Treatment guidelines for advanced, metastatic and castration-resistant prostate cancer

The authors presented guidelines for treatment of advanced, relapsing and castration-resistant prostate cancer.

The knowledge about treatment of advanced, metastatic (spread of the cancer) and castration-resistant (cancer that continues to grow despite low levels of testosterone) prostate cancer continues to grow.

Thus far, there is no single best treatment for men with locally advanced prostate cancer. Most experts recommend a combination of either androgen deprivation therapy (the reduction of androgen hormones, including testosterone) plus radiation therapy or surgery and adjuvant (follow-up) radiotherapy.

Treatment for advanced (stage IV) prostate cancer usually begins with androgen deprivation therapy. If the cancer recurs within approximately two years (“castration-resistant” prostate cancer), secondary hormone therapy is usually considered. This line of therapy includes additional or alternative antiandrogens, or trying other drugs that block androgens.

The authors of this paper presented the latest updates on guidelines for treatment of advanced, metastatic and castration-resistant prostate cancer.

Luteinizing hormone-releasing hormone controls the release of luteinizing hormone, required for control of the reproductive system. Luteinizing hormone-releasing hormone agonists are drugs that elicit the same response as the natural hormone, and have become the standard of care in hormonal therapy.

Conversely, luteinizing hormone-releasing hormone antagonists are drugs that inhibit the response to the natural hormone. Administration of these drugs results in a rapid decrease in the levels of luteinizing hormone and testosterone levels without the flare (an initial temporary surge in testosterone levels) that is associated with agonist drugs. In a recent phase 3 trial, 610 men with prostate cancer requiring androgen deprivation therapy were randomly assigned to receive either degeralix (Firmagon; a luteinizing hormone-releasing hormone antagonist) or leuprolide (Eligard; a luteinizing hormone-releasing hormone agonist) for 12 months. Degeralix achieved a more rapid suppression of testosterone within the first 3 days and avoided a flare phenomenon compared to leuprolide.

Recent reviews and analyses suggest that at a follow-up of 5 years, maximum androgen blockage (using luteinizing hormone blockers plus antiandrogens) provides a 5% survival advantage compared to luteinizing hormone-releasing hormone therapy alone. However, this can be associated with severe impairment of quality of life in terms of sexuality and cognitive function.

Intermittent androgen deprivation alternates androgen blockade with treatment cessation to allow hormonal recovery between treatment cycles. Patients on intermittent androgen deprivation experience greater bone health, less metabolic and blood-related disturbances, fewer hot flashes and improved sexual function. A trial of 1535 patients who had undertaken 7 months of induction androgen deprivation therapy to reduce prostate-specific antigen (a protein that is elevated in prostate cancer) levels to less than 4 ng/ml subsequently randomized men to either continuous or intermittent androgen therapy.  Follow-up of 9.8 years revealed that average survival in the continuous arm was 5.8 years compared to 5.1 years in the intermittent arm. However, the statistical data is as yet inconclusive.

In locally advanced and metastatic prostate cancer, early androgen deprivation therapy does not result in a significant survival advantage when compared with late androgen deprivation therapy. In a trial of 235 men with lymph-node positive prostate cancer, the 10-year incidence of prostate cancer-specific death was 52.1% for those who underwent early therapy compared to 55.6% for those who underwent late therapy.

The authors defined cancer relapse after radical prostatectomy (surgical removal of the prostate) as prostate specific antigen levels greater than 0.2 ng/ml (i.e. two consecutive increases following surgery), and levels more than 2 ng/ml higher than the lowest prostate-specific antigen levels the patient experienced after radiotherapy. Therapy for prostate specific antigen relapse after radical prostatectomy includes salvage radiation therapy (therapy to obtain local control and prevent or delay metastasis) at prostate specific antigen levels greater than 0.5 ng/ml or cryosurgical ablation (using very precise freezing and thawing to destroy cancer cells) of the prostate where radiation fails.

Treatment of castration-resistant prostate cancer can include sipuleucel-T (Provenge), a therapeutic cancer vaccine. A trial of 512 patients saw those being treated with sipuleucel-T achieving an average survival time of 25.8 months compared to 21.7 months for those treated with placebo (a substance with no therapeutic effect). The most commonly reported side effects for sipuleucel-T were fever, chills and headache.

 Another treatment used in castration-resistant prostate cancer is abiraterone acetate (Zytiga) plus prednisone (Deltasone). In a trial of 1088 men with non-symptomatic or mildly symptomatic metastatic prostate cancer, treatment with abiraterone acetate plus prednisone was associated with an average survivial of 35.3 months compared to 27.2 months for placebo. Progression-free survival (the length of time after treatment that the disease does not get worse) was 16.5 months in the treatment arm compared to 8.3 months in the placebo arm. Chemotherapy with docetaxel  (Taxotere) 75mg/m² every 3 weeks is also recommended.

Second-line treatment for castration-resistant prostate cancer following docetaxel includes cabazitaxel (Jevtana), enzalutamide (Xtandi) and radium-233 (Xofigo).

These guidelines represent the latest knowledge in the field of advanced, metastatic and castration-resistant prostate cancer.