Early Prostate Cancer (clinical programme) explained

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

The three trials in the EPC programme were as follows:[5]

Several combined follow-up papers of the EPC programme results were published, including at median 3.0years in August 2002,[14] median 5.4years in November 2004,[15] median 7.4years in February 2006,[16] and median 9.7years in April 2010.[17]

The EPC programme found that bicalutamide was effective in treating locally advanced prostate cancer. 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 7.4years follow-up: = 1.16; 95% = 0.99–1.37; = 0.07). 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. The preceding findings led to the withdrawal of pre-existing approval of bicalutamide for localized prostate cancer in the United Kingdom and Canada.

Liver safety is an important concern with bicalutamide. In the first analysis of the EPC programme at median 3.0years of follow-up, abnormal liver function tests had occurred in 3.4% of men treated with bicalutamide and 1.9% of men with placebo. 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. However, liver changes with bicalutamide were usually transient and rarely severe. Abnormal liver function tests led to treatment withdrawal in 1.4% with bicalutamide and 0.5% with placebo. No cases of fatal hepatotoxicity occurred with bicalutamide in the SPCG-6 substudy of the EPC programme.

Notes and References

  1. Iversen P, Roder MA . The Early Prostate Cancer program: bicalutamide in nonmetastatic prostate cancer . Expert Rev Anticancer Ther . 8 . 3 . 361–9 . March 2008 . 18366284 . 10.1586/14737140.8.3.361 . 207189398 .
  2. Wellington K, Keam SJ . Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer . Drugs . 66 . 6 . 837–50 . 2006 . 16706554 . 10.2165/00003495-200666060-00007 . 46966712 .
  3. Anderson J . The role of antiandrogen monotherapy in the treatment of prostate cancer . BJU Int . 91 . 5 . 455–61 . March 2003 . 12603397 . 10.1046/j.1464-410x.2003.04026.x .
  4. Fradet Y . Bicalutamide (Casodex) in the treatment of prostate cancer . Expert Rev Anticancer Ther . 4 . 1 . 37–48 . February 2004 . 14748655 . 10.1586/14737140.4.1.37 . 34153031 .
  5. See WA, McLeod D, Iversen P, Wirth M . The bicalutamide Early Prostate Cancer Program. Demography . Urol Oncol . 6 . 2 . 43–47 . March 2001 . 11166619 . 10.1016/s1078-1439(00)00118-6 .
  6. McLeod DG, See WA, Klimberg I, Gleason D, Chodak G, Montie J, Bernstein G, Morris C, Armstrong J . 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 . July 2006 . 16753373 . 10.1016/S0022-5347(06)00495-2 .
  7. 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 . 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 . August 2001 . 11489683 . 10.1016/s0090-4295(01)01213-4 .
  8. 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 . 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 . 2005 . 15931272 . 10.1038/sj.pcan.4500799 . free .
  9. Wirth M, Tyrrell C, Delaere K, Sánchez-Chapado M, Ramon J, Wallace DM, Hetherington J, Pina F, Heyns CF, Navani S, Armstrong J . 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 . 2007 . 17102802 . 10.1038/sj.pcan.4500916 .
  10. 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 . 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 . September 2002 . 12234503 . 10.1016/s0302-2838(02)00311-1 .
  11. Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K . 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 . November 2004 . 15540741 . 10.1097/01.ju.0000139719.99825.54 .
  12. Iversen P, Johansson JE, Lodding P, Kylmälä T, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Armstrong J . 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 . 2006 . 17130095 . 10.1080/00365590601017329 . 25862814 .
  13. Thomsen FB, Brasso K, Christensen IJ, Johansson JE, Angelsen A, Tammela TL, Iversen P . 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 . July 2015 . 25892647 . 10.1016/j.ejca.2015.03.021 .
  14. 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 . 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 . August 2002 . 12131282 . 10.1016/S0022-5347(05)64652-6 .
  15. Wirth MP, See WA, McLeod DG, Iversen P, Morris T, Carroll K . 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 . November 2004 . 15540740 . 10.1097/01.ju.0000140159.94703.80 .
  16. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP . Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer . BJU Int . 97 . 2 . 247–54 . February 2006 . 16430622 . 10.1111/j.1464-410X.2005.06051.x .
  17. Iversen P, McLeod DG, See WA, Morris T, Armstrong J, Wirth MP . 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 . April 2010 . 22129214 . 10.1111/j.1464-410X.2010.09319.x . 1261264 .

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