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

282s Genitourinary Cancer
4520 Clinical Science Symposium, Sat, 8:00 AM-9:30 AM
Neoadjuvant androgen pathway suppression prior to prostatectomy. Presenting
Author: Elahe A. Mostaghel, Fred Hutchinson Cancer Research Center,
Seattle, WA
Background: Optimizing tissue androgen suppression may provide better
local and systemic control of prostate cancer (PCa). Standard androgen
deprivation therapy (ADT) has limited effect on tissue androgens which
remain in a range which supports tumor survival. We determined whether
targeting androgen metabolism using CYP17 and 5a-reductase (SRD5A)
inhibitors would more effectively suppress tissue androgens and tumor
volume. Methods: Open label, multicenter neoadjuvant study in men with
localized PCa treated for 3 months prior to prostatectomy with zoladex and
1) avodart 3.5 mg QD; 2) avodart and casodex 50 mg QD; or 3) casodex,
avodart and ketoconazole 200 mg TID. Serum and tissue androgens were
measured by LC/MS/MS. Data were compared to men treated with standard
ADT (LHRH agonist plus Casodex), and untreated prostatectomy tissue.
The primary outcome measure was suppression of tissue dihydrotestosterone
(DHT). Results: 35 men with intermediate/high risk PCa were enrolled.
Tissue DHT was suppressed 30 fold (� 95%) in all groups vs. LHRH
agonist/Casodex (0.92 � 0.20 pg/mg vs. 0.03� 0.03 for all groups
combined, p�0.0001). Tissue testosterone was 3-4 fold higher (consistent
with SRD5A inhibition) in all treatment groups vs. LHRH agonist/Casodex
(0.33 vs. 0.07 pg/mg, p � 0.05). Differences in DHT/T between groups 1
through 3 were not statistically significant. There was no correlation
between tissue and serum androgens, or tissue androgen and tumor volume
(p� 0.05). In subset analysis, total serum DHEA declined significantly in
group 3, with free DHEA unchanged, suggesting differential effect on free
and total DHEA. Pathologic complete response (CR) was seen in 2 men,
and an additional 8 men had �0.2 cc of tumor, with the largest number of
CR or near CR in the cohort treated with ADT, CYP17 and SRD5A inhibitor,
4 of 12 men (33%). Due to small cohort size, differences were not
statistically significant. Conclusions: Addition of high dose SRD5A inhibition
(with and without CYP17 inhibition) achieves prostate DHT levels 30
fold below standard ADT. In this relatively high risk population, CR or near
CR was seen in 10 of 35 men receiving protocol therapy. Further
suppressing the androgen receptor signaling axis may provide better local
and systemic control of PCa.
4522 Poster Discussion Session (Board #1), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Time from prior chemotherapy (TFPC) as a prognostic factor in advanced
urothelial carcinoma (UC) receiving second-line systemic therapy. Presenting
Author: Gregory R. Pond, McMaster University, Hamilton, ON, Canada
Background: Prognostic factors for overall survival (OS) in patients receiving
second-line chemotherapy for advanced platinum-pretreated UC include
ECOG performance status (PS) �0, hemoglobin (Hb) �10g/dL and the
presence of liver metastasis (LM) (Bellmunt J, J Clin Oncol 2010). We
hypothesized that time from prior chemotherapy (TFPC) independently
impacts OS. Methods: Of 11 available phase II trials evaluating second-line
therapy for advanced UC (n�698), 6 trials with available baseline Hb, PS
and LM were utilized (n�534). The trials evaluated vinflunine (2 trials),
docetaxel plus vandetanib or placebo, paclitaxel-gemcitabine, nanoparticlealbumin-bound
paclitaxel and paclitaxel-cetuximab. The Kaplan-Meier
method was used to estimate OS from date of starting second-line therapy.
Cox proportional hazards regression stratified for trial was used to evaluate
the prognostic effect of factors on OS. TFPC was evaluated as a continuous
variable, and based on cutpoints of 3, 6, 9 and 12 months (mo) from prior
chemotherapy to first study treatment. The choice of optimal cutpoint for
TFPC was determined by the maximum likelihood ratio �2 statistic. Results:
Overall, 513 patients were evaluable. 64.1% received prior chemotherapy
for metastatic disease. Median OS was 6.8 mo (95% CI: 6.1 to 7.4); range
was 0 to 84.2 mo. Median OS was 5.2, 7.1, 8.8, 7.6 and 10.6 mo
respectively for TFPC �3 (n�181), 3 to �6 (n�133), 6 to �9 (n�77), 9
to �12 (n�45) and �12 (n�77) mo, respectively. Shorter TFPC was
independently prognostic for decreased survival. The optimal cutpoint for
TFPC was �3 mo, but no well-defined plateau was observed. PS�0
(HR�1.72, p�0.001), LM (HR�1.41, p�0.002), Hb �10 g/dl (HR�1.59,
p�0.001) and TFPC �3 mo (HR�1.67, p�0.001) were significantly
prognostic in the multivariate model. Timing of prior chemotherapy
(metastatic disease vs. perioperative) was not prognostic. Conclusions: A
shorter duration of TFPC exhibited a significant negative prognostic impact
on OS independent of known prognostic factors in patients receiving
second-line therapy for advanced UC. If externally validated, TFPC should
be a stratification factor in trials of second-line therapy for advanced UC.
4521 Clinical Science Symposium, Sat, 8:00 AM-9:30 AM
Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate
(LHRHa) on PSA, pathological complete response (pCR), and near pCR in
localized high-risk prostate cancer (LHRPC): Results of a randomized
phase II study. Presenting Author: Mary-Ellen Taplin, Dana-Farber Cancer
Institute, Boston, MA
Background: LHRPC is infrequently cured with prostatectomy (RP). To date
neoadjuvant androgen deprivation therapy (ADT) has not improved outcomes
and residual intra-prostatic androgens remain. AA lowers serum
testosterone (T) and DHT to � 1 ng/dL and has improved survival in
advanced PC. Methods: We conducted a neoadjuvant, phase II trial of
AA/LHRHa in LHRPC. The primary aim was to evaluate intra-prostatic
T/DHT with LHRHa vs LHRHa/AA. We report secondary endpoints of PSA,
pCR and near pCR ([� 5mm residual tumor]) and safety. Eligibility: � 3
positive biopsies and either Gleason � 7(4�3), T3, PSA � 20 ng/mL or
PSA velocity � 2 ng/mL/year. For the first 12 wks men were randomized to
LHRHa or LHRHa/AA/prednisone (P) 5mg qd. After 12 wks, a prostate
biopsy was done to measure T/DHT. Men received 12 more wks of
LHRHa/AA/P followed by RP. Results: 58 men enrolled: 28 to initial LHRHa
and 30 to initial AA/LHRHa. 2 withdrew prior to RP (1/group). Median age
was 58 (50-75). pCR/near pCR was 14/56 (25%). Grade 3 AEs included
elevated AST/ALT 5/58 (9%) and hypokalemia 3/58 (5%). No grade 4
mineralocorticoid-related AEs were observed. Conclusions: Neoadjuvant
ADT with AA was well tolerated in LHRPC. PSA (�0.2) declines were high
and achieved earlier on AA/LHRHa compared to LHRHa. The pCR/near pCR
rates were higher for 24 wks AA (34%) than 12 wks AA (15%). No new
safety signals were seen with AA used with P 5 mg. These results support
further evaluation of aggressive ADT as neoadjuvant/adjuvant therapy for
LHRPC.
Baseline
12 wks AA/
24 wks LHRHa
n� 28
24 wks AA/
24 wks LHRHa
n�30
Gleason: 7/8/9/10 8/10/10/0 9/7/11/3
PSA (median) 10.6 6.8
PSA: < 10/10-20/> 20 12/9/7 20/6/4
Elevated PSA velocity 6 3
Stage T3 8 6
Results n�27 n�29
PSA: wk 4/8/12/16/20/24 4.34/1.35/1.06/0.20/0.09/0.06 0.65/0.17/0.10/0.09/0.06/0.05
12 wk nadir PSA < 0.2 1/27 (4%) 26/29 (90%) p�0.0001
24 wk nadir PSA < 0.2 23/27 (85%) 25/29 (86%) p�0.9131
pCR 1/27 (4%) 3/29 (10%) p�0.3349
Near pCR (tumor < 5mm) 3/27 (11%) 7/29 (24%) p�0.2034
Total pCR/near pCR 4/27 (15%) 10/29 (34%) p�0.0894
pT3 16/27 14/29
Positive nodes 3/27 (11%) 7/29 (24%)
Positive margins 5/27 (19%) 5/29 (17%)
4523 Poster Discussion Session (Board #2), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Neoadjuvant chemotherapy with DD-MVAC and bevacizumab in high-risk
urothelial cancer: Results from a phase II trial at the University of Texas
M. D. Anderson Cancer Center. Presenting Author: Arlene O. Siefker-
Radtke, University of Texas M. D. Anderson Cancer Center, Houston, TX
Background: DD-MVAC has shown an improved 5-year survival in metastatic
urothelial cancer; however, there is no prospective data on its use in the
neoadjuvant setting. Previous work suggested that over-expression of VEGF
was associated with a high risk of relapse in our neoadjuvant patients,
leading to the hypothesis that combining a VEGFR inhibitor with chemotherapy
may improve patient outcomes. Methods: Between 8/07 and
12/10, 60 patients with urothelial carcinoma of the bladder or upper tract
tumor were enrolled on a prospective phase II clinical trial. Eligibility
requirements included at least one of the following: 3-D mass on EUA
(cT3b disease), LVI, hydronephrosis, micropapillary features, tumor in a
diverticula, and for upper tract tumors a high grade tumor or radiographically
measurable sessile mass. The primary endpoint was pathologic
down-staging to ��pT1N0M0. Results: Forty-four patients with bladder/
urethral tumors and 16 patients with upper tract tumors were enrolled.
Pathologic down-staging to �� pT1N0M0 occurred in 53% of patients
overall (bladder/urethra 45%, upper tract 75%), and to �� pT0N0M0 in
38% overall (bladder/urethra 39%, upper tract 38%). At a median
follow-up of 26 months, the 2-year OS and DSS was 78% and 82%,
respectively (bladder 2-yr OS and DSS 75%, 78%; upper tract 93%, 93%).
The median OS and DSS have not yet been reached. The most common
grade 3 or greater toxicity was neutropenia in 27% of patients, followed by
fatigue in 10%. The following grade 3 toxicities were observed in � 10% of
patients: mucositis, DVT/PE, hypertension, nausea/vomiting, thrombocytopenia.
One patient experienced cardiac ischemia. Conclusions: Neoadjuvant
chemotherapy leads to pathologic down-staging in 45% of patients
with bladder cancer. DD-MVAC appears an acceptable alternative to
traditional M-VAC in the neoadjuvant setting. Although bevacizumab did
not impact down-staging based upon historical expectations, determining
the effect on recurrence requires longer follow-up.
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