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

312s Genitourinary Cancer
4642 General Poster Session (Board #10A), Sun, 8:00 AM-12:00 PM
Baseline covariates impacting overall survival (OS) in a phase III study of
men with bone metastases from castration-resistant prostate cancer.
Presenting Author: Karim Fizazi, Institut Gustave Roussy, Villejuif, France
Background: Prognostic models of OS in men with metastatic castrateresistant
prostate cancer (M�CRPC), have been limited. Here we present
an analysis of baseline covariates associated with OS from an international
phase 3 study that demonstrated superiority of denosumab over zoledronic
acid for prevention of skeletal-related events (SRE) in this population
(Fizazi et al., Lancet 2011;377:813-822). Methods: Patients had confirmed
bone metastases (BM) from CRPC (a rising PSA despite castrate
testosterone levels) and no prior bone anti-resorptive therapy. Proportional
hazards modeling with various selection strategies was used to assess the
prognostic significance of baseline covariates in multivariate analyses.
Study-specified factors (previous SRE [Y vs N], PSA level [�10 vs �10 ng
/mL]) and additional variables (Cook et al., Clin Cancer Res 2006;12:3361-
3367; Halabi et al., J Clin Oncol 2003;21:1232-1237; Halabi et al., J Clin
Oncol 2008;26:2544-2549) were explored. As no difference in OS was
observed between treatment arms, analyses were performed using the
pooled overall patient population. Results: Analyses included all randomized
subjects with available baseline covariate data (n�1745). At the
primary analysis date (median study duration 12.2 months), OS was 51%.
Various selection strategies produced consistent results. In multivariate
analysis, bone-specific alkaline phosphatase (BAP) �146 �g/L (p�0.0001)
and corrected urinary N-telopeptide (uNTx) �50 nmol/mmol (p�0.0008)
were associated with shorter OS, as were prior SRE (p�0.0002), PSA �10
ng /mL (p�0.0001), visceral metastases (p�0.0002), greater time from
either diagnosis to first BM or first BM to randomization (p�0.0001 for
both), ECOG performance status 2 vs. 0/1 (p�0.017), BPI-SF pain score
�4 (p�0.0001), age (p�0.008), alkaline phosphatase �143 U/L
(p�0.0001), and hemoglobin �128 g/L (p�0.0001). Conclusions: Besides
known factors previously associated with OS in men with CRPC
(Halabi et al., 2003), we show that bone-associated covariates (pain, prior
SRE, BAP, and uNTx) are also important and independent prognostic
factors for OS.
4644 General Poster Session (Board #10C), Sun, 8:00 AM-12:00 PM
Prognostic stratification of post-docetaxel metastatic castration resistant
prostate cancer (mCRPC) from a phase III randomized trial. Presenting
Author: Guru Sonpavde, Texas Oncology, Houston, TX, and Department of
Medicine, Section of Medical Oncology, Michael E. DeBakey Veterans
Affairs Medical Center, Baylor College of Medicine, Houston, TX
Background: A prognostic model for mCRPC post docetaxel is necessary to
guide therapy. We retrospectively analyzed a phase III trial enrolling
progressive mCRPC following docetaxel to construct a prognostic model.
Additionally, we studied the impact of neutrophil-lymphocyte ratio (NLR), a
potential marker for inflammatory and immune state. Methods: A phase III
trial (SUN-1120) comparing prednisone combined with sunitinib (N�584)
or placebo (N�289) for mCRPC following docetaxel-based chemotherapy
was evaluated. The treatment arms were combined for analysis, since no
statistical difference was observed in the primary endpoint of overall
survival (OS). A logarithmic transformation was applied to non-normal
factors. The Kaplan-Meier method was used for OS estimation. To identify
an optimal prognostic model for survival, we used a Cox proportional
hazards regression methods with forward stepwise selection, stratifying for
ECOG PS, progression type (PSA or radiographic) and treatment group. A
risk score was calculated and patients were categorized into risk groups to
assess model performance. Results: Data from patients without missing
data (n�806) were used to construct an optimal model. The factors used in
the model that remained individually significant in multivariate analysis
were: log-LDH (HR 2.77 [95% CI�2.23, 3.44], p�0.001), hemoglobin
(0.81 [0.76, 0.87], p�0.001), log-NLR (1.63 [1.38, 1.92], p�0.001),
�1 organ involved (1.53 [1.24, 1.88], p�0.001), log-alkaline phosphatase
(1.14 [1.01, 1.30], p�0.041) and log-PSA (1.07 [1.00, 1.13],
p�0.036). No clear cutpoints were identified; thus, these prognostic
factors were used to group patients into 3 equally sized risk categories.
Low, medium and high risk patients (n�268-270 per group) had median
(95% CI) OS estimates of 23.7 (21.4-not reached), 13.5 (11.6-15.8) and
7.3 (6.3-8.4) months, respectively. Conclusions: A prognostic risk model
with readily available variables significantly discriminated between outcomes
in post-docetaxel mCRPC and may provide valuable information in
future studies. High NLR was associated with an independent poor
prognostic impact, and warrants prospective validation.
