AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer - results of two parallel first-in-human phase I studies.
BACKGROUND
AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD).


METHODS
In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule.


RESULTS
In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (≥50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1.


CONCLUSIONS
AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.
Prostate Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, UK.
A
A
Omlin
R J
RJ
Jones
R
R
van der Noll
T
T
Satoh
M
M
Niwakawa
S A
SA
Smith
J
J
Graham
M
M
Ong
R D
RD
Finkelman
J H M
JH
Schellens
A
A
Zivi
M
M
Crespo
R
R
Riisnaes
D
D
Nava-Rodrigues
M D
MD
Malone
C
C
Dive
R
R
Sloane
D
D
Moore
J J
JJ
Alumkal
A
A
Dymond
P A
PA
Dickinson
M
M
Ranson
G
G
Clack
J
J
de Bono
T
T
Elliott
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000000981:diagnostic imaging / Q000188:drug therapy*; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011859:Radiography; D011944:Receptors, Androgen / Q000378:metabolism*
C410798:AR protein, human; C583656:AZD3514; D000970:Antineoplastic Agents; D011724:Pyridazines; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen