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

280s Genitourinary Cancer
LBA4512 Oral Abstract Session, Tue, 9:45 AM-12:45 PM
Updated analysis of the phase III, double-blind, randomized, multinational
study of radium-223 chloride in castration-resistant prostate cancer
(CRPC) patients with bone metastases (ALSYMPCA). Presenting Author:
Chris Parker, The Royal Marsden NHS Foundation Trust, Sutton, United
Kingdom
The full, final text of this abstract will be available at
abstract.asco.org at 12:01 AM (EDT) on Monday, June 4,
2012, and in the Annual Meeting Proceedings online
supplement to the June 20, 2012, issue of Journal of
Clinical Oncology. Onsite at the Meeting, this abstract will
be printed in the Monday edition of ASCO Daily News.
4514 Oral Abstract Session, Tue, 9:45 AM-12:45 PM
A randomized phase II study of OGX-427 plus prednisone (P) versus P
alone in patients (pts) with metastatic castration resistant prostate cancer
(CRPC). Presenting Author: Kim N. Chi, British Columbia Cancer Agency,
Vancouver, BC, Canada
Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone
protein that regulates cell signaling and survival pathways implicated
in cancer progression. In prostate cancer models, Hsp27 complexes with
androgen receptor (AR) and enhances transactivation of AR-regulated
genes. OGX-427 is a 2nd generation antisense oligonucleotide that inhibits
Hsp27 expression with in vitro and in vivo efficacy and was well tolerated
with single agent activity in phase I studies. Methods: Chemotherapy-naïve
pts with no/minimal symptoms were randomized to receive OGX-427 600
mg IV x 3 loading doses then 1000 mg IV weekly with P5mgPOBIDorP
only. Primary endpoint was the proportion of pts progression free (PPF) at
12 weeks (PCWG2 criteria). A 2-stage MinMax design (H0 � 5%, HA �20%, ��0.1, ��0.1) with 32 pts/arm provides 70% power to detect the
difference at 0.10 1-sided significance. Secondary endpoints include PSA
decline, measurable disease response, and circulating tumour cell (CTC)
enumeration. Results: 38 pts have been enrolled; 1st stage of accrual
completed with 2nd stage accruing. In the 1st 32 pts randomized (17 to
OGX-427�P, 15 to P), baseline median age was 71 years (53-89), ECOG
PS 0 or 1 in 66% and 34% of pts, median PSA 66 (6-606), metastases in
bone/lymph nodes/liver or lung was 75/56/9%, 31% had prior P treatment,
and 93% had �5 CTC/7.5 ml. Predominantly grade 1/2 infusion reactions
(chills, diarrhea, flushing, nausea, vomiting) occurred in 47% of pts
receiving OGX-427�P. One pt on OGX-427�P developed hemolytic
uremic syndrome. A PSA decline of �50% occurred in 41% of pts on
OGX-427�P, and 20% of pts treated with P. A measurable disease partial
response was seen in 3/8 (38%) evaluable pts on OGX-427�P and 0/9 pts
on P. CTC conversion from �5 to�5/7.5 ml occurred in 50% of pts on
OGX-427�P and 31% treated with P. Thus far, in 26 evaluable pts the PPF
at 12 weeks was 71% (95% CI: 42-92) in OGX-427�P treated pts and
33% (95% CI: 10-65) in pts on P. Conclusions: These data provide clinical
evidence for the role of Hsp27 as a therapeutic target in prostate cancer
and support continued evaluation of OGX-427 for pts with CRPC. Funded
by a grant from the Terry Fox Research Institute.
4513 Oral Abstract Session, Tue, 9:45 AM-12:45 PM
Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration
resistant prostate cancer (mCRPC): Results from a phase II nonrandomized
expansion cohort (NRE). Presenting Author: Matthew R. Smith, Massachusetts
General Hospital Cancer Center, Boston, MA
Background: Cabozantinib (cabo) inhibits MET and VEGFR2. High rates of
bone scan resolution, pain relief and overall disease control, independent
of PSA changes, were previously reported in a phase II study in mCRPC
patients (pts). This is a NRE cohort in docetaxel (D)-pretreated pts with a
novel primary endpoint of bone scan response based on computer-aided
quantitative assessment of bone scan lesion area (BSLA) and a doublereader,
independent, blinded review (Nucl Med Commun, in press).
