editorials

New Therapies for Castration-Resistant Prostate Cancer

Dan L. Longo, M.D.
On April 29, 2010, the Food and Drug Administration (FDA) approved a new immunotherapy,
sipuleucel-T, for the treatment of patients with
asymptomatic or minimally symptomatic castration-resistant prostate cancer. Traditionally,
immune-based therapies have been categorized
according to whether the agent has direct antitumor effects (so-called passive immunotherapy)
or stimulates a host antitumor response (active
immunotherapy) and whether the agent elicits a
general increase in immune activation (nonspecific) or an immune response based on tumor
recognition (specific). Sipuleucel-T is a form of
active specific immunotherapy.
The sipuleucel-T intervention involves harvesting the patients peripheral-blood mononuclear
cells (PBMCs), culturing them with a chimeric
protein containing granulocytemacrophage colony-stimulating factor (GM-CSF) to activate antigen presentation together with prostatic acid
phosphatase as a tumor-associated antigen, and
then infusing the antigen-pulsed antigen-presenting cells (APCs) back into the patient. Three intravenous infusions of antigen-pulsed APCs are
given once every 2 weeks; a course of therapy is
completed in a month.
In this issue of the Journal, Kantoff et al.1 report the results of a clinical trial that helped convince the FDA to approve sipuleucel-T for clinical
use. Men whose tumors had progressed after
combined androgen blockade were randomly assigned in a 2:1 ratio to receive sipuleucel-T immune activation or a placebo composed of autologous PBMCs not cultured with the chimeric
protein. Tumor response was assessed on the basis of the level of prostate-specific antigen (PSA),
computed tomography, and bone scans. The median survival was 25.8 months in the sipuleucel-T
group, as compared with 21.7 months in the placebo group (unadjusted hazard ratio for death in
the sipuleucel-T group, 0.77; P=0.02). Study-group
assignment had no significant effect on the time
to tumor progression; 1 of 341 patients in the
sipuleucel-T group had a partial tumor response,
and 3% had a reduction of at least 50% in PSA
level on two visits at least 4 weeks apart. Thus,
the improvement in survival came without evidence of a measurable antitumor effect. Two
thirds of patients receiving sipuleucel-T had anti-

body responses to the immunogen, and nearly

three fourths had T-cell proliferative responses.
Survival was improved for patients who had an
antibody response but not for those with a T-cell
response. Nearly identical results emerged from a
previous smaller study with the same agent.2
Patients with metastatic cancer have myriad
tumor-induced immune defects,3 including abundant regulatory T cells that suppress cytotoxic
T-cell responses, myeloid suppressor cells, immunosuppressive cytokines, defective antigen presentation, and T cells bearing signaling defects.
Any immune therapy in a tumor-bearing host has
an uphill battle that probably involves barriers
that have not yet been defined. The adjuvant setting may provide a larger window of opportunity for immune-activating therapies. Thus, a
23% reduction in the risk of death in patients
with metastatic disease is an important step.
The findings in this study raise a few questions. First, a better control group would have included patients receiving PBMCs incubated with
GM-CSF alone so that the main variable between
the two study groups would be the tumor antigen. The current design does not allow one to
conclude that the tumor antigen is a key component of the therapy. Second, the prolongation of
survival without a measurable antitumor effect is
surprising. It is hard to understand how the natural history of a cancer can be affected without
some apparent measurable change in the tumor,
either evidence of tumor shrinkage or at least disease stabilization reflected in a delay in tumor
progression. This lack of tumor effect raises concern that the results could have been influenced
by an unmeasured prognostic variable that was
accidentally imbalanced in study-group assignments. As the authors point out, differences in
subsequent treatments (e.g., docetaxel) do not
appear to account for the survival differences, but
methods for assessing such effects are imperfect.
New prognostic variables such as statin use,4
the duration of the first off-treatment interval,5
circulating tumor cells (as assessed as EpCAM+
CK+CD45 objects),6 and new prognostic algorithms may need to be accounted for in assessing therapeutic effects.
Other immunization strategies are being tested in patients with prostate cancer. A vaccine

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The New England Journal of Medicine

