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: HR Tooltip hazard ratio = 1.16; 95% CI Tooltip confidence interval = 0.99–1.37; P Tooltip 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]

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<span class="mw-page-title-main">Antiandrogen</span> Class of pharmaceutical drugs

Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.

<span class="mw-page-title-main">Bicalutamide</span> Prostate cancer treatment

Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC). To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration. Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings. Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women, as a puberty blocker and component of feminizing hormone therapy for transgender girls and women, to treat gonadotropin-independent early puberty in boys, and to prevent overly long-lasting erections in men. It is taken by mouth.

<span class="mw-page-title-main">5α-Reductase inhibitor</span> Class of medications

5α-Reductase inhibitors (5-ARIs), also known as dihydrotestosterone (DHT) blockers, are a class of medications with antiandrogenic effects which are used primarily in the treatment of enlarged prostate and scalp hair loss. They are also sometimes used to treat excess hair growth in women and as a component of hormone therapy for transgender women.

<span class="mw-page-title-main">Dutasteride</span> Hormone replacement medication

Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of a benign prostatic hyperplasia (BPH), an enlarged prostate not associated with cancer. A few months may be required before benefits occur. It is also used for scalp hair loss in men and as a part of hormone therapy in transgender women. It is usually taken by mouth.

<span class="mw-page-title-main">Flutamide</span> Chemical compound

Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. It is taken by mouth, usually three times per day.

<span class="mw-page-title-main">Nilutamide</span> Chemical compound

Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. It is taken by mouth.

<span class="mw-page-title-main">Enzalutamide</span> Antiandrogen medication used in treatment of prostate cancer

Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC), nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer (mCSPC). It is taken by mouth.

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<span class="mw-page-title-main">Active surveillance of prostate cancer</span>

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Sexual motivation is influenced by hormones such as testosterone, estrogen, progesterone, oxytocin, and vasopressin. In most mammalian species, sex hormones control the ability and motivation to engage in sexual behaviours.

<span class="mw-page-title-main">Cyproterone acetate</span> Chemical compound

Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treatment of androgen-dependent conditions such as acne, excessive body hair growth, early puberty, and prostate cancer, as a component of feminizing hormone therapy for transgender women, and in birth control pills. It is formulated and used both alone and in combination with an estrogen. CPA is taken by mouth one to three times per day.

<span class="mw-page-title-main">Nonsteroidal antiandrogen</span> Antiandrogen with a nonsteroidal chemical structure

A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like testosterone and dihydrotestosterone (DHT). NSAAs are used in the treatment of androgen-dependent conditions in men and women. They are the converse of steroidal antiandrogens (SAAs), which are antiandrogens that are steroids and are structurally related to testosterone.

Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. It is specifically approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration. The medication is taken by mouth twice per day with food.

<span class="mw-page-title-main">Apalutamide</span> Chemical compound

Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC). It is taken by mouth.

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The side effects of bicalutamide, a nonsteroidal antiandrogen (NSAA), including its frequent and rare side effects, have been well-studied and characterized. The most common side effects of bicalutamide monotherapy in men include breast tenderness, breast growth, feminization, demasculinization, and hot flashes. Less common side effects of bicalutamide monotherapy in men include sexual dysfunction, depression, fatigue, weakness, and anemia. Bicalutamide is well tolerated and has few side effects in women. General side effects of bicalutamide that may occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash.

Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.

<span class="mw-page-title-main">Pharmacology of bicalutamide</span>

The pharmacology of bicalutamide is the study of the pharmacodynamic and pharmacokinetic properties of the nonsteroidal antiandrogen (NSAA) bicalutamide. In terms of pharmacodynamics, bicalutamide acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR. It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its AR antagonist activity and can increase androgen, estrogen, and neurosteroid production and levels. This results in a variety of differences of bicalutamide monotherapy compared to surgical and medical castration, such as indirect estrogenic effects and associated benefits like preservation of sexual function and drawbacks like gynecomastia. Bicalutamide can paradoxically stimulate late-stage prostate cancer due to accumulated mutations in the cancer. When used as a monotherapy, bicalutamide can induce breast development in males due to its estrogenic effects. Unlike other kinds of antiandrogens, it may have less adverse effect on the testes and fertility.

The Scandinavian Prostate Cancer Group (SPCG) is a group of scientific researchers who have conducted a series of clinical trials of treatments for prostate cancer. The group was founded in 1981 and the first study, SPCG-1, began in 1984.

The FinnProstate Group (FP), or FinnProstate Study Group, is a group of scientific researchers in Finland who have conducted a series of clinical trials of treatments for prostate cancer. The first publication by the group was in 1985 and the latest publication was in 2019.

References

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  2. 1 2 3 4 5 6 7 8 9 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. 1 2 3 4 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. 1 2 3 4 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. 1 2 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. 1 2 3 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. 1 2 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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