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Early Prostate Cancer (clinical programme)

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The Early Prostate Cancer (EPC) programme was a large clinical trial programme of monotherapy with the nonsteroidal antiandrogen bicalutamide (Casodex) plus standard care versus standard care alone in men with early prostate cancer.[1][2][3] It was started in August 1995,[1] with the first analysis published in 2002[4] and the final follow-up published in 2010.[5] The programme consisted of three large randomized, double-blind, placebo-controlled trials in which a total of 8,113 men with localized or locally advanced prostate cancer were treated with 150 mg/day bicalutamide plus standard care (watchful waiting, radical prostatectomy, or radiation therapy) (n=4052) or given placebo (standard care alone) (n=4061).[3][2] It constituted the largest clinical trial of prostate cancer treatment to have ever been conducted at the time.[1][3][6]

The three trials in the EPC programme were as follows:[2][7]

Several combined follow-up papers of the EPC programme results were published, including at median 3.0 years in August 2002,[4] median 5.4 years in November 2004,[16] median 7.4 years in February 2006,[17] and median 9.7 years in April 2010.[5]

The EPC programme found that bicalutamide was effective in treating locally advanced prostate cancer.[2] Conversely, it was not effective for localized prostate cancer, where there was instead a statistically insignificant trend toward reduced overall survival with bicalutamide therapy (at median 7.4 years follow-up: HRTooltip hazard ratio = 1.16; 95% CITooltip confidence interval = 0.99–1.37; PTooltip p-value = 0.07).[1][2] The increased mortality with bicalutamide in men with localized prostate cancer was however statistically significant at certain follow-ups in the Trial 25/SPCG-6 substudy of the EPC programme.[13][15] The preceding findings led to the withdrawal of pre-existing approval of bicalutamide for localized prostate cancer in the United Kingdom and Canada.[2]

Liver safety is an important concern with bicalutamide. In the first analysis of the EPC programme at median 3.0 years of follow-up, abnormal liver function tests had occurred in 3.4% of men treated with bicalutamide and 1.9% of men with placebo.[2][3][4] Clinically relevant increases in aspartate transaminase (AST), alanine transaminase (ALT), and bilirubin occurred in 1.6%, 1.6%, and 0.7% with bicalutamide and in 0.5%, 0.3%, and 0.4% with placebo.[2] However, liver changes with bicalutamide were usually transient and rarely severe.[2] Abnormal liver function tests led to treatment withdrawal in 1.4% with bicalutamide and 0.5% with placebo.[4] No cases of fatal hepatotoxicity occurred with bicalutamide in the SPCG-6 substudy of the EPC programme.[13]

