Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting

Abstract

Prostate cancer is the most common noncutaneous cancer and the second leading cause of death from cancer in men in most western countries. Advanced prostate cancer is typically sensitive to androgen-deprivation therapy, but invariably progresses to the castration-resistant state. Most current prostate cancer treatments are based on cytotoxicity directed against tumor cells via androgen-deprivation therapy or chemotherapy. Chemotherapy with docetaxel represents the standard first-line treatment in patients with castration-resistant prostate cancer (CRPC). Following progression after treatment with docetaxel, cabazitaxel (XRP6258)-prednisone treatment leads to a significantly longer overall survival (OS) time than with mitoxantrone-prednisone. Several other novel agents are currently being evaluated, including sipuleucel-T, abiraterone acetate, and MDV3100, as well as the radionuclide alpharadin. The cell-based immunotherapy sipuleucel-T produces longer OS times in chemotherapy-naïve patients, whereas the androgen biosynthesis inhibitor abiraterone acetate results in longer OS times following docetaxel. It is envisioned that these agents will change the standard of care for patients with metastatic CRPC. This review focuses on the clinical development of cabazitaxel and abiraterone acetate.

Figure 1.

Chemical structure of cabazitaxel and docetaxel.

Figure 2.

Overall survival with cabazitaxel (TROPIC) [26]. Abbreviation: CI, confidence interval. Reprinted from 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;376:1147–1154, Copyright 2010, with permission from Elsevier.

Figure 3.

Abiraterone acetate mode of action and chemical structure. (A): The cytochrome P450 enzyme CYP17 and steroids. Androgen biosynthesis pathway. The physiological effects of abiraterone acetate on steroidogenesis are indicated by arrows next to each steroid precursor. Abiraterone acetate inhibits 17α-hydroxylase (blunt arrow), causing a decline in serum cortisol and a consequent rise in adrenocorticotrophic hormone (ACTH) (broken arrow). This, in turn, results in a rise in deoxycorticosterone and corticosterone by approximately 10- and 40-fold, respectively. The elevated deoxycorticosterone levels result in the expected toxicities of secondary mineralocorticoid syndrome. Abiraterone acetate also inhibits C17,20-lyase (blunt arrow), resulting in significant declines in dehydroepiandrosterone (DHEA), androstenedione, and testosterone. Aldosterone levels fall as a result of suppression of the renin–angiotensin pathway by high levels of deoxycorticosterone. However, there is a fourfold increase in 11-deoxycortisol, which may be a result of the higher ACTH levels driving the partial reversal of the activity of 17α-hydroxylase but not C17,20-lyase. (B): Chemical structures of abiraterone acetate and abiraterone [29]. Reprinted from Ang JE, Olmos D, de Bono JS. CYP17 blockade by abiraterone: Further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer. Br J Cancer 2009;100:671–675, Copyright 2009, with permission from Macmillan Publishers Ltd.