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479

The

Sipuleucel-T

n e w e ng l a n d j o u r na l

of

m e dic i n e

Adipose tissue

Adrenal gland

Bone

Abiraterone

Osteoblastic
stromal cell

RANKL
Denosumab

APC

EGF

PAP
peptide

GM-CSF PAP

T cell

Androgenic
steroids

T cell

RANK
Osteoclast
precursor

HER2

PAP peptide

Cetuximab

Heregulin
Trastuzumab

EGFR

Zibotentan
Src

Ack1

Lipid membrane
PAP peptide bound
to MHC1 on
prostate-cancer cell

Endothelin-1

Dasatinib
HSP90

Cytosol
Androgen
receptor

Cell death
T

HSP90
Prostatecancer cell

Geldanamycin

MDV3100

Gene transcription

CoACT
Nucleus

Figure 1. Promising Targets in Castration-Resistant Prostate Cancer.

Sipuleucel-T and other vaccine approaches are aimed at inducing the immune system to recognize and kill prostate-cancer cells. Castrationresistant prostate cancer retains dependence on the androgen receptor. Abiraterone inhibits the 17-hydroxylase and C17,20-lyase activity of
cytochrome P-450 CYP17A1, which blocks androgen synthesis. Experimental drug MDV3100 blocks androgen binding, nuclear translocation of the receptor, and coactivator recruitment to the DNA-binding complex. Heat-shock protein 90 (HSP90) is a chaperone that
assists in nuclear transport of the receptor. It can be blocked by geldanamycin and its congeners. Tumor-produced endothelin is involved in bone metastasis, which may be blocked by endothelin receptor antagonists (zibotentan and atrasentan). RANK ligand (RANKL)
increases osteoclast activity that may be blocked by RANK ligand inhibitor denosumab. Heregulin and epidermal growth factor (EGF)
activate tyrosine kinases that phosphorylate the androgen receptor, and their activity is inhibited by dasatinib. Antiangiogenic agents (sunitinib and bevacizumab) are being evaluated, and several classes of chemotherapeutic agents hold promise, including newer taxanes
(cabazitaxel), newer platinum compounds (satraplatin and picoplatin), and epothilones (ixabepilone) (not shown). Trastuzumab can
block HER2 signaling, and cetuximab can block EGF receptor (EGFR) signaling. Ack1 denotes activated CDC-42associated kinase, APC
antigen-presenting cell, CoACT androgen receptor coactivator, GM-CSF granulocytemacrophage colony-stimulating factor HER2 human
epidermal growth factor receptor 2, MHC1 major histocompatibility complex class I, PAP prostatic acid phosphatase, Src sarcomarelated tyrosine kinase, and T androgenic steroid hormone.
COLOR FIGURE

Version 6

called GVAX that is composed of two allogeneic

prostate-cancer cell lines infected with adenoviruses that allow the cells to secrete GM-CSF
was unsuccessful in phase 3 testing.7 However,
another product, called PROSTVAC-VF, composed
of two recombinant vaccinia-based viral vectors
containing PSA and three immune costimulatory
molecules, prolonged median survival by 8.5
months in a randomized phase 2 study.8 Like
sipuleucel-T, PROSTVAC-VF improved survival
480

n engl j med 363;5

Author
Fig #
Title
ME

Longo

07/14/10

without improving progression-free1 survival. It

Prostate Cancer
is now being tested in phase 3 studies.
MP
Other prospects for vaccine
development
inDL
DE
Artist
LAM
clude peptide vaccines, DNA-based
vaccines,
and
AUTHOR PLEASE NOTE:
Figure hasantigens
been redrawn and type
been reset
novel strategies such as targeting
tohasmaPlease check carefully
jor histocompatibility complex
class07/29/10
I pathways
Issue date
with chemokineantigen chimeric molecules.9
Another concern with sipuleucel-T treatment is
the cost. The current cost of care for men with
prostate cancer has been estimated to be about

