Selective inhibition of CYP17 with abiraterone acetate is well tolerated and results in a high response rate in castration-resistant prostate cancer (CRPC) (2007)

B73 Introduction:  Despite androgen deprivation therapy, recent studies demonstrate high levels of intra-tumoral androgens and continued androgen receptor signalling in CRPC. AA is an oral, selective inhibitor of CYP17, a key enzyme in androgen synthesis.  Methods:  AA was administered once daily, continuously: (i) to chemotherapy-naive CRPC patients (pts) in a dose escalation phase I/II trial with phase II cohort expansion at the optimal dose (ii) at the optimal dose to pts previously treated with docetaxel chemotherapy in a parallel phase II study. All pts were resistant to castration, antiandrogens and frequently diethylstilboestrol and steroids. The primary objective of both studies was to evaluate the anti-tumor activity of AA with rejection of the null hypothesis if ≥7 pts from a maximum of 35 pts had a PSA decline ≥50% (Ho: ≤ 10%, Ha: >30% [power 86%; α 5%]). Secondary objectives included evaluating: (i) safety; (ii) CYP17 inhibition; (iii) pharmacokinetic (PK) profile; (iv) response rate by RECIST; (v) median time to progression (MTTP); (vi) reversal of resistance by addition of dexamethasone (D) 0.5mg od at progression on AA; (vii) circulating tumor cell (CTC) counts; (viii) ERG and PTEN tumor and CTC gene status.  Results:  AA was well tolerated at all doses (250mg - 2000mg). Although not dose-related, the anticipated toxicities secondary to mineralocorticoid (M) excess were successfully managed with an M-receptor antagonist. Anti-tumor activity was observed at all doses but 1000mg was selected for phase II evaluation owing to a plateau in pharmacodynamic effect at 1000mg. The null hypothesis was rejected in both phase II studies. 44 chemotherapy-naive pts received AA (median baseline PSA: 75, range: 8.8 - 964; 31/44 had bone metastasis on bone scan). 27/44 (61%) had ≥ 50% PSA decline confirmed ≥ 1 month, 22/44 (50%) and 11/44 (25%) had ≥75% and ≥90% declines in PSA respectively. MTTP by PSA: 252 days. 21/44 pts had measurable disease on CT scan - by RECIST: 12/21 partial response (PR) (57%), 7/21 stable disease (SD) (33%). 18 pts continue on AA alone; median follow-up (FU): 171 days (range: 581 - 108). Addition of D reversed resistance in 3/13 pts. 28 docetaxel-treated pts received AA (median baseline PSA: 523, range: 33.3 - 10325; 22/28 had bone disease). 14/28 (50%) had ≥ 50% PSA decline confirmed ≥ 1 month, 9/28 (32%) and 5/28 (18%) had ≥ 75% and ≥ 90% declines in PSA respectively. 18/28 pts had measurable disease on CT scan - by RECIST: 3/18 PR (17%); 11/18 SD (61%). MTTP by PSA: 165 days. 11 pts continue on AA; median FU: 213 days (range: 248 - 103). Symptom relief and falls in CTC counts were observed. At all dose levels, treatment was associated with a rise in ACTH and steroids upstream of CYP17 as well as significant suppression of downstream androgenic steroids, testosterone and oestradiol. PK analysis on 21 pts showed a consistent terminal half-life (mean: 10.3 hours) and a non-linear increase in AUC and Cmax with dose (r2 0.186, 0.049 respectively). When administered with high fat food, drug exposure was significantly increased (4.4 fold) in comparison with fasting (p=0.049).  Conclusion:  The significant anti-tumor activity observed with AA suggests that 50-60% of CRPC remain hormone driven. Selective CYP450c17 inhibition with AA could represent a novel therapeutic option for pts with CRPC. Randomized Phase III trials will start in 2008.