Safety, tolerability and anti-tumour activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer: Multi-centre phase I/II study

Summary Background: ASP9521 is a first-in-class orally available inhibitor of the enzyme 17 β-hydroxysteroid dehydrogenase type 5 (17 βHSD5; AKR1C3), catalysing the conversion of dehydroepiandrosterone and androstenedione into 5-androstenediol and testosterone. It has demonstrated antitumour activity in in vitro and in vivo preclinical models. Material and methods: This first-in-man phase I/II study utilised a 3+3 dose escalation design starting at 30 mg ASP9521/day, with the aim of defining a maximum tolerated dose, as defined by the incidence of dose-limiting toxicities. Eligible patients received ASP9521 orally for 12 weeks. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics and anti-tumour activity were assessed. Results: Thirteen patients (median age: 68 years; range 52-76) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy were included; 12 patients discontinued treatment at or before week 13, mainly due to disease progression. The most common adverse events were grade 1/2 and included asthenia (N=5), constipation (N=4), diarrhoea (N=3), back pain (N=3) and cancer pain (N=3). PK demonstrated a half-life (t1/2) ranging from 16 to 35 h, rapid absorption and dose proportionality. No biochemical or radiological responses were identified; neither endocrine biomarker levels nor circulating tumour cell counts were altered by ASP9521. Given the lack of observable clinical activity, the study was terminated without implementing a planned 12-week dose expansion part at selected doses or a planned food-effect study part. Conclusions: In patients with mCRPC, ASP9521 demonstrated dose-proportional increase in exposure over the doses evaluated, with an acceptable safety and tolerability profile. However, the novel androgen biosynthesis inhibitor showed no relevant evidence of clinical activity.