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.
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.


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.
Institute Gustave Roussy, Department of Cancer Medicine, University of Paris Sud, Villejuif, France, yohann.loriot@gustaveroussy.fr.
Yohann
Y
Loriot
Karim
K
Fizazi
Robert J
RJ
Jones
Jan
J
Van den Brande
Rhoda L
RL
Molife
Aurelius
A
Omlin
Nicholas D
ND
James
Edwina
E
Baskin-Bey
Marten
M
Heeringa
Benoit
B
Baron
Gertjan M
GM
Holtkamp
Taoufik
T
Ouatas
Johann S
JS
De Bono
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000368:Aged; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000726:Androgen Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002452:Cell Count; D013196:Dihydrotestosterone / Q000097:blood; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007610:Kallikreins / Q000097:blood; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D013739:Testosterone / Q000097:blood; D016896:Treatment Outcome
C000598424:1-(1-((5-methoxy-1H-indol-2-yl)carbonyl)piperidin-4-yl)-2-methylpropan-2-ol; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D007211:Indoles; D010880:Piperidines; D013196:Dihydrotestosterone; D013739:Testosterone; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen