Management of Metastatic Castration-resistant Prostate Cancer

European Oncology & Haematology, 2011;7(4):251-256

Abstract:

The management of men with metastatic castration-resistant prostate cancer (CRPC) has taken several leaps forwards in the last two years, with the demonstration of improved overall survival with three novel agents (sipuleucel-T, cabazitaxel and abiraterone acetate) and a significant delay in skeletal-related events observed with denosumab. The pipeline of systemic therapies in prostate cancer remains strong, as multiple agents with a diverse array of mechanisms of action are demonstrating preliminary signs of clinical benefit, leading to more definitive Phase III confirmatory trials. In this review, we will discuss the evolving landscape of treatment options for men with CRPC, with a particular focus on currently approved and emerging treatment options for these patients. Knowledge of these evolving standards will help to optimise delivery of care and long-term outcomes in men with advanced CRPC.
Keywords: Castration-resistant prostate cancer, novel therapies, drug development, sipuleucel-T, cabazitaxel, abiraterone, denosumab, orteronel, MDV3100, ipilimumab
Disclosure: Emmanuel S Antonarakis has served as an advisor/consultant for Sanofi-Aventis.
Received: August 12, 2011 Accepted October 19, 2011 Citation European Oncology & Haematology, 2011;7(4):251-256
Correspondence: Emmanuel S Antonarakis, Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB1-1M45, Baltimore, MD 21231-1000, US. E: eantona1@jhmi.edu

