be a high priority for those health care professionals who treat this disease.

The recent approval of sipuleucel-T represents an important step towards the validation of immunotherapy as an effective anticancer therapeutic modality. However, as pointed out by the authors, the lack of PSA and tumor response seen during treatment with sipuleucel-T remains puzzling. The delayed therapeutic benefit of this agent has been confirmed by other immunotherapy approaches, such as PROSTVAC-VF, but the drawbacks to its use include the costs and complex administration, and the lack of correlation between immunological response and clinical benefit.[1] Some progress has been made in dissecting potential predictors, but prospective validation is still needed. The possibility of enhancing immune response of vaccines and cell-based immunotherapies with immunocheckpoint inhibitors (i.e. anti-PD1 and PD1-L antibodies) is also quite appealing. These combination strategies will most likely represent the next generation of immunotherapy-based clinical trials. Sipuleucel-T has been approved for asymptomatic or minimal symptomatic castrate refractory disease, and the possible role of testosterone in modulating immune response is currently being evaluated.[2]

A real paradigm shift occurred when laboratory studies first demonstrated that castrate refractory disease is not necessarily hormone-independent,[3] and these findings led to the development of specific CYP17A enzyme inhibitors and more potent anti-androgen receptor molecules. The positive data from the abiraterone study and the promising results from the MDV3100 trial confirmed that more effective hormonal therapies may have an impact on the progression of advanced prostate cancer. Sequential hormonal therapies with the continuous use of LHRH agonists have become the standard of care for advanced prostate cancer. The challenge will be in further developing these novel agents and refining their potential role in earlier disease. Androgen deprivation therapies (ADT) impair quality of life and induce many serious biological changes similar to the metabolic syndrome, and ADT may impact on overall survival. Currently, the third generation of anti-androgen receptor agents is in development, but as a drug class these small molecules may still carry off-target effects through GABA-A inhibition.[4] ADT that is selective for prostate tumors and spares normal tissue is in the early stages of development. The availability of more potent hormonal therapies should not lead to early use of ADT for recurrent prostate cancer: There are many patients committed to early ADT in whom the risk benefit ratio probably does not justify this intervention.

Rove et al briefly mention the clinical testing of targeted therapies in their article. Interestingly, as we most likely learn more from our failures than from our successes, the lack of FDA approval of the endothelin receptor antagonist atrasentan has led to a review of the clinical endpoints and assessment of disease progression for prostate cancer clinical trials. The Prostate Cancer Clinical Trials Working Group has set new guidelines that are now followed in the clinical testing of targeted therapies.[5] Inhibitors of signal transduction pathways (i.e. PI3K/Akt, src, c-met, etc) and histone deacetylases are being developed in rational combination strategies and may prove to be effective in the setting of low-burden, not heavily pretreated disease. Recent studies on prostate cancer initiation and progression have shed additional light on the molecular mechanisms of prostate cancer, suggesting an important role of fusion gene products.[6] Compelling animal models have also been developed that will allow drug development in those with defined genetic backgrounds (i.e myc overexpression, PTEN ablation).[7] There is reasonable optimism that these basic research findings will one day translate into “personalized” treatments for prostate cancer, as has been the case with other malignancies.

The word Renaissance or Rinascimento means “rebirth” after the “dark age”. The recent approvals of sipuleucel-T and cabazitaxel, though important, are not worthy of signifying a “renaissance” in the current accepted treatment for prostate cancer; the clinical benefit achieved remains modest. There are many therapeutic challenges ahead of us in treating this disease. However, a fundamental advance was made in 2004 following the approval of docetaxel, and the “dogma” that prostate cancer is a chemotherapy refractory disease was confuted. Certainly, the latest preclinical and clinical advances in prostate cancer have raised new enthusiasm for a search for effective therapeutics to control this disease, which still takes the life of one man every 20 minutes in the United States.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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References

1. Longo DL . New therapies for castration-refractory prostate cancer. N Engl J Med. 2010;363(5):411-22.

2. Drake CG, Doody AD, Mihalyo MA, et al. Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. Cancer Cell. 2005;7(3):239-49.

3. Mohler JL, Gregory CW, Ford OH 3rd, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10(2):440-8.

4. Foster WR, Car BD, Shi H, et al. Drug safety is a barrier to the discovery and development of new androgen receptor antagonists. Prostate. 2010 Sep 28.

5. Scher HI, Halabi S, Tannock I, et al. Prostate Cancer Clinical Trials Working Group. Design and end points of clinical 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(7):1148-59.

6. Yu J, Yu J, Mani RS, et al. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell. 2010;17(5):443-54.

7. Ellwood-Yen K, Graeber TG, Wongvipat J,et al.. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell. 20034(3):223-38.