References

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  1. ^ a b c d Iversen P, Roder MA (March 2008). "The Early Prostate Cancer program: bicalutamide in nonmetastatic prostate cancer". Expert Rev Anticancer Ther. 8 (3): 361–9. doi:10.1586/14737140.8.3.361. PMID 18366284. S2CID 207189398.
  2. ^ a b c d e f g h i Wellington K, Keam SJ (2006). "Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer". Drugs. 66 (6): 837–50. doi:10.2165/00003495-200666060-00007. PMID 16706554. S2CID 46966712.
  3. ^ a b c d Anderson J (March 2003). "The role of antiandrogen monotherapy in the treatment of prostate cancer". BJU Int. 91 (5): 455–61. doi:10.1046/j.1464-410x.2003.04026.x. PMID 12603397.
  4. ^ a b c d See WA, Wirth MP, McLeod DG, Iversen P, Klimberg I, Gleason D, Chodak G, Montie J, Tyrrell C, Wallace DM, Delaere KP, Vaage S, Tammela TL, Lukkarinen O, Persson BE, Carroll K, Kolvenbag GJ (August 2002). "Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program". J Urol. 168 (2): 429–35. doi:10.1016/S0022-5347(05)64652-6. PMID 12131282.
  5. ^ a b Iversen P, McLeod DG, See WA, Morris T, Armstrong J, Wirth MP (April 2010). "Antiandrogen monotherapy in patients with localized or locally advanced prostate cancer: final results from the bicalutamide Early Prostate Cancer programme at a median follow-up of 9.7 years". BJU Int. 105 (8): 1074–81. doi:10.1111/j.1464-410X.2010.09319.x. PMID 22129214. S2CID 1261264.
  6. ^ Fradet Y (February 2004). "Bicalutamide (Casodex) in the treatment of prostate cancer". Expert Rev Anticancer Ther. 4 (1): 37–48. doi:10.1586/14737140.4.1.37. PMID 14748655. S2CID 34153031.
  7. ^ See WA, McLeod D, Iversen P, Wirth M (March 2001). "The bicalutamide Early Prostate Cancer Program. Demography". Urol Oncol. 6 (2): 43–47. doi:10.1016/s1078-1439(00)00118-6. PMID 11166619.
  8. ^ McLeod DG, See WA, Klimberg I, Gleason D, Chodak G, Montie J, Bernstein G, Morris C, Armstrong J (July 2006). "The bicalutamide 150 mg early prostate cancer program: findings of the North American trial at 7.7-year median followup". J Urol. 176 (1): 75–80. doi:10.1016/S0022-5347(06)00495-2. PMID 16753373.
  9. ^ Wirth M, Tyrrell C, Wallace M, Delaere KP, Sánchez-Chapado M, Ramon J, Hetherington J, Pina F, Heynes CF, Borchers TM, Morris T, Stone A (August 2001). "Bicalutamide (Casodex) 150 mg as immediate therapy in patients with localized or locally advanced prostate cancer significantly reduces the risk of disease progression". Urology. 58 (2): 146–51. doi:10.1016/s0090-4295(01)01213-4. PMID 11489683.
  10. ^ Wirth M, Tyrrell C, Delaere K, Sánchez-Chapado M, Ramon J, Wallace DM, Hetherington J, Pina F, Heyns C, Borchers T, Morris T, Armstrong J (2005). "Bicalutamide ('Casodex') 150 mg in addition to standard care in patients with nonmetastatic prostate cancer: updated results from a randomised double-blind phase III study (median follow-up 5.1 y) in the early prostate cancer programme". Prostate Cancer Prostatic Dis. 8 (2): 194–200. doi:10.1038/sj.pcan.4500799. PMID 15931272.
  11. ^ Wirth M, Tyrrell C, Delaere K, Sánchez-Chapado M, Ramon J, Wallace DM, Hetherington J, Pina F, Heyns CF, Navani S, Armstrong J (2007). "Bicalutamide (Casodex) 150 mg plus standard care in early non-metastatic prostate cancer: results from Early Prostate Cancer Trial 24 at a median 7 years' follow-up". Prostate Cancer Prostatic Dis. 10 (1): 87–93. doi:10.1038/sj.pcan.4500916. PMID 17102802.
  12. ^ Iversen P, Tammela TL, Vaage S, Lukkarinen O, Lodding P, Bull-Njaa T, Viitanen J, Hoisaeter P, Lundmo P, Rasmussen F, Johansson JE, Persson BE, Carroll K (September 2002). "A randomised comparison of bicalutamide ('Casodex') 150 mg versus placebo as immediate therapy either alone or as adjuvant to standard care for early non-metastatic prostate cancer. First report from the Scandinavian Prostatic Cancer Group Study No. 6". Eur Urol. 42 (3): 204–11. doi:10.1016/s0302-2838(02)00311-1. PMID 12234503.
  13. ^ a b c Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K (November 2004). "Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6". J Urol. 172 (5 Pt 1): 1871–6. doi:10.1097/01.ju.0000139719.99825.54. PMID 15540741.
  14. ^ Iversen P, Johansson JE, Lodding P, Kylmälä T, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Armstrong J (2006). "Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer: updated results from the Scandinavian Prostate Cancer Period Group-6 Study after a median follow-up period of 7.1 years". Scand J Urol Nephrol. 40 (6): 441–52. doi:10.1080/00365590601017329. PMID 17130095. S2CID 25862814.
  15. ^ a b Thomsen FB, Brasso K, Christensen IJ, Johansson JE, Angelsen A, Tammela TL, Iversen P (July 2015). "Survival benefit of early androgen receptor inhibitor therapy in locally advanced prostate cancer: long-term follow-up of the SPCG-6 study". Eur J Cancer. 51 (10): 1283–92. doi:10.1016/j.ejca.2015.03.021. PMID 25892647.
  16. ^ Wirth MP, See WA, McLeod DG, Iversen P, Morris T, Carroll K (November 2004). "Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median followup of 5.4 years". J Urol. 172 (5 Pt 1): 1865–70. doi:10.1097/01.ju.0000140159.94703.80. PMID 15540740.
  17. ^ McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP (February 2006). "Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer". BJU Int. 97 (2): 247–54. doi:10.1111/j.1464-410X.2005.06051.x. PMID 16430622.
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