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

4556 Poster Discussion Session (Board #10), Mon, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Cytoreduction and androgen signaling modulation by abiraterone acetate
(AA) plus leuprolide acetate (LHRHa) versus LHRHa in localized high-risk
prostate cancer (PCa): Preliminary results of a randomized preoperative
study. Presenting Author: Eleni Efstathiou, University of Athens, Athens,
Greece; University of Texas M. D. Anderson Cancer Center, Houston, TX
Background: Endocrine to “intracrine” androgen signaling transition, a
milestone in the lethal progression of PCa, has not been characterized in
localized high risk disease. Signaling heterogeneity under the selective
pressure of castration may account for response differences. Methods: A
single institution preoperative study of 12 weeks AA 1g/prednisone 5 mg �
LHRHa compared to LHRHa (randomized 2:1) was conducted in patients
(pts) with high risk PCa (clinical stage �T1c and biopsy Gleason score �8,
or �T2b, Gleason � 7 and PSA � 10ng/ml). Primary aim: Assess
difference in down staging (� ypT2) and safety. Secondary aims: Assess
difference in androgen biosynthesis, androgen signaling (AR, AR variants,
NKX 3.1, ERG, PSA) proliferation apoptosis and candidate treatment
resistance pathways. Results: We report on 37 (50 enrolled) pts who had
prostatectomy. AA�LHRHa was given to 25pts, LHRHa to 12. Median age
is 61 ys (46-74). Preoperative PSA was �0.1ng/ml in 17/25 (68%)
AA�LHRHa vs 0/12 LHRHa (p 0.0001). ypT2N0 occurred in 15/25 (60%)
AA�LHRHa treated pts vs 4/12 (33%) LHRHa (p 0.17). Near complete
cytoreduction (�6mm scattered cells) occurred in 6/25 (24%) AA�LHRHa
vs 1/12 (8%) LHRHa. Lymph node infiltration in 7/25 (28%) AA�LHRHa
vs 6/12 (50%) LHRHa. Margin positivity in 2/25 (8%) AA�LHRHa vs 4/12
(33%) LHRHa (p 0.07). Grade 3 AA related AEs: elevated AST/ALT 4
(discontinued AA), hypertension 3. One AA�LHRHa pt had postop pulmonary
embolism. Androgen signaling and proliferation suppression is more
profound in AA�LHRHa treated remaining tumor cells (Table). Conclusions:
Addition of AA to LHRHa results in greater cytoreduction, suppression of
PSA and androgen signaling compared to LHRHa in high risk PCa. Findings
support the hypothesis that intracrine androgen signaling is a therapy target
in patients with untreated PCa and form the foundation for a marker driven
treatment strategy.
Mean tumor expression (involvement)% by IHC (standard deviation).
Marker AA�LHRHa LHRHa P value Wilcoxon
AR 27 (26) 69 (22.3) 0.0001
Nkx3.1 50 (29.8) 83 (14.3) 0.002
CYP17 64 (22) 75 (14.4) 0.13
Ki67 3.4 (5) 8.6 (5.7) 0.003
4558 Poster Discussion Session (Board #12), Mon, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Exploratory analysis of survival benefit and prior docetaxel (D) treatment in
COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone
(P) in metastatic castration-resistant prostate cancer (mCRPC). Presenting
Author: Oscar B. Goodman, National Cancer Institute, Las Vegas, NV
Background: AA, a selective androgen biosynthesis inhibitor, blocks the
action of CYP17, thereby inhibiting adrenal and intratumoral androgen
production. AA has demonstrated improved overall survival (OS) by 4.6
months (mos) vs placebo (HR�0.74) in patients (pts) previously treated
with D. Methods: COU-AA-301 is a randomized double blind study of AA (1
g) � P (5 mg po BID) vs placebo � P administered to mCRPC pts post-D
with a primary endpoint of OS. To further evaluate primary survival result
robustness, we performed post hoc exploratory analyses to assess whether
the timing of first and last dose of D and reason for D discontinuation
impacted OS. Results: At randomization, treatment arms were balanced
with respect to baseline characteristics, prior D use, and reasons for
discontinuation. In both arms, almost half (45%) discontinued D due to
progressive disease (PD); remainder discontinued D after completing all
planned cycles (37%), due to toxicity (12%), or for other reasons (5%) per
investigator. Median OS from first and last dose of D were longer with AA vs
placebo (Table). Median OS was longer with AA vs placebo in pts who
discontinued D for PD, or for all other reasons. Conclusions: These
exploratory analyses suggest that the OS benefit of AA in mCRPC was
maintained when calculated from first or last dose of prior D, and whether
or not pts discontinued D for PD. Pts in AA arm of this study had a
prolonged median OS of � 32 mos from time of initial D therapy. Congruity
among these analyses and lack of dependence on D timing demonstrate
robustness of the primary survival result.
Median OS, mos (95% CI)
Category a
AA
(N�797)
Placebo
(N�398)
Time from D b
From first dose D 32.6 (30.7, 35.0) 27.6 (25.9, 30.3)
HR � 0.75 (0.65, 0.88); p�0.0002
From last dose D 23.2 (22.4, 24.5) 19.4 (17.5, 20.8)
HR � 0.74 (0.64, 0.86); p �0.0001
Reason for D discontinuation c
PD 14.2 (12.0, 15.8) 10.5 (9.3, 11.8)
HR � 0.77 (0.62, 0.97); p�0.0222
All other reasons 17.0 (15.6, 18.2) 12.6 (10.4, 14.9)
HR � 0.73 (0.59, 0.89); p�0.0025
a
Investigator reported (limited source verification);
b
calculated from first or last dose of D;
c
calculated
from randomization.
