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abstracts<br />
re-inventing <strong>the</strong> medical treatment<br />
of advanced prostate cancer<br />
46IN IMMUNOTHERAPY FOR ADVANCED PROSTATE CANCER<br />
P.W. Kantoff<br />
Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, UNITED STATES<br />
OF AMERICA<br />
While <strong>the</strong> concept of immuno<strong>the</strong>rapy for cancer has been proposed for many years, proof<br />
of principle did not exist. In <strong>the</strong> context of prostate cancer, <strong>the</strong> allogeneic cell based agent,<br />
GVAX has been tested. GVAX consists of a platform of irradiated hormone sensitive<br />
(LNCaP) and hormone resistant (PC-3) prostate cancer cell lines transduced with a<br />
replication-defective retrovirus bearing GM-CSF. Unfortunately, two phase III studies in<br />
men with metastatic castration resistant prostate cancer (CRPC) failed to demonstrate a<br />
survival advantage. More recently, <strong>the</strong> improved survival observed with sipuleucel-T, an<br />
autologous antigen presenting cell (APC)-based agent, for <strong>the</strong> treatment of patients with<br />
metastatic CRPC supports immuno<strong>the</strong>rapy as a valid approach for this disease.<br />
Sipuleucel-T uses a fusion antigen of prostatic acid phosphatase and GM-CSF. Evidence<br />
exists to support activation of APCs and T cells in an antigen specific fashion and that <strong>the</strong><br />
degree of activation correlates with overall survival. PROSTVAC-VF TRICOM, a poxvirus<br />
vector based PSA antigen targeted vaccine showed promising results in a randomized<br />
Phase II study and is now being tested in a international Phase III study. The CTLA-4<br />
inhibiting human monoclonal antibody, ipilimumab, has extended survival in advanced<br />
melanoma. Early phase I clinical trials of ipilimumab have yielded clinical and PSA<br />
responses in advanced CRPC. A Phase I/II trial was conducted using ipilimumab 10 mg/<br />
kg every 3 weeks x 4 with or without prior priming by single fraction of radiation to a<br />
metastatic bony site. Results were promising enough to launch 2 phase III clinical trials in<br />
men with metastatic CRPC who were ei<strong>the</strong>r chemo-naive or following prior<br />
chemo<strong>the</strong>rapy. The outcomes of <strong>the</strong>se 2 studies are pending.<br />
Disclosure: P.W. Kantoff: Amgen USA consultant (con), Bayer con, Bellicum con,<br />
BIND Biosciences SAB, BN Immuno<strong>the</strong>rapeutics con, Celgene DSMB, Dendreon<br />
con, Genetech con, Progenics Pharmaceuticals con, Janssen con, Takeda/Millenium<br />
DSMB, Oncogenex DSMB, Tokai con<br />
47IN HOW SHOULD WE USE CYTOTOXIC CHEMOTHERAPY IN THE<br />
TREATMENT OF CASTRATION-RESISTANT PROSTATE<br />
CANCER?<br />
O. Sartor<br />
Department of Medicine: Section of Hematology & Medical Oncology and<br />
Department of Urology, Tulane Cancer Center, New Orleans, LA, UNITED<br />
STATES OF AMERICA<br />
The recent incremental advances in metastatic castrate-resistant prostate cancer<br />
(mCRPC) may one day translate into more meaningful change. Today mCRPC<br />
<strong>the</strong>rapeutic choices are a sequential series of affairs with several ei<strong>the</strong>r/or decisions.<br />
Optimal sequencing is unstudied and endless speculation abound as to which drug is<br />
best best for which patient. Combination <strong>the</strong>rapies are in <strong>the</strong>ir infancy. In <strong>the</strong> past,<br />
<strong>the</strong> world of mCRPC was conveniently divided into <strong>the</strong> pre- and post-docetaxel<br />
space. That being said, <strong>the</strong> biologic basis for this was lacking and now we have new<br />
spaces such as <strong>the</strong> post-abiraterone/MDV3100 space that might in fact be more<br />
biologically meaningful. What do we do with patients progressing post-abiraterone or<br />
MDV3100? The data are sparse to date and so we gear up with new studies and read<br />
tea leaves in <strong>the</strong> interim. What is <strong>the</strong> role for cytotoxic chemo<strong>the</strong>rapies today’s<br />
mCRPC <strong>the</strong>rapeutic armamentarium? The new hormonal <strong>the</strong>rapies are now<br />
marching forward with provovative data in <strong>the</strong> “pre-chemo<strong>the</strong>rapy” space. Novel<br />
immuno<strong>the</strong>rapies have seized imaginations. The new world of truly active<br />
bone-targeted radiopharmaceuticals has arrived. Several facts seem clear. 1) <strong>the</strong><br />
newer hormonal <strong>the</strong>rapies are not effective for very long in mCRPC and after <strong>the</strong>y<br />
fail, <strong>the</strong> progression rate can be very rapid. Exotic new molecular mechanisms of<br />
resistance are discovered with regularity; <strong>the</strong> CRPC cells are truly devious little<br />
Darwinian machines. 2) Today, death from prostate cancer is a foregone conclusion<br />
for mCRPC patient. So does this help us answer how we use cytotoxic chemo<strong>the</strong>rapy<br />
today? Perhaps it si reasonable to point out that both docetaxel and cabazitaxel are<br />
clearly active agents and that some but not all patients will tolerate <strong>the</strong>m well.<br />
Currently many men die from prostate cancer without having had <strong>the</strong> opportunity to<br />
benefit from known active agents. The best responses to chemo<strong>the</strong>rapy, as with any<br />
agent, occur in patients with <strong>the</strong> best performance status. The concept that <strong>the</strong>rapies<br />