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editorials

$1,800 per month.10 The manufacturer has set

the cost of a 1-month course of sipuleucel-T at
$93,000, or $23,000 per month of survival advantage. The high cost may affect use. It is also
uncertain what role sipuleucel-T will ultimately
play in the treatment of prostate cancer, given
the other promising treatments in development.
Castration-resistant prostate cancer was formerly known as hormone-refractory prostate cancer. However, even after tumors progress through
combined androgen blockade, they retain dependence on the androgen receptor.11 Many novel
agents are in development, some of which have
shown dramatic antitumor effects in the earliest
phases of clinical testing12 (Fig. 1). Abiraterone
blocks the synthesis of androgens; 51% of men
who were treated with 1 g of the drug per day
had a reduction in PSA levels of at least 50%,
and 27% of patients had a partial tumor response.13 Experimental drug MDV3100 blocks
nuclear translocation of the androgen receptor.
In a phase 1 and 2 study, antitumor effects were
noted at every dose of the agent, including a reduction in PSA levels of at least 50% in 56% of
patients, responses in soft-tissue lesions in 22%
and in stabilized bone lesions in 56%, and a reduction in circulating tumor-cell counts in 49%.14
The prospects for improved therapy for prostate cancer have never been so encouraging. The
poor prognosis for men with prostate cancer
will probably be substantially improved by the
findings that emerge from ongoing clinical research.
1. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immu-

notherapy for castration-resistant prostate cancer. N Engl J Med

2010;363:411-22.

2. Small EJ, Schellhammer PF, Higano CS, et al. Placebo-con-

trolled phase III trial of immunologic therapy with sipuleucel-T

(APC8015) in patients with metastatic, asymptomatic hormone
refractory prostate cancer. J Clin Oncol 2006;24:3089-94.
3. de Souza AP, Bonorino C. Tumor immunosuppressive environment: effects on tumor-specific and nontumor antigen immune responses. Expert Rev Anticancer Ther 2009;9:1317-32.
4. Gutt R, Tonlaar N, Kunnavakkam R, et al. Statin use and risk
of prostate cancer recurrence in men treated with radiation
therapy. J Clin Oncol 2010;28:2653-9.
5. Yu EY, Gulati R, Telesca D, et al. Duration of first off-treatment interval is prognostic for time to castration resistance and
death in men with biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation.
J Clin Oncol 2010;28:2668-73.
6. Coumans FA, Doggen CJ, Attard G, de Bono JS, Terstappen
LW. All circulating EpCAM+CK+CD45- objects predict overall
survival in castration-resistant prostate cancer. Ann Oncol 2010
February 10 (Epub ahead of print).
7. Antonarakis ES, Drake CG. Current status of immunological
therapies for prostate cancer. Curr Opin Urol 2010;20:241-6.
8. Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II randomized controlled trial of a
Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 2010;28:1099-105.
9. Schiavo R, Baatar D, Olkhanud P, et al. Chemokine receptor
targeting efficiently directs antigens to MHC class I pathways
and elicits antigen-specific CD8+ T-cell responses. Blood 2006;
107:4597-605.
10. Alemayehu B, Buysman E, Parry D, et al. Economic burden
and healthcare utilization associated with castration-resistant
prostate cancer in a commercial and Medicare Advantage US
patient population. J Med Econ 2010;13:351-61.
11. Knudsen KE, Penning TM. Partners in crime: deregulation
of AR activity and androgen synthesis in prostate cancer. Trends
Endocrinol Metab 2010;21:315-24.
12. Di Lorenzo G, Buonerba C, Autorino R, et al. Castrationresistant prostate cancer: current and emerging treatment strategies. Drugs 2010;70:983-1000.
13. Reid AH, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant
prostate cancer with CYP17 inhibitor abiraterone acetate. J Clin
Oncol 2010;28:1489-95.
14. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of
MDV3100 in castration-resistant prostate cancer: a phase 1-2
study. Lancet 2010;375:1437-46.
Copyright 2010 Massachusetts Medical Society.

In CPR, Less May Be Better

Myron L. Weisfeldt, M.D.
Fifty years have passed since Kouwenhoven, Jude,
and Knickerbocker1 proposed external chest compression to provide circulation of blood to the
brain and heart after cardiac arrest. Shortly
thereafter, mouth-to-mouth rescue breathing was
adopted as an essential addition to this lifesaving
procedure. Since that time, there has been very
little fundamental change in the method or
manner of cardiopulmonary resuscitation (CPR).
Decades of observational studies have shown that
survival is improved if CPR is performed by

bystanders rather than being provided only when

emergency medical services (EMS) staff arrives.
The use of automated external defibrillators by
bystanders and the use of in-hospital hypothermia
in comatose patients have also been found to improve outcomes in patients with cardiac arrest.
Only relatively recently, however, have the fundamentals of the initial resuscitation been investigated. Focused, impressive laboratory research
has resulted in a surge of interest in these fundamentals. Most of the studies have involved pigs

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