Annual Meeting Proceedings Part 1 - American Society of Clinical ...

4548 Poster Discussion Session (Board #2), Mon, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
A phase I study of the androgen signaling inhibitor ARN-509 in patients
with metastatic castration-resistant prostate cancer (mCRPC). Presenting
Author: Dana E. Rathkopf, Sidney Kimmel Center for Prostate and Urologic
Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY
Background: ARN-509 is a novel small molecule AR antagonist that impairs
AR nuclear translocation and binding to DNA, inhibiting tumor growth and
promoting apoptosis, with no partial agonist activity. (Clegg et al., 2012)
We conducted a phase I trial to assess safety, pharmacokinetics (PK), and
determine the recommended phase II dose (RP2D). Methods: Eligible
patients with mCRPC received ARN-509 orally on a continuous daily dosing
schedule. Seven doses (30, 60, 90, 120, 180, 240, and 300 mg) were
tested using standard 3x3 dose escalation criteria. Once drug concentrations
were achieved that met or exceeded optimal levels predicted
preclinically, an additional 2 dose levels were tested to further confirm the
safety margin of ARN-509 (390 and 480 mg). Anti-tumor activity was
assessed by PSA, radiographic responses, and FDHT-PET imaging. Results:
Thirty patients were enrolled. The most common grades 1-2 treatmentrelated
adverse events were fatigue (38%), nausea (29%), and pain (24%).
There was only 1 treatment-related grade 3 adverse event (abdominal pain)
at 300 mg, possibly related to a higher pill burden. PK was shown to be
linear and dose-dependent. At 12 weeks, 42% of patients have had � 50%
PSA declines. Eleven (37%) patients have discontinued the study due to
progression, with the longest patient still on study for more than 16
months. FDHT-PET imaging demonstrated AR blockade at 4 weeks across
multiple dose levels. Conclusions: In this phase I study, ARN-509 was
shown to be safe and well tolerated with linear PK. Based on promising
activity across all dose levels and pharmacodynamic evidence of AR
antagonism, an optimal biologic dose of 240 mg daily was selected for
phase II investigation. DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals.
4550 Poster Discussion Session (Board #4), Mon, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Tasquinimod and survival in men with metastatic castration-resistant
prostate cancer: Results of long-term follow-up of a randomized phase II
placebo-controlled trial. Presenting Author: Andrew J. Armstrong, Duke
Cancer Institute, Durham, NC
Background: Tasquinimod (T) is an oral quinoline-3-carboxamide derivative
that binds S100A9 protein and has preclinical anti-angiogenic and
anti-tumor activity. Between 12/07-6/09, 201 (134 T, 67 Placebo (P))
men with metastatic CRPC were randomized and received treatment
once-daily at an initial dose of 0.25 mg/day escalated to 1.0 mg/day over 4
weeks. Placebo patients could cross over to T after 6 months or at disease
progression. The primary endpoint of improved PCWG2 criteria-defined
progression at 6 months was met (69 vs. 37% of patients (T/P) were
progression free) with PFS of 7.6 vs. 3.3 months for pts on T vs. P1 with
acceptable toxicity. This abstract provides the first analysis on symptomatic
progression, overall survival (OS) as well as a multivariate analysis for PFS
and OS. Methods: Survival data were collected between June 2011 and
January 2012 with a median time to censoring of 32 months. Survival data
was also evaluated in an exploratory multivariate model of known prognostic
factors in CRPC. Results: An imbalance of several baseline prognostic
criteria favored placebo (e.g. baseline PSA of 29 vs. 19 (T/P)) (JCO
2011;20:4022). Time to symptomatic progression was longer in T treated
patients (p�0.039, HR�0.42). Record of death (97 events) or survival
�13 months was documented in 182 patients. Median time to death was
34.2 vs. 30.2 months (T/P). Median time to death in the PCWG2
bone-metastatic subgroup (N�92/44) was 34.2 vs. 25.6 months. A
multivariate analysis of known prognostic factors including PSA, LDH, PSA
kinetics, and hemoglobin demonstrated an adjusted HR for PFS of 0.54
(95% CI 0.37,0.81) and OS of 0.72 (95% CI 0.46,1.12) in the total
population and 0.63 (95% CI 0.37,1.07, n�136) in the bone-metastatic
group. Conclusions: OS observed after tasquinimod treatment is longer than
previously reported in this patient population. The current exploratory data
indicates that the prolongation in PFS observed with tasquinimod treatment
may lead to a survival advantage in men with metastatic CRPC. A
phase III placebo-controlled study (NCT01234311) is ongoing in men with
bone-metastatic CRPC powered to detect an OS improvement.
Genitourinary Cancer
289s
4549 Poster Discussion Session (Board #3), Mon, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Safety and activity of the investigational agent orteronel (ortl) without
prednisone in men with nonmetastatic castration-resistant prostate cancer
(nmCRPC) and rising prostate-specific antigen (PSA): Updated results of a
phase II study. Presenting Author: Daniel J. George, Duke University
Medical Center, Durham, NC
Background: Ortl is an investigational, oral, non-steroidal selective 17,20lyase
inhibitor that suppresses androgen production. Ortl affects cortisol
synthesis less than similar agents due to limited inhibition of 17�hydroxylase,
and may permit steroid-free dosing. Ortl 300 mg BID was
examined in patients (pts) with nmCRPC and rising PSA. Methods: Eligible
pts had nmCRPC with PSA �2 ng/mL (PSA �8 ng/mL if doubling time �8
mo), and surgical/medical castration, with testosterone (T) �50 ng/dL.
