Abiraterone acetate for metastatic prostate cancer

In The Lancet Oncology, Karim Fizazi and colleagues update the landmark COU-AA-301 trial, which assessed abiraterone acetate, an inhibitor of CYP17 that suppresses androgen synthesis, for men with progressive metastatic castration-resistant prostate cancer after docetaxel treatment. The update ratifi es the extension of median overall survival with abiraterone acetate plus prednisone compared with placebo plus prednisone (15·8 vs 11·2 months; p<0·0001), accompanied by manageable toxic eff ects due to mineralocorticoid excess. This large phase 3 trial (n=1195) provides convincing evidence for the continued importance of androgen-axis signalling, even after chemotherapy, and represents an important advance in the therapy of metastatic castration-resistant prostate cancer. In the previous report of this trial, abiraterone acetate plus prednisone was preliminarily shown to yield a signifi cant improvement in radiographic progression-free survival and a trend for improved overall survival in chemonaive metastatic castrationresistant prostate cancer. These data will probably result in the preferred use of abiraterone acetate before the institution of docetaxel in the near future. On the heels of abiraterone acetate, other androgen synthesis inhibitors (orteronel), androgen receptor inhibitors (enzalutamide, ARN-509), and agents with both of these mechanisms of activity (galeterone) are undergoing clinical assessment. Despite the extension of median overall survival and a decrease in risk of death (HR 0·74 [95% CI 0·64–0·86]) in the COU-AA-301 trial, there seems to be little diff erence in the overall survival at 2 years between the two groups. Although durable response or stability has been reported anecdotally, these data suggest no durable benefi t in most patients. Patients were deemed to have progressive disease on the basis of radiographic and clinical variables and not for prostate-specifi c antigen (PSA) progression alone in accordance with Prostate Cancer Working Group (PCWG)-2 guidelines. Indeed, the possibility of clinical progression in the context of decreasing PSA concentrations exists. Moreover, early radiologic bone scan “fl ares” have been noted in the context of decreasing PSA, which tend to improve or stabilise with time. Hence, careful and periodic clinical and radiographic monitoring is imperative. Furthermore, a retrospective analysis of the COU-AA-301 trial indicated that unfavourable changes in circulating tumour cells are a poor prognostic factor, although this fi nding requires validation and should not, at this time, guide clinical practice. Whether abiraterone acetate compromises the activity of subsequent therapy is unknown. One small retrospective study suggested lower activity for docetaxel after abiraterone acetate treatment, especially in abiraterone acetate-refractory patients. Ketoconazole seemed to have poor or no activity after abiraterone acetate treatment in a small cohort, and the reverse sequence of ketoconazole followed by abiraterone acetate has also shown somewhat lower activity with abiraterone acetate. Indeed, both of the phase 3 trials assessing abiraterone acetate excluded patients exposed to previous ketoconazole. Emerging preclinical data suggest that resistance to abiraterone acetate may be due to amplifi cation of CYP17, androgen receptors, and androgen receptor splice variants. Moreover, high doses of abiraterone acetate might suppress 3β-hydroxysteroid dehydrogenase, which is involved in dihydrotestosterone synthesis. Thus, higher doses of abiraterone acetate, more potent CYP17 inhibitors, and androgen receptor inhibitors might all have a therapeutic role in patients resistant to the conventional dose of abiraterone acetate. Interestingly, preliminary retrospective data in a small cohort (n=24) show PSA responses in 13% of patients treated with abiraterone acetate after exposure to both docetaxel and enzalutamide. Determination of the activity of the combination of abiraterone acetate and enzalutamide is of considerable interest and is undergoing early investigation. In regards to other commonly used prostate cancer drugs, abiraterone acetate is a weak inhibitor of CYP3A4 enzymes that might be safe in combination with docetaxel (unlike ketoconazole) and thus such a combination is being assessed. Early use of abiraterone acetate plus prednisone in combination with agonists of lutenising hormone releasing hormone (LHRH) has shown promising activity in the neoadjuvant setting (pathological complete remission or near-pathological complete remission in 25% of patients, n=56), although the prolonged administration of prednisone from an earlier stage of the disease might be a limiting factor. Preliminary data suggest that optimum selection of patients likely to benefi t might be possible. A retrospective analysis of COU-AA-301 showed that those with baseline Published Online September 18, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70392-3