Download Metastatic castration-resistant prostate cancer

Sipuleucel-T Immunotherapy for CastrationResistant
Prostate Cancer
Philip W. Kantoff, M.D., Celestia S. Higano, M.D., Neal D. Shore, M.D., E. Roy Berger, M.D.,
Eric J. Small, M.D., David F. Penson, M.D., Charles H. Redfern, M.D., Anna C. Ferrari, M.D.,
Robert Dreicer, M.D., Robert B. Sims, M.D., Yi Xu, Ph.D., Mark W. Frohlich, M.D., and Paul F.
Schellhammer, M.D.
N Engl J Med 2010;363:411-22
R1 Kang Sung-wook / prof. Kim Si-young
BACKGROUND
Prostate cancer
the most common cancer among men in the United States
the second leading cause of death from cancer in men
Metastatic castration-resistant prostate cancer
median survival : 12.2 to 21.7 months
Docetaxel : a median survival benefit of 2 to 3 months, as
compared with mitoxantrone and prednisone.
BACKGROUND
Sipuleucel-T
active cellular immunotherapy
: autologous peripheral-blood mononuclear cells (PBMCs),
including antigen-presenting cells (APCs)
PA2024 : recombinant fusion protein consists of a prostate
antigen, prostatic acid phosphatase, that is fused to GM-CSF
Two studies
1st : reduction in the risk of death of 41%
2nd : not statistically significant
No significant effect on the time to disease progression
(the primary end point)
METHODS -
Patients
Eligibility criteria
metastatic castration-resistant prostate cancer
expected survival of at least 6 months
any Gleason score, asymptomatic or minimally symptomatic disease
Serum PSA ≥ 5ng/ml, testosterone < 50ng/dl
progressive disease on imaging studies or PSA measurements
Exclusion criteria
ECOG performance status ≥ 2, visceral metastases
pathologic long-bone fractures, spinal cord compression
treatment within the previous 28 days
: systemic glucocorticoids, external-beam radiation, surgery, initiated
or discontinued bisphosphonate therapy
treatment with more than two chemotherapy regimens or
chemotherapy within the previous 3 months
METHODS -
Randomization and Treatment
Patients stratifing
Primary Gleason grade : ≤3 or ≥4
The number of bone metastases : ≤5, 6 to 10 or >10
Bisphosphonate use : yes or no
Treatment
premedication : acetaminophen, antihistamine
sipuleucel-T or placebo iv during 60 minutes
Sipuleucel-T : culturing APCs for 36 to 44 hours at 37°C with
media containing PA2024
Placebo : at 2 to 8°C without PA2024
Disease progression monitoring : CT, bone scanning
METHODS -
Others
Adverse Events
grade with the National Cancer Institute’s Common Terminology
Criteria for Adverse Events, version 3.0
Primary end point
overall survival
the time from randomization until death from any cause
Secondary end point
objective disease progression
increase of at least 50% diameters for index lesions
new appearance or unequivocal progression of nonindex
lesions
at least two new lesions on bone scanning
new pathologic fracture or spinal cord compression
METHODS -
Others
Statistical methods
Two-sided Wald’s test
: To analyze The primary end point of overall survival
Stratified, unadjusted Cox model and log-rank test
: To assese the treatment effect
Primary Cox model
: To determination of prostate-cancer–specific survival
Inverted Kaplan–Meier technique
: To estimate median follow-up time
RESULTS
Sipuleucel-T
Death
Median
survival
Placebo
210/341(61.6%) 121/171(70.8%)
25.8months
21.7months
Adjusted hazard ratio
for death : 0.78 (P= 0.03)
median survival
 4.1 months longer
23.0%
31.7%
The median time to objective disease progression
Sipuleucel-T group : 14.6 weeks (3.7 months)
Placebo group : 14.4 weeks (3.6 months)
 hazard ratio = 0.95 (P = 0.63)
The results of the median time to clinical disease progression
was similar
 hazard ratio = 0.92 (P = 0.40)
PA2024
PAP
(prostatic acid
phosphatase)
Sipuleucel-T
Placebo
Ab titer > 400
100/151(66.2%)
2/70(2.9%)
T-cell
proliferation
46/63(73.0%)
4/33(12.1%)
Ab titer > 400
43/151(28.5%)
1/70(1.4%)
T-cell
proliferation
15/55(27.3%)
2/25(8.0%)
PA2024 or PAP Ab titer > 400 at any time
 survival benefit (P<0.001 and P = 0.08)
PA2024 or PAP T-cell proliferation responses at week 6
 No survival difference
These events occurred within 1 day after infusion and
resolved within 1 to 2 days (except groin pain )
CONCLUSION
Sipuleucel-T prolonged survival among men with
asymptomatic or minimally symptomatic metastatic
castration-resistant prostate cancer.
No significant effect on the time to objective
disease progression was observed.
The treatment was associated with infusional
adverse events, including fever and chills, which
were mainly grade 1 or 2 in severity.