Two Paths Forward in Metastatic Castration-Resistant Prostate Cancer
Two Paths Forward in Metastatic Castration-Resistant Prostate Cancer
Derleth and Yu have summarized the progress made in treating metastatic castration-resistant prostate cancer (mCRPC). Since the US Food and Drug Administration (FDA) approval of mitoxantrone and docetaxel (Taxotere) in 1999 and 2003, respectively, the agency has approved two other non–androgen receptor (AR)-targeting agents, sipuleucel-T (Provenge) and radium-223 (Xofigo) (although docetaxel may target the AR via the tubulin transport of the AR complex) and two AR-targeting agents, abiraterone (Zytiga) and enzalutamide (Xtandi). In the next several years, the FDA will potentially receive applications to approve orteronel, an AR-targeting agent, as well as tasquinimod and custirsen, both non–AR-targeted agents. Meanwhile, the dual MET/vascular endothelial growth factor (VEGF) inhibitor cabozantinib and the immunotherapeutic agent PROSTVAC are in phase III trials. If the results of these phase III trials are all positive, there could be 11 FDA-approved agents for the treatment of mCRPC within 5 years (Table).
Unfortunately, although these agents each extend life, none are curative. Therefore, physicians who investigate and treat mCRPC have two paths they can follow to further improve outcomes:
1. Investigate sequences and combinations to increase duration of disease control.
2. Identify new agents to treat the progressively less AR-driven variants of mCRPC.
If the first path is chosen, the task of the clinical investigator will be daunting, since there are up to 11 factorial combinations. (Over 3.6 million combinations would be possible with just 10 drugs.) Phase I disease-specific combination trials will be difficult to advance to phases II and III. Although progression-free survival endpoints might be achieved, patients would already be receiving most FDA-approved agents in sequence; therefore, overall survival might not be different.
For clinical investigators who choose to follow the second path, the task will be no less daunting. Derleth and Yu reviewed some of the most promising targets, such as inhibitors of phosphatidylinositol 3-kinase (PI3K), poly(ADP-ribose) polymerase (PARP), target of rapamycin complex (TORC), and heat shock protein (HSP). To test these agents, it will be necessary to define the genetic makeup of the tumors and the hosts. This may lead to very small subsets of patients eligible for trials. For example, mCRPC arising in BRCA2-positive men is very rare, yet some PARP inhibitors may be highly potent in that subgroup.
Conducting clinical trials focused on path 2 also raises other challenges. The prospective clinical trial patients:
• Often have immune function and bone marrow compromise after years of glucocorticoids, radiation therapy, and chemotherapy.
• Are likely to be elderly with comorbidities.
• Are likely to have highly proliferative tumors that display significant heterogeneity.
Heitzer et al demonstrated that, after sequencing the DNA of circulating tumor cells (CTCs) from patients with metastatic colon cancer, the CTCs had both “private” mutations (ie, those found only in some CTCs and at a subclonal level in the original tumor) and common mutations (ie, those found in virtually all of the cells). A similar degree of tumor heterogeneity is also seen in mCRPC: Tzelepi et al found that the AR signaling pathway was absent in up to 25% of mCRPC specimens previously treated with chemotherapy.
In conclusion, progress in mCRPC will continue, but at a slower pace due to the complex issues involved.
Financial Disclosure: Dr. Vogelzang serves as a consultant to Bayer/Algeta and Janssen Pharmaceuticals, and as a speaker for Dendreon and Medivation.
1. Derleth C, Yu EY. Targeted therapy in the treatment of castration-resistant prostate cancer. Oncology (Williston Park). 2013;27:620-8.
2. Mistry SJ, Oh WK. New paradigms in microtubule-mediated endocrine signaling in prostate cancer. Mol Cancer Ther. 2013;12:555-66.
3. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996;14:1756-64.
4. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer.N Engl J Med. 2004;351:1513-20.
5. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-22.
6. Parker C, Nilsson S, Heinrich D, et al. Radium-223 dichloride, a targeted alpha-emitter, improves survival in metastatic prostate cancer. N Engl J Med. In press.
7. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.
8. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-97.
9. Dreicer R, Agus DB, MacVicar GR, et al. Safety, pharmacokinetics, and efficacy of TAK-700 in metastatic castration-resistant prostate cancer: a phase I/II, open-label study. J Clin Oncol. 2010;28:15s.
10. Pili R, Haggman M, Stadler WM, et al. Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer. J Clin Oncol. 2011;29:4022-8.
11. Chi KN, Hotte SJ, Yu EY, et al. Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:4247-54.
12. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31:412-9.
13. Gulley JL, Arlen PM, Madan RA, et al. Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother. 2010;59:663-74.
14. Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31:1748-57.
15. de Bono J, Mina LA, Gonzalez M, et al. First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. J Clin Oncol. 2013;31(suppl):abstr 2580.
16. Heitzer E, Auer M, Gasch C, et al. Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing. Cancer Res. 2013;73:2965-75.
17. Tzelepi V, Zhang J, Lu JF, et al. Modeling a lethal prostate cancer variant with small-cell carcinoma features. Clin Cancer Res. 2012;18:666-77.