Methods: D-pretreated (�225 mg/m2 ) CRPC pts with bone metastasis were
required to have progressed in soft-tissue or bone within 6 months of last
dose of D. Pts received 100 mg cabo qd. Tumor response was assessed q6
wks. Bone scan response (BSR) was defined by a �30% decline in BSLA.
Pain intensity (worst pain over the past 24 hrs; BPI scale 0-10) and
interference with sleep and daily activity were prospectively assessed using
an IVR system. Analgesic use was collected by diary. Bone turnover markers
and CTCs were assessed. Results: 93 D-pretreated pts were enrolled (89
evaluable with �6 wks f/u). Median age was 67, 46% received cabazitaxel
and/or abiraterone, 32% had visceral disease, 51% had fatigue, and 18%
had anemia. 44% had worst pain �4 of which 95% were taking narcotics.
Median CTC count was 49 and 80% had �5. Median f/u was 125 days
(range, 23-305). Of 85 pts evaluable for BSR, 51 (60%) had a PR, 24
(28%) SD, 5 (6%) PD and 5 (6%) d/c’d prior to f/u scan. 21/30 pts (70%)
had reduction of measurable disease.16/33 pts (49%) with BPI �4 and
�12 wks f/u had pain reduction durable for �6 wks; 46% had decreased
narcotic use, including 27% who discontinued use. Sleep and daily activity
were improved in pts with pain relief. Among pts with elevated serum
levels, 74%, 67% and 47% had declines on treatment of �30% in CTx,
NTx and bALP, respectively. In 59 pts with CTCs �5, 92% had a decrease
of �30% and 39% converted to �5 CTCs at weeks 6 or 12. 12%
discontinued cabo due to AEs. Most common Gr 3/4 AEs were fatigue
(19%), nausea (10%) and anemia (10%). Conclusions: Cabo treatment
resulted in high rates of bone scan response, durable pain relief, and
reductions in bone turnover markers and CTCs in D-pre-treated CRPC pts
with bone metastases.
4515 Oral Abstract Session, Tue, 9:45 AM-12:45 PM
Prostate-specific antigen decline (PSA) as a surrogate for overall survival
(OS) in patients (pts) with metastatic castrate-resistant prostate cancer
(mCRPC) who failed first-line chemotherapy. Presenting Author: Susan
Halabi, Duke University Medical Center, Durham, NC
Background: PSA kinetics, and more specifically a 30% decline in PSA
following initiation of first-line chemotherapy with docetaxel, has been
reported to be a surrogate endpoint for OS in mCRPC pts. The objective of
this analysis was to evaluate PSA kinetics as surrogate endpoints for overall
survival (OS) in patients who were receiving second line chemotherapy
following progression after docetaxel front line therapy. Methods: Data from
a phase III trial of 755 mCRPC pts randomized to treatment with
cabazitaxel in combination with prednisone (C�P) every 3 weeks or
mitoxantrone in combination with prednisone (M�P) were used. All pts
were previously treated with a docetaxel-containing regimen. PSA decline
(�30% and �50% ) and PSA velocity within the first three months of
treatment were evaluated as potential surrogate endpoints for OS. The
proportional hazards (PH) model was used to test for Prentice’s criteria and
the proportion of treatment explained (PTE) was computed as a second test
of surrogacy. PTE was defined as one minus the ratio of the treatment
coefficient in the adjusted PH model (includes PSA decline or velocity) to
the treatment coefficient in the unadjusted PH model. Results: Of 755
men, 654 had sufficient PSA data to be included in the analysis. Treatment
arm (C�P vs. M�P) was prognostic of OS with a hazard ratio (HR) of 0.65
(95% CI�0.54-0.79, p�0.001). A 30% PSA decline within three months
of treatment was associated with a HR of 0.46 (95% CI 0.37-0.57,
p-value�0.001) for OS. After adjusting for treatment effect, the HR for
30% PSA decline was 0.50 (95% CI� 0.40-0.62, p�0.001) but treatment
arm remained statistically significant thus failing Prentice’s third
criterion. The PTE for �30% decline in PSA within three months was 0.39
(95% CI� 0.36-0.42) indicating a lack of surrogacy for OS. Similar results
were observed for pts who experienced �50% decline in PSA and PSA
velocity. Conclusions: Neither PSA decline (�30% and �50%) nor PSA
velocity within the first three months of therapy are surrogate endpoints for
OS in pts receiving second line chemotherapy.
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