Prior chemotherapy, ketoconazole, or concomitant corticosteroids were
excluded. Starting dose of ortl was 300 mg BID and continued until PSA
progression, metastases, or unacceptable toxicity. The primary endpoint
was the percentage of pts with PSA �0.2 ng/mL after 3 mo. Secondary
endpoints included safety, PSA kinetics, time to metastases, changes in
endocrine markers and circulating tumor cells (CTCs). Results: 39 pts were
enrolled with baseline demographics including median age 71 y, ECOG PS
�1, median PSA 12.1 ng/mL (range 2.6-67.8), T 7.9 ng/dL (1.4–17.3),
and ACTH 19 ng/L (n�33; 0-47); 3 pts had dose reduction due to adverse
events (AEs). Gr �3 AEs occurred in 16 pts (drug-related in 14); Gr �3 AEs
�5% were dyspnea (8%), hypertension (13%), fatigue, hypokalemia,
pneumonitis (5% ea). 7 pts (18%) had serious AEs; most common was
pneumonitis (2�Gr 3, 1�Gr 2). 8 pts discontinued due to AEs; 2 pts
required corticosteroids. At 3 mo, 6 pts (16%) achieved PSA �0.2 ng/mL;
PSA50 and PSA90 rates were 76% and 32%, respectively; median PSA
declined by 83% (n�34); median T declined by 89% to 0.78 ng/dL
(n�31), and median ACTH increased by 171% to 43 ng/L; median cortisol
declined by 21%. At 6 mo, PSA50 and PSA90 rates were 45% and 21%,
respectively. Median time to PSA progression was 14.8 mo. 17 pts (44%)
were on treatment �6 mo. Of 37 pts with baseline CTC/7.5 mL assessed,
only 1 had CTC �5 and converted to �5; 6 had 1–4 CTCs at baseline, none
converted to �5 during treatment. Conclusions: Ortl without steroids
produces marked and durable declines in T and PSA, has manageable
toxicities, and is feasible in men with nmCRPC.
4551 Poster Discussion Session (Board #5), Mon, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Radium-223 chloride (Ra-223) impact on skeletal-related events (SREs)
and ECOG performance status (PS) in patients with castration-resistant
prostate cancer (CRPC) with bone metastases: Interim results of a phase III
trial (ALSYMPCA). Presenting Author: A. Oliver Sartor, Tulane Cancer
Center, New Orleans, LA
Background: Ra-223, a 1st-in-class alpha-pharmaceutical, targets bone
metastases (mets) with high-energy alpha-particles of short range (�100
�m). ALSYMPCA, a phase III, double-blind, randomized, multinational
study, compared Ra-223 plus best standard of care (BSC) v placebo (pbo)
plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint
was OS; secondary endpoints included SREs and ECOG PS. Methods:
Eligible pts had progressive, symptomatic CRPC with � 2 bone mets on
scintigraphy and no known visceral mets; were receiving BSC; and either
previously received docetaxel, were docetaxel ineligible, or refused docetaxel.
Pts were randomized 2:1 to 6 injections of Ra-223 (50 kBq/kg IV)
q4 wks or matching pbo and stratified by prior docetaxel use, baseline ALP
level, and current bisphosphonate use. Results: 921 pts were randomized
from 6/2008-2/2011. In a planned interim analysis (n � 809), Ra-223
significantly improved OS v pbo (median OS 14.0 v 11.2 mo, respectively;
two-sided P � .00185; HR � .695; 95% CI, .552-.875).SREs were lower
in the Ra-223 v pbo group, and time to 1st SRE was significantly delayed
(median time to SRE 13.6 mo v 8.4 mo, respectively; P � .00046; HR �
.610; 95% CI, .461-.807). The proportion of pts with ECOG PS deterioration
(� 2 points) was less in Ra-223 v pbo group at Wk 12 and Wk 24 (4%,
15/389 v 9%, 16/180 and 7%, 16/236 v 12%, 10/83, respectively). Time
to ECOG PS deterioration (� 2 points) was significantly delayed by Ra-223
v pbo (P � .003; HR � .62; 95% CI, .46-.85). Conclusions: Ra-233
significantly delayed time to 1st SRE and SRE components, notably SCC.
Fewer pts in the Ra-223 group had ECOG PS deterioration. Ra-223
improves OS with excellent safety and may provide a new standard of care
for CRPC pts with bone mets.
Time to 1st event
No. (%) of patients
(Ra-223 vs Pbo)
Ra-223 Pbo
HR
SRE component
n � 541 n � 268 p value* (95%CI)
External beam radiotherapy 122 (23) 72 (27) .0038 .65
(.48-.87)
Spinal cord compression 17 (3) 16 (6) .016 .44
(.22-.88)
Pathologic bone fracture 20 (4) 18 (7) .013 .45
(.24-.86)
Surgical intervention 9 (2) 5 (2) .69 .80
(.27-2.4)
*Not adjusted for multiplicity.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.