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Beyond the Abstract - An update on the changing indications for androgen deprivation therapy for prostate cancer, by Dan Arnett, Megan Griffiths, Mike Glode, and Shandra Wilson

BERKELEY, CA (UroToday.com) - Prostate cancer is the most common non-cutaneous cancer among men in the United States and the second most common cause of cancer death.[2] Since about 19% [3] of men require medical therapy, the risks and benefits of this therapy are worth understanding. This update follows “An Update on the Changing Indications for Androgen Deprivation Therapy for Prostate Cancer” [1] which focused on risks and benefits of androgen deprivation therapy (ADT). This review examines recent evidence for the use of some recently investigated agents, including Abiraterone, MDV3100, and Sipuleucel-T.

Multiple new treatments for castration resistant prostate cancer have emerged in recent years increasing overall survival for a disease that has been previously refractory to most drug therapies.

Abiraterone is a potent and irreversible inhibitor of the enzyme 17 α-hydroxylase/C17,20 lyase (CYP17) that has FDA approval in the US [4] and Europe [5] for castration resistant prostate cancer (CRPC) and has been tested in several Phase I and II studies to evaluate safety and tolerability.[6-11] The anticipated toxicities are attributable to a syndrome of secondary mineralocorticoid excess—namely hypertension (10%), hypokalemia (17%), and lower-limb edema (31%). These are successfully managed with mineralocorticoid receptor antagonists.[6,12] Cardiac events include tachycardia (3%) and atrial fibrillation (2%); however, in published studies, there has been no significant increase in fatal cardiac events in the abiraterone group. Abiraterone was not tested in patients with baseline ejection fraction <50%. A post baseline ejection fraction of <50% was seen in 7.7% of patients on abiraterone and 5% of patients on placebo, leading the U.S. Food and Drug Administration to recommend caution when using abiraterone in patients with a history of cardiovascular disease. It is also recommended that monthly monitoring occur for blood pressure, serum potassium, and symptoms of fluid retention.[13] Long-term events related to osteoporosis, weight gain, and the metabolic syndrome are not yet fully elucidated but would not be unexpected. A phase III trial using 1195 post-docetaxel CRPC patients, treatment with abiraterone acetate with prednisone versus placebo with prednisone resulted in a 36% increase in median survival (14.8 vs. 10.9 months) and a 35% reduction in the risk of death (hazard ratio, 0.65; 95% CI, 0.54 to 0.77; P <0.001), respectively.[12] An improvement in progression-free survival (5.6 vs. 3.6 months; P <0.001), time to PSA progression (10.2 vs. 6.6 months; P <0.001), and PSA response rate (29% vs. 6%; P <0.001) was also seen.[12] A phase III trial using chemotherapy-naïve patients is currently in progress (Clinicaltrials.gov registry number: NCT00887198). Though promising results have been shown thus far, resistance to abiraterone may develop due to up-regulation of CYP17 and/or the induction of androgen receptor (AR) splice variants.[14] This could lead to the suggestion for combination therapy with direct AR antagonism.