4643 General Poster Session (Board #10B), Sun, 8:00 AM-12:00 PM
Phase I trial of NY-ESO-1/LAGE1 peptide vaccine for metastatic castration
resistant prostate cancer (mCRPC). Presenting Author: Teresa Gray Hayes,
Michael E. DeBakey VA Medical Center and Baylor College of Medicine,
Houston, TX
Background: The NY-ESO-1 and LAGE-1 antigens are amplified in malignancies
including prostate cancer. Preclinical induction of immune responses
and anti-tumor activity has been demonstrated upon administration of
these peptides. A phase I/II clinical trial evaluated the feasibility of a
combined HLA class-I and class-II peptide vaccine in mCRPC. Methods:
Men with progressive mCRPC, Performance Status �2, PSA �10 ng/ml
and had appropriate HLA class I (A2) and class II haplotypes (DR4, DP4,
DR13) were eligible. Three groups with 3 patients each received the
vaccine subcutaneously every 2 weeks for 6 doses. Group 1 was treated
with a peptide directed at a HLA class I haplotype (HLA A2), Group 2 was
treated with a peptide reacting to a HLA class II haplotype (DR4, DP4, or
DR13), and Group 3 received peptides directed at both Class I and II
haplotypes. Group I and Group II received 1 dose of 1000 mcg and Group
III received doses of 1000 mcg for each of 2 peptides. Androgendeprivation
was continued. Results: Of 14 patients enrolled, all were
evaluable for toxicities and 9 patients completed all 6 treatments per
amended protocol and were evaluable for efficacy. The median baseline
PSA was 85.19 ng/ml. Four patients were chemo naive and 5 were
post-docetaxel. One patient had a grade 5 event (myocardial infarction)
unlikely therapy-related. Potential therapy related toxicities were local
grade 1 injection site erythema (n�5), fatigue (n�2), flu-like symptoms
(n�1), myalgias (n�1), anorexia (n�1), nausea (n�1) and leukocytosis
(n�1). The median PSA doubling time pre-therapy and during therapy were
3.1 and 4.92 months, respectively. The PSA-DT was prolonged compared
to baseline in 6 patients, including a negative PSA slope in 2 patients.
Antigen-specific immune response determined by ELISPOT was observed,
and its association with slowing of PSA-doubling time will be further
examined. Conclusions: In men with mCRPC, HLA class-I and/or class-II
restricted NY-ESO-1 and LAGE-1 peptides administered subcutaneously
demonstrated excellent tolerability, slowing of PSA doubling time and
antigen-specific immune responses. Further development of peptide vaccines
alone or in combination with other regimens may be warranted.
4645 General Poster Session (Board #10D), Sun, 8:00 AM-12:00 PM
Inhibition of 3�-hydroxysteroid dehydrogenase by abiraterone: A rationale
for increasing drug exposure in castration-resistant prostate cancer. Presenting
Author: Nima Sharifi, University of Texas Southwestern Medical Center,
Dallas, TX
Background: Treatment with abiraterone acetate (abi) increases the survival
of men with castration-resistant prostate cancer (CRPC). Resistance to abi
invariably occurs, probably due in part to up-regulation of steroidogenic
enzymes and/or other mechanisms that sustain the synthesis of dihydrotestosterone
(DHT), which raises the possibility of reversing resistance by
concomitant inhibition of other required steroidogenic enzymes. The 1,000
mg daily abi dose was selected for the phase III trials despite the absence of
dose-limiting toxicities at higher doses. Based on the 3�-hydroxyl, �5- structure, we hypothesized that abi also inhibits 3�-hydroxysteroid dehydrogenase/isomerase
(3�HSD), which is absolutely required for the intratumoral
synthesis of DHT in CRPC, regardless of origins or routes of synthesis.
Methods: We tested if abi inhibits recombinant 3�HSD2 activity in vitro or
endogenous 3�HSD activity in LNCaP and LAPC4 cells, including conversion
of [ 3H]-dehydroepiandrosterone (DHEA) to androstenedione (AD),
androgen receptor (AR) nuclear translocation, expression of AR-responsive
genes, and LAPC4 xenograft growth in orchiectomized mice supplemented
with DHEA. Results: Abi has a mixed inhibition pattern of 3�HSD2 in vitro,
blocks the conversion from DHEA to AD and DHT with an IC50 of � 1 �Min
CRPC cell lines, inhibits AR nuclear translocation and expression of
TMPRSS2, and decreases CRPC xenograft growth in DHEA-supplemented
mice. Conclusions: Abi blocks 3�HSD enzymatic activity, synthesis of AD
and DHT, inhibits the AR-response, and suppresses growth of CRPC cells at
concentrations that are clinically achievable. Variable abi inhibition of
3�HSD might account in part for the heterogeneous clinical response to
abi. More importantly, 3�HSD inhibition with abi might be clinically
harnessed to reverse resistance to CYP17A1 inhibition at the standard dose
by dose-escalation, or simply by administration with food to increase drug
exposure.
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