Abiraterone acetate, the prodrug of abiraterone, blocks endogenous androgen synthesis by inhibiting cytochrome p-450c17, a critical enzyme in androgen biosynthesis. Its active D4A metabolite also has anti-tumour effects through possibly multiple mechanisms. 3-5% of men diagnosed with prostate cancer in western countries have metastases, and as high as 60% in some asian countries. The LATITUDE trial was a double-blind, placebo-controlled, multinational phase 3 trial involving almost 1200 men with newly diagnosed, metastatic, castration-sensitive, prostate cancer, who were assigned to either androgen-deprivation therapy + abiraterone acetate + prednisone or androgen-deprivation therapy + dual placebos. Median follow-up was for 30.4 months. The median radiologic progression-free survival was 33 months in the abiraterone group vs. 14.8 months for the placebo group, with median overall survival being better as well (not reached vs. 34.7 months). This translates into a 38% lower relative risk of death or a hazard ratio of 0.62 in the abiraterone group. All secondary end-points were significantly better as well: these included time until pain progresses, serum PSA progression, time to next subsequent therapy for prostate cancer and initiation of chemotherapy. The rates of mineralocorticoid-rated hypertension and hypokalaemia were higher in the abiraterone group, which have also been reported in earlier studies and do not seem to significantly alter overall survival.
Previous trials have shown that abiraterone acetate in combination with prednisone increases surgical in metatastatic, hormone-resistant prostate cancer who have not received chemotherapy or docitaxel. In LATITUDE, newly diagnosed, castration sensitive men with metastatic prostate cancer were evaluated. This trial therefore provides evidence of survival advantage when used at an earlier stage of treatment, and the management algorithms for newly diagnosed high-risk metastatic prostate cancer is likely to change as a result of this new standard of care. The abiraterone arm of STAMPEDE also demonstrated a pronounced survival benefit, as discussed at the ASCO annual meeting in June. The clinical benefit of adding docetaxel to androgen-deprivation therapy compared to androgen-deprivation alone has been demonstrated in clinical trials such as STAMPEDE, CHAARTED and GETUG-15 and is now a standard of care for metastatic, castrate-sensitive prostate cancer; but the use of docetaxel is limited by advanced patient age, coexisting co-morbidities, or poor performance status. Current NICE guidelines recommends use of abiraterone in combination with prednisone only in castrate-resistant men and consequently we will wait to see if this recommendation will change based on the weight of the current evidence.