of lesser toxicity should be administered first is appropriate but <strong>the</strong> concept that<br />
Annals of Oncology 23 (Supplement 9): ix38, <strong>2012</strong><br />
doi:10.1093/annonc/mds378<br />
active <strong>the</strong>rapies should be on <strong>the</strong> shelf when treating an incurable disease is not.<br />
Striving for patients to receive as many active <strong>the</strong>rapies as feasible seems reasonable<br />
in an era when predicting <strong>the</strong>rapeutic response is more art than science.<br />
Disclosure: O. Sartor: Investigator and consultant for Algeta, Bayer, JNJ, Sanofi, and<br />
Dendreon. Consultant for Medivation and Astellas.<br />
48IN INTEGRATING NOVEL ENDOCRINE THERAPIES: SEQUENTIAL<br />
OR CONCOMITANT TREATMENT?<br />
J.S. de Bono<br />
Division of Cancer Therapeutics, Institute of Cancer Research Royal Marsden<br />
Hospital, Sutton, UNITED KINGDOM<br />
Prostate cancer progression is associated with continued androgen receptor (AR)<br />
activation despite treatment with castration and/or currently available anti-androgens.<br />
Abiraterone, a rationally- designed inhibitor of CYP17A1 has been recently approved<br />
for <strong>the</strong> treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is<br />
often effective, but requires co-administration with glucocorticoids to curtail side<br />
effects. Enzalutamide (MDV3100) is a novel AR antagonist that effectively blocks AR<br />
signaling when currently available AR antagonists are unable to do this and has shown<br />
impressive antitumor activity and a similar impact on overall survival as abiraterone.<br />
We now report that <strong>the</strong>se two drugs in combination may be superior to ei<strong>the</strong>r drug<br />
alone. We have hypo<strong>the</strong>sized that progressive disease on abiraterone may occur<br />
secondary to glucocorticoid-induced activation of mutated AR. We also found that<br />
prednisolone plasma levels in CRPC patients were sufficiently high to activate mutant<br />
AR. Mineralocorticoid receptor antagonists, such as spironoloactone and eplerenone<br />
that are used to treat side-effects related to mineralocorticoid excess, also bound to and<br />
activated signaling through both wild-type and mutant AR. Activation of mutant AR<br />
was inhibited by MDV3100, bicalutamide or greater concentrations of abiraterone.<br />
Moreover, higher androgenic steroid concentrations resulted in decreased enzalutamide<br />
antitumour activity. Toge<strong>the</strong>r, our findings provide a strong rationale for <strong>the</strong> clinical<br />
evaluation of combined CYP17A1 inhibition and AR antagonism by enzalutamide.<br />
Disclosure: J.S. de Bono: I am an employee of The Institute of Cancer Research that<br />
has a commercial interest in abiraterone. I have served as an advisor for J&J,<br />
Medivation, Astellas and Takeda.<br />
49IN HOW SHOULD WE UTILIZE BONE TREATMENTS:<br />
BISPHOSPHONATES, DENOSUMAB AND RADIUM-223<br />
C. Parker<br />
Academic Urology, Royal Marsden Hospital NHS Foundation Trust, Sutton,<br />
UNITED KINGDOM<br />
How should we utilize bone treatments: Bisphosphonates, denosumab and<br />
radium-223? Bone metastases are a prominent feature of CRPC, and can lead to<br />
significant skeletal-related events (SREs) such as spinal cord compression,<br />
pathological fracture, and <strong>the</strong> need for surgery or external-beam radio<strong>the</strong>rapy.<br />
Zoledronate, a bisphosphonate, reduces <strong>the</strong> risk of SREs (1) and has been widely,<br />
although not universally, regarded as a standard treatment for metastatic CRPC.<br />
More recently, denosumab, an antibody targeted at <strong>the</strong> RANK-ligand, has shown<br />
greater efficacy for SRE prevention with an acceptable toxicity profile (2), and has<br />
also been licensed for use. Radium-223, a bone-targetted alpha emitter, has been<br />
reported not only to reduce <strong>the</strong> risk of SREs, but also to improve overall survival.<br />
Although radium-223 is <strong>the</strong> first bone-targetted agent to improve overall survival in<br />
CRPC, it is not yet licensed for clinical use. I will review <strong>the</strong> clinical trial data<br />
concerning <strong>the</strong>se bone-targetted agents in CRPC, and give my personal view as to<br />
how <strong>the</strong>y should be used.<br />
References 1. A randomized, placebo-controlled trial of zoledronic acid in patients<br />
with hormone-refractory metastatic prostate carcinoma. Saad F, Gleason DM, Murray<br />
R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B;<br />
Zoledronic Acid Prostate Cancer Study Group. J Natl Cancer Inst. 2002 Oct 2;94<br />
(19):1458-68. 2. Denosumab versus zoledronic acid for treatment of bone metastases<br />
in men with castration-resistant prostate cancer: a randomised, double-blind study.<br />
Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N,<br />
Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C. Lancet. 2011 Mar 5;377<br />
(9768):813-22. 3. Overall survival benefit of radium-223 chloride (Alpharadin) in<br />
<strong>the</strong> treatment of patients with symptomatic bone metastases in castration-resistant<br />
prostate cancer (CRPC): A phase III randomized trial (ALSYMPCA). C. Parker,<br />
D. Heinrich, J.M. O’Sullivan, S. Fosså, A. Chodacki, T. Demkow, A. Cross, B. Bolstad,<br />
J. Garcia-Vargas, and O. Sartor. Eur J Cancer 47:Supp 2, Sept 2011 p3<br />
Disclosure: C. Parker: Advisory board membership for Amgen, BMS, Bayer,<br />
Dendreon, Janssen and Takeda<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
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