MDV3100 is an AR antagonist designed to improve binding affinity and reduce agonist activity compared with other available therapies and ultimately functions by inducing apoptosis[15,16] Phase I/II studies of CRPC patients treated in ascending dose cohorts (30-600mg once daily) showed preliminary evidence for therapeutic response of ≥50% reduction in PSA (56%), soft tissue response (22%), stabilized bone disease (56%), and an improvement in circulating tumor cell counts (49%). These favorable outcomes resulted in a subsequent phase III trial (AFFIRM) with significant improvement in overall survival compared to placebo (18.4 vs. 13.6 months, respectively; P <0.0001), and a 37% reduction in the risk of death (HR: 0.63) in patients previously treated with docetaxel-based chemotherapy.[17] The Independent Data Monitoring Committee halted the study early, and men randomized to placebo were offered therapy with MDV3100.[17] Several other phase II/III trails are underway, including the PREVAIL trial in men with advanced prostate cancer naïve to chemotherapy (registry number: NCT01212991), TERRAIN trial (MDV3100 vs. bicalutamide) looking at men who have progressed while on LHRH analogue therapy or following surgical castration (registry number: NCT01288911), and a phase II trial evaluating MDV3100 as a monotherapy (registry number: NCT01302041). The most common adverse event reported has been fatigue (11%) with a significant portion of patients requiring dose reductions and resulting in the maximum-tolerated dose to be defined as 240mg/day.[15] Two witnessed seizures were seen at doses of 600mg and 360mg/day with each patient taking concurrent medications, possibly contributing to a lower seizure threshold.[15] Anemia, arthralgias, and asthenia were seen in 3%, 2%, and 2%, respectively.[15] Common mild adverse events were nausea, constipation, diarrhea and anorexia.[15] MDV3100’s release is expected in 2012 pending FDA regulatory approva.[18]

Sipuleucel-T (Provenge) is a first in its class immunotherapy designed to stimulate a T-Cell immune response against Prostatic Acid Phosphatase (PAP), which is expressed in most prostate cancers. It has been FDA approved to treat asymptomatic metastatic CRPC [19]. Phase I and II trials of Sipuleucel-T demonstrated PSA response (>50% decline) in 10% of patients and a longer time to disease progression, 34 weeks with Sipuleucel-T versus 13 weeks with placebo (P=0.03).[20,21] Phase III trials demonstrated a statistically significant improvement in overall survival of 4.5 months (P=0.01) [20,21] and an increased rate of survival in patients treated with Sipuleucel-T at 36 months (34% with Sipuleucel-T versus 11% with placebo).[20,21] The authors of this study note that progression-free survival is very similar between Sipuleucel-T and placebo for the first 2 months with Sipuleucel showing a later improvement in progression-free survival. This is thought to be due to the vaccine requiring 8-10 weeks for an adequate response.[20,21] The drug was administered in three infusions and was well tolerated by most study participants.[19] The most common adverse events were related to cytokine release syndrome [22] and included rigors (59.8%), pyrexia (29.3%), tremor (9.8%) and chills (8.5%).[19] Most toxicities, 70.7%, were grade 1 or 2 and 95% of patients were able to complete all 3 infusions.[23] More serious adverse events included central venous catheter infection or other serious infection in 5% of treated patients.[19] Sipuleucel-T has not been tested against other drugs for hormone resistant prostate cancer such as Docetaxel, thus it is still unclear whether Sipuleucel-T has an advantage over more conventional treatments.[24]

Multiple new treatments for castration resistant prostate cancer have emerged in recent years increasing overall survival for a disease that has been previously refractory to most drug therapies. Adverse events include increased cardiovascular risk and mineralocorticoid excess with Abiraterone; fatigue, anemia, arthralgias and asthenia with MDV 3100; and cytokine release syndromes and serious infection when using Sipuleucel-T. It is important to select patients for treatment in whom evidence predicts the most benefit and to carefully weigh the benefits of treatment against the costs and risks.

References:

  1. Myklak, K., Wilson, S. "An update on the changing indications for androgen deprivation therapy for prostate cancer." Prostate Cancer. (2011).
  2. American Cancer Society, "Cancer facts and figures 2012." Accessed April 30, 2012. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf.
  3. Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review. 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, 2012.
  4. Zytiga [package insert]. Centocor Ortho Biotech Inc., Horsham, PA, April 2011.
  5. Zytiga [package leaflet]. Janssen-Cilag International NV, Beerse, Belgium, September 2011.
  6. Attard, G., Reid, A.H., Yap, T.A., 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. 26. no. 28 (2008): 4563-71.
  7. Attard, G., Reid, A.H., 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. 27. no. 23 (2009): 3742-48.
  8. Ryan, C.J., Smith, M.R., Fong, L., Rosenberg, J.E., Kantoff, P., 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. 28. no. 9 (2010): 1481-88.
  9. Danila, D.C., Morris, M.J., de Bono, J.S., Ryan, C.J., Denmeade, S.R., et al. “Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer.” J Clin Oncol. 28. no. 9 (2010): 1496-1501.
  10. Reid, A.H., Attard, G., Danila, D.C., Oommen, N.B., Olmos, D., et al. “Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate.” J Clin Oncol. 28. no. 9 (2010): 1489-95.
  11. Ryan, C.J., Shah, S., Efstathiou, E., Smith, M.R., Taplin, M.E., et al. “Phase II study of abiraterone acetate in chemotherapy-naïve metastatic castration resistant prostate cancer displaying bone flare discordant with serologic response.” Clin Cancer Res. 17. no. 14 (2011): 4854-61.
  12. de Bono, J.S., Logothetis, C.J., Molina, A., Fizazi, K., North, S., et al. “Abiraterone and increased survival in metastatic prostate cancer.” N Engl J Med. 364. no. 21 (2011): 1995-2005.
  13. Stein, M.N., Goodin, S., Dipaola, R.S. “Abiraterone in prostate cancer: a new angle to an old problem.” Clin Cancer Res. 18. no. 7 (2012): 1848-54.
  14. Mostaghel, E.A., Marck, B.T., Plymate, S.R., Vessella, R.L., Balk, S., et al. “Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants.” Clin Cancer Res. 17. no. 18 (2011): 5913-25.
  15. Scher, H.I., Beer, T.M., Higano, C.S., Anand, A., Taplin, M.E., et al. “Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study.” The Lancet. 375. no. 9724 (2010): 1437-46.
  16. Chen, Y., Clegg, N.J., Scher, H.I. “Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target.” Lancet Oncol. 10. no. 10 (2009): 981-91.
  17. Press release, Medivation, Inc., San Francisco, CA, USA., 3 November 2011.
  18. Loftus, P. "Prostate cancer drug shows promise in study." Health & Wellness. The Wall Street Journal, 04-11-2011. Retrieved 4-20-2012.
  19. Small, E., Schellhammer, P., Higano, C., Redfern, C., Nemunaitis, J., Valone, F., Suleman, V., Jones, L., Hershberg, R. "Placebo-controlled phase III trial of immunologic therapy with Supuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer." J Clin Oncol. 24. no. 19 (2006): 3089-94.
  20. Kantoff, P., Higano, C., Shore, N., Berger, R., Small, E., Penson, D., Redfern, C., Ferrari, A., Dreicer, R., Sims, R., Xu, Y., Frohlich, M., Schellhammer, P. "Sipuleucel-T immunotherapy for castration resistant prostate cancer." N Engl J Med. 363. no. 5 (2012): 411-22.
  21. Osanto, S., Van Poppel, H. "Emerging novel therapies for advanced prostate cancer." Therapeutic Advances in Urology. 4. no. 1 (2012): 3-12.
  22. Hall, S., Klotz, L., Pantuck, A., George, D., Whitmore, J., Frohlich, M., Sims, R. "Integrated safety data from 4 randomized, double blind, controlled trials of autologous cellular immunotherapy with Sipuleucel-T in patients with prostate cancer." J Urol. 186. no. 3 (2011): 877-81.
  23. Garcia, J., Dreicer, R. "Immunotherapy in castration resistant prostate cancer: integrating Sipuleucel-T into our current treatment regimen." Oncology. 25. no. 3 (2011): 242.
  24. Berthold, D.R., Pond, G.R., de Wit, R., Eisenberger, M., Tannock, I.F. “Survival and PSA response of patients in the Tax 327 study who crossed over to receive docetaxel after mitoxantrone or vice versa.” Ann Oncol. 19. no. 10 (2008):1749-53.

 

 

 

Written by:
Dan Arnett, Megan Griffiths, Mike Glode, and Shandra Wilson as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

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An update on the changing indications for androgen deprivation therapy for prostate cancer - Abstract

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