While much of the recent focus on prostate cancer relates to the over-diagnosis and over-treatment of this disease, each year almost 100,000 men in Europe and more than 30,000 men in the US still die of advanced prostate cancer, making it the second most common cause of cancer-related deaths.1 Androgen deprivation therapy is the most effective systemic treatment for recurrent prostate cancer; however, the vast majority of these patients will eventually develop resistance to hormonal approaches (see Table 1) necessitating other forms of therapy. Although several chemotherapeutic strategies have been employed to treat castration-resistant prostate cancer (CRPC), it was not until 2004 that one such approach was shown to be life-prolonging. In that year, two Phase III clinical trials reported a survival advantage with the use of docetaxel chemotherapy in men with metastatic CRPC,2,3 resulting in the US Food and Drug Administration (FDA) approval of this agent. However, while docetaxel is both palliative and life-prolonging, it is not the ultimate answer for patients with CRPC, as virtually all men develop eventual resistance to this chemotherapy agent or are unable to tolerate its toxicities long term.
Until 2010, there were no additional treatment options conferring a survival benefit for patients with CRPC, although mitoxantrone was often employed in these patients for its palliative effects on bone pain.4 This situation changed in 2010 when an autologous immunotherapy product, sipuleucel-T, was FDA approved for the treatment of minimally symptomatic or asymptomatic metastatic CRPC, based on the results of a randomised Phase III trial comparing this agent against a placebo. In that same year, a randomised Phase III trial demonstrated a survival advantage for a novel taxane, cabazitaxel, over mitoxantrone in men with metastatic CRPC that had progressed after prior docetaxel therapy. Based on those results, cabazitaxel was approved by the FDA for the second-line treatment of metastatic CRPC. Several months later, an oral agent with the ability to suppress extra-gonadal androgen synthesis, abiraterone, was also reported to improve survival in a Phase III study when evaluated against placebo in men with docetaxel-pre-treated metastatic CRPC, resulting in the FDA approval of this agent for patients that have previously received docetaxel (see Figure 1). In addition to these life-prolonging therapies, novel bone-targeting approaches are also being developed to address skeletal complications resulting from bone metastases. To this end, an osteoclast-inhibiting agent, denosumab, was FDA approved in 2010 for the prevention of skeletal-related events (SREs) in men with castration-resistant bone metastases after showing superiority against the previously approved bisphosphonate zoledronic acid (see Figure 1).
References:
  1. Jemal A, Siegel R, Xu J, Ward E, Cancer statistics, 2010, CA Cancer J Clin, 2010;60:277–300.
  2. Tannock IF, de Wit R, Berry WR, et al., Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer, N Engl J Med, 2004;351:1502–12.
  3. 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.
  4. 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.
  5. Antonarakis ES, Drake CG, Current status of immunological therapies for prostate cancer, Curr Opin Urol, 2010;20:241–6.
  6. Small EJ, Fratesi P, Reese DM, et al., Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells, J Clin Oncol, 2000;18:3894–903.
  7. Small EJ, Schellhammer PF, Higano CS, et al., Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer, J Clin Oncol, 2006;24:3089–94.
  8. Higano CS, Schellhammer PF, Small EJ, et al., Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer, Cancer, 2009;115:3670–9.
  9. Kantoff PW, Higano CS, Shore ND, et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer, N Engl J Med, 2010;363:411–22.
  10. Kantoff PW, Schuetz TJ, Blumenstein BA, et al., Overall survival analysis of a phase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer, J Clin Oncol, 2010;28:1099–105.
  11. Hoos A, Eggermont AM, Janetzki S, et al., Improved endpoints for cancer immunotherapy trials, J Natl Cancer Inst, 2010; 102:1388–97.
  12. Paller CJ, Antonarakis ES, Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer, Drug Des Devel Ther, 2011;5:117–24.
  13. Attard G, Greystoke A, Kaye S, de Bono J, Update on tubulin-binding agents, Pathol Biol, 2006;54:72–84.
  14. Mita AC, Denis LJ, Rowinsky EK, et al., Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors, Clin Cancer Res, 2009; 15:723–30.
  15. De Bono JS, Oudard S, Ozguroglu M, et al., Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial, Lancet, 2010;376:1147–54.
  16. Mohler J, Bahnson RR, Boston B, et al., NCCN clinical practice guidelines in oncology: prostate cancer, J Natl Compr Canc Netw, 2010;8:162–200.
  17. O’Donnell A, Judson I, Dowsett M, et al., Hormonal impact of the 17α-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer, Br J Cancer, 2004; 90:2317–25.
  18. Attard G, Reid AH, Yap TA, et al., Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven, J Clin Oncol, 2008;26:4563–71.
  19. Attard G, Reid AH, A’Hern R, et al., Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer, J Clin Oncol, 2009;27:3742–8.
  20. Ryan CJ, Smith MR, Fong L, et al., Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy, J Clin Oncol, 2010; 28:1481–8.
  21. Reid AH, Attard G, Danila DC, et al., Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate, J Clin Oncol, 2010;28:1489–95.
  22. Danila DC, Morris MJ, de Bono JS, et al., Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer, J Clin Oncol, 2010;28:1496–501.
  23. 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.
  24. Antonarakis ES, Eisenberger MA, Expanding treatment options for metastatic prostate cancer, N Engl J Med, 2011;364:2055–8.
  25. Brown JM, Corey E, Lee ZD, et al., Osteoprotegerin and RANK ligand expression in prostate cancer, Urology, 2001;57:611–6.
  26. Vallet S, Smith MR, Raje N, Novel bone-targeted strategies in oncology, Clin Cancer Res, 2010;16:4084–93.
  27. Fizazi K, Lipton A, Mariette X, et al., Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates, J Clin Oncol, 2009;27:1564–71.
  28. Fizazi K, Carducci M, Smith M, et al., Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomized double-blind study, Lancet, 2011;377:813–22.
  29. Vasaitis TS, Bruno RD, Njar VC, CYP17 inhibitors for prostate cancer therapy, J Steroid Biochem Mol Biol, 2011;125:23–31.
  30. 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(Suppl.): abstract 3084.
  31. Chen Y, Clegg NJ, Scher HI, Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target, Lancet Oncol, 2009;10:981–91.
  32. Watson PA, Chen YF, Balbas MD, et al., Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor, Proc Natl Acad Sci U S A, 2010;107:16759–65.
  33. Tran C, Ouk S, Clegg NJ, et al., Development of a second-generation antiandrogen for treatment of advanced prostate cancer, Science, 2009;324:787–90.
  34. Scher HI, Beer TM, Higano CS, et al., Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study, Lancet, 2010;375:1437–46.
  35. Foster WR, Car BD, Shi H, et al., Drug safety is a barrier to the discovery and development of new androgen receptor antagonists, Prostate, 2011;71:480–8.
  36. Drake CG, Jaffee E, Pardoll DM, Mechanisms of immune evasion by tumors, Adv Immunol, 2006;90:51–81.
  37. Hodi FS, Cytotoxic T-lymphocyte-associated antigen-4, Clin Cancer Res, 2007;13:5238–42.
  38. Small EJ, Tchekmedyian NS, Rini BI, et al., A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer, Clin Cancer Res, 2007;13:1810–5.
  39. Fong L, Kwek SS, O’Brien S, et al., Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF, Cancer Res, 2009;69:609–15.
  40. Dillard T, Yedinak CG, Alumkal J, Fleseriu M, Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes, Pituitary, 2010;13:29–38.
Keywords: Castration-resistant prostate cancer, novel therapies, drug development, sipuleucel-T, cabazitaxel, abiraterone, denosumab, orteronel, MDV3100, ipilimumab