Genitourinary Cancer
4557 Poster Discussion Session (Board #11), Mon, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Time to testosterone (T) and PSA rises during first “off treatment” interval
(1OFF-2ON) of intermittent androgen deprivation (IAD) as prognostic for
time to castration resistance (CRPC) and prostate cancer mortality (PCM) in
men with biochemical relapse (BR). Presenting Author: Evan Y. Yu, Fred
Hutchinson Cancer Research Center, Seattle, WA
Background: A recent phase III trial of intermittent vs. continuous AD
supports IAD as standard of care for men treated with AD for BR. To identify
potential prognostic factors during 1OFF, times to T and PSA rises from our
prospective trial of IAD in men with BR were analyzed in relation to times to
CRPC and PCM. Methods: 72 men with BR after definitive local therapy
were treated with IAD, each cycle consisting of 9 months of leuprolide and
flutamide followed by a variable “off treatment” interval. T and PSA were
followed monthly; AD was resumed when PSA reached a pre-specified
value. Cycles repeated until CRPC, defined as �2 PSA rises with T�50
ng/dL. Markers of interest from 1OFF-2ON were time to first T�50, time
from first T�50 to first PSA rise �0.1 ng/mL, time to first PSA rise �0.1,
and PSA doubling time (PSAdt), calculated using the first 3 PSA measurements
starting from first PSA �0.1. The associations of these markers with
CRPC and PCM were evaluated using Cox proportional hazards models (or
logistic regression if the Cox proportional hazards assumption was not met),
controlling for age at study entry and Gleason score categorized to �7 or
�7. Results: A 30-day increase in time to first T�50 was significantly
associated with a 75% increase in the risk of PCM. A 30-day increase in
time to PSA rise from 1OFF or after T�50 was significantly associated with
a 23% or 72% reduction in the risk of CRPC, respectively. While neither of
the associations of PSAdt with CRPC or PCM were significant, they were of
moderate size: PSAdt displayed a moderate reduction in risk of CRPC by
35% and PCM by 38%. Conclusions: During the first “off treatment”
interval of IAD, the time to first T�50 is prognostic for PCM. Time to first
PSA rise after 1OFF and after first T�50 are both prognostic for CRPC.
Time to CRPC Time to PCM
Marker
N HR P value 95% CI N HR P value 95% CI
1OFF to T>50
T>50 to PSA>0.1
46
45
1.1
0.28
0.67
0.05
(0.71, 1.7)
(0.08, 0.99)
49
48
1.75
0.28
0.01
0.19
(1.14, 2.68)
(0.03, 1.63) ��
1OFF to PSA>0.1 57 0.77 0.01 (0.63, 0.93) 60 0.85 0.24 (0.65, 1.11)
PSAdt 49 0.65 0.08 (0.4, 1.06) 52 0.62 0.29 (0.26, 1.5)
�� Odds ratio.
291s
4559 Poster Discussion Session (Board #13), Mon, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
The effect of PSA frequency and duration on PSA doubling time (PSADT)
calculations in men with biochemically recurrent prostate cancer (BRPC)
after definitive local therapy. Presenting Author: Channing Judith Paller,
The Johns Hopkins Hospital, Baltimore, MD
Background: The prognostic nature of PSADT in men with BRPC makes it an
attractive intermediate endpoint for assessing novel therapies in these
patients. Although a number of investigational agents appear to favorably
modulate PSADT, slowing in PSADT has also been observed in placebotreated
men. We aimed to determine whether PSADT calculations could be
influenced by the frequency and duration of PSA measurements. Methods:
We performed a retrospective analysis of men with BRPC who chose to
defer hormonal therapy. Eligible men were those with PSA values �0.2
ng/mL and at least 6 values taken on average 3 mo apart, and whose local
prostate cancer therapy was completed �1 year prior. To examine the
influence of PSA frequency and duration on PSADT, we calculated median
PSADT using different subsets of available PSA values (e.g. each vs every
other; and first 3 vs. remaining PSA values). Results: After a median
follow-up of 58 mo (range, 6-185 mo), 213 men with BRPC had �6 PSA
values and 127 men had �9 PSA values for analysis. Men (77% white,
23% black/other) had a median age of 61 y with Gleason score distribution
as follows (�6: 30%; 7: 40%; �8: 18%; NOS: 12%). For men with �6
data points: PSADT calculated using earlier values ranged from 13.2 to
16.6 mo, compared to 16.6 to 17.8 mo, respectively, for the remaining
values (within-patient change range: 0.6-1.2 mo). For men with �9 data
points: PSADT calculated using earlier values ranged from 15.3 to 19.9 mo
compared to 22.1 to 22.3 mo, respectively, for the remaining values
(within-patient change range: 3.5 to 4.5 mo). When we examined the
frequency of PSADT by using every other value, we found little difference
(22.3 vs 22.1 mo). Conclusions: These data show that PSADT appears to
increase even in the absence of therapy, and may be influenced by duration
of PSA follow up. This finding explains PSADT slowing on placebo arms and
calls into question the utility of PSADT as a surrogate endpoint. Placebocontrolled
trials and the use of standard clinical endpoints are recommended
to screen novel agents in men with BRPC to mitigate bias because
of natural PSADT variability.
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