Clinical activity and safety of ASN001, a selective CYP17 lyase inhibitor, administered without prednisone in men with metastatic castration-resistant prostate cancer (mCRPC)

Background: ASN001 is a novel, non-steroidal, potent inhibitor of CYP17 lyase. It selectively inhibits synthesis of testosterone over cortisol in the adrenals to avoid the need for co-administration of prednisone. ASN001 also exhibits high oral bioavailability and low potential for drug-drug interaction supporting its use in future combination trials. Methods: This Phase 1/2 clinical trial in men with progressive mCRPC evaluates once-daily, oral ASN001 at escalating doses of 50, 100, 200, 300 and 400 mg (NCT02349139). While the Phase 1 also allowed enrollment of pretreated patients, no prior enzalutamide (ENZA) or abiraterone (ABI) is permitted in Phase 2. Endpoints included maximum dose (MTD) and dose limiting toxicities, recommended Phase 2 dose, pharmacokinetics, effect on steroid hormone biosynthesis and clinical efficacy (PSA and imaging). Results: To date, 23 mCRPC pts have been enrolled. No prednisone was administered and no mineralocorticoid excess has been reported. Overall, ASN001 was well tolerated. Most drug-related adverse events were Gr 1/2 and included fatigue, nausea and dizziness. At 400mg, two pts experienced asymptomatic, reversible Gr 3 elevation of ALT/AST, but no recurrence when retreated at a lower dose (300mg). Testosterone decreased to below quantifiable limits and DHEA decrease of up to 80% was observed in ABI/ENZA naïve patients. Systemic exposure was high (C , AUC and T at 300 mg QD was 6.7 μm, 80 μm.h and 21.5h, respectively). RECIST defined Stable Disease up to 15+ months has been observed at the 100mg cohort despite prior ABI and ENZA exposure. PSA decline of > 50% (51%-70%) was observed in 3 of 3 ABI/ENZA naïve patients at doses of 300/400mg. Conclusions: Overall, ASN001 was safe and well tolerated without need for prednisone co-administration. Encouraging preliminary evidence of efficacy is based on the PSA decline observed in evaluable mCRPC pts not pretreated with ABI or ENZA and based on durable disease stabilization after progression on ABI and ENZA. Enrollment is ongoing at doses below 400mg QD in ABI/ENZA naïve mCRPC pts. Updated and detailed results will be presented at the meeting.