Prostate Cancer - Management - Castration-resistant Cancer

Castration-resistant Cancer

Most hormone dependent cancers become refractory after one to three years and resume growth despite hormone therapy. Previously considered "hormone-refractory prostate cancer" or "androgen-independent prostate cancer", the term castration-resistant has replaced "hormone refractory" because while they are no longer responsive to castration treatment (reduction of available androgen/testosterone/DHT by chemical or surgical means), these cancers still show reliance upon hormones for androgen receptor activation. Before 2004, all treatments for castration-resistant prostate cancer (CRPC) were considered palliative and not shown to prolong survival. However, there are now several treatments available to treat CRPC that improve survival.

The cancer chemotherapic docetaxel has been used as treatment for (CRPC) with a median survival benefit of 2 to 3 months. Docetaxel's FDA approval in 2004 was significant as it was the first treatment proven to prolong survival in CRPC. In 2010, the FDA approved a second-line chemotherapy treatment known as cabazitaxel.

Off-label use of the oral drug ketoconazole is sometimes used as a way to further manipulate hormones with a therapeutic effect in CRPC. However, many side effects are possible with this drug and abiraterone is likely to supplant usage since it has a similar mechanism of action with less toxic side effects.

A combination of bevacizumab (Avastin), docetaxel, thalidomide and prednisone appears effective in the treatment of CRPC.

The immunotherapy treatment with sipuleucel-T is also effective in the treatment of CRPC with a median survival benefit of 4.1 months.

The second line hormonal therapy abiraterone (Zytiga) completed a phase 3 trial for CRPC patients who have failed chemotherapy in 2010. Results were positive with overall survival increased by 4.6 months when compared to placebo. On April 28, 2011, the U.S. Food and Drug Administration approved abiraterone acetate in combination with prednisone to treat patients with late-stage (metastatic) castration-resistant prostate cancer who have received prior docetaxel (chemotherapy).

Enzalutamide is another second line hormonal agent approved in August 2012 by the U.S. FDA. Results of a phase 3 trial in CRPC patients who had failed chemotherapy demonstrated a 5 month survival advantage over placebo.

Both abiraterone and enzalutamide are currently being tested in clinical trials with CRPC patients who have not previously received chemotherapy.

Now, it has been noted that only a subset of a patient respond to androgen signaling blocking drugs and certain cells with characteristics resembling stem cells remain unaffected. Therefore, the desire to improve outcome of CRPC patients has resulted into the claims of increasing doses further or combination therapy with synergistic androgen signaling blocking agents. But even these combination will not affect stem -like cells that do not exhibit androgen signaling. It is possible that for further advances, a combination of androgen signaling blocking agent with stem-like cell directed differentiation therapy drug would prove ideal.