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.

Abstract

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 anti-tumour 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.

• Authors: Yohann Loriot, Karim Fizazi, Robert J Jones, Jan Van den Brande, Rhoda L Molife, Aurelius Omlin, Nicholas D James, Edwina Baskin-Bey, Marten Heeringa, Benoit Baron, Gertjan M Holtkamp, Taoufik Ouatas, Johann S De Bono
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 5 Pg. 995-1004 (Oct 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24771350 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(1-((5-methoxy-1H-indol-2-yl)carbonyl)piperidin-4-yl)-2-methylpropan-2-ol
• Androgen Antagonists
• Antineoplastic Agents
• Indoles
• Piperidines
• Dihydrotestosterone
• Testosterone
• 3-Hydroxysteroid Dehydrogenases
• Hydroxyprostaglandin Dehydrogenases
• AKR1C3 protein, human
• Aldo-Keto Reductase Family 1 Member C3
• KLK3 protein, human
• Kallikreins
• Prostate-Specific Antigen

Topics

• 3-Hydroxysteroid Dehydrogenases (antagonists & inhibitors)
• Aged
• Aldo-Keto Reductase Family 1 Member C3
• Androgen Antagonists (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Antineoplastic Agents (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Cell Count
• Dihydrotestosterone (blood)
• Humans
• Hydroxyprostaglandin Dehydrogenases (antagonists & inhibitors)
• Indoles (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Kallikreins (blood)
• Male
• Middle Aged
• Piperidines (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Prostate-Specific Antigen (blood)
• Prostatic Neoplasms, Castration-Resistant (blood, drug therapy, pathology)
• Testosterone (blood)
• Treatment Outcome