Huber et al. made three observations related to the phase III IMPACT trial leading them to suggest that the observed difference in overall survival (OS) could have been attributed to age-dependent immunodepletion resulting from leukapheresis of the control arm patients ( 1 ). Evidence from the sipuleucel-T trials and the literature refute this alternative explanation.

Observation 1: Two Unexpected Interactions Between Patient Age and Survival

Studies have shown age to be prognostic in castration-resistant prostate cancer ( 2 , 3 ). Most studies investigating prognostic factors in castration-resistant prostate cancer have focused on chemotherapy-treated patients in whom other prognostic factors might be expected to outweigh age. The sipuleucel-T studies exclusively enrolled patients with asymptomatic or minimally symptomatic disease, 85% of whom were chemotherapy naïve ( 4 , 5 ). In a pooled analysis of these studies, age (in 10-year increments) was a statistically significant predictor of OS in both sipuleucel-T (hazard ratio [HR] of death = 1.28, 95% confidence interval [CI] = 1.12 to 1.47) and control (HR of death = 1.31, 95% CI = 1.10 to 1.56) arms (Dendreon data on file), which would not be anticipated if the control group had experienced relative immunodepletion.

Among 63 subgroups assessed for the IMPACT study report, OS favored sipuleucel-T (ie, a HR of death < 1.0) in all subgroups including above and below the median age of 71 ( 4 ); only the subgroup of patients aged less than 65 years did not favor sipuleucel-T. Given the high probability of a false-positive result with this number of subgroup analyses, it is important to seek additional data for consistency. In an analysis of the first two phase III sipuleucel-T trials, positive treatment effects were observed in patients less than 65 years of age (HR of death = 0.57, 95% CI = 0.27 to 1.21) and 65 years or older (HR of death = 0.69, 95% CI = 0.49 to 0.98), with the trend actually favoring a greater treatment effect in the younger subgroup (Dendreon data on file). Furthermore, when both IMPACT and the earlier phase III studies are dichotomized at the median age of 71, the treatment effect of sipuleucel-T is consistent in both the younger and older patients ( 4 , 5 ).

The US Food and Drug Administration (FDA) performed an analysis of pooled data across the three phase III sipuleucel-T trials and obtained a favorable estimate for the treatment effect in patients younger than 65 years (HR of death = 0.92, 95% CI = 0.62 to 1.37). The FDA reviewers’ conclusion was that the “… analyses of the data from all three studies … support the hypothesis that the subgroup of patients who were less than 65 years of age also benefit from treatment with sipuleucel-T. The hazard ratio in the subgroup of Study D9902B [IMPACT] patients who were less than 65 years of age most likely resulted from chance, related to the multiplicity of comparisons…” ( 6 ).

Observation 2: Older Patients in the Placebo Group Appear to Have Shorter OS Than Might Be Expected From Other Studies

A review of recent trials with patient populations comparable to that in IMPACT demonstrates consistency of the median survival of the control arms, ranging from 16.6 to 21.5 months ( Table 1 ) ( 4 , 7 ). Huber et al. ( 1 ) cited the 27.1-month median OS shown for the control group in a subset analysis of 264 patients from the GVAX trial who enrolled with a Halabi-predicted survival of greater than 18 months. We calculated the median OS of IMPACT control patients with a more than 18-month Halabi-predicted survival (n = 114); at 26.7 months, it compares favorably to the median OS of control patients from the GVAX subset analysis, particularly given that the GVAX control arm involved active treatment with docetaxel. Furthermore, the definition of “minimally symptomatic” used for the subgroup of patients from TAX327 who had a 25.6-month median OS (n = 110) included a minimal score on a quality-of-life questionnaire ( 8 ), which was not included in the IMPACT definition. A larger TAX327 minimally symptomatic subgroup (n = 550) that did not include the quality-of-life criterion for defining symptomatology revealed a median survival of 21.3 months for all three treatment arms combined ( Table 1 ) and 19.8 months specifically in the control arm ( 9 ).

Table 1.

Key prognostic factors and outcomes from clinical trials of patient populations comparable to those enrolled in IMPACT (4,7)*

Feature Study† 
IMPACT Prostvac Tax 327 minimally symptomatic subgroup Zibotentan ASCENT-2 Atrasentan 
Treatment arm PV D3P/D1P/MP Z15 Z10 CD1 PD3 
No. of patients 341 171 82 40 550 98 107 107 477 476 408 401 
Median OS, mo 25.8 21.7 25.1 16.6 21.3 23.5 24.5 17.3 17.8 20.2 20.5 20.3 
Prognostic features             
Median age, y 72 70 71.5 79 NR 70 70 72 70.4 70.9 73 72 
Narcotic free, % 100 100 100 100 NR 100 100 100 NR NR 100 100 
Prior chemotherapy, % 19.6 15.2 NR NR 
PSA (ng/mL), median 51.7 47.2 36 45 NR 72 55 64 73.1 64 69.8 79.6 
LDH (u/L), median 194 193 194 205 NR NR NR NR 205 202 186 188 
Alk Phos (u/L), median 99 109 100 115 NR NR NR NR 126 113 NR NR 
Gleason 
score≤7, % 75.4 75.4 100 100 NR NR NR NR NR NR NR NR 
ECOG 0–1, % 100 100 100 100 NR NR NR NR 93 95 98 97 
Hemoglobin 
(g/dL), median 12.9 12.7 13.0 12.7 NR NR NR NR 12.5 12.6 13.4 13.2 
Visceral 
disease, % NR NR NR NR NR NR NR NR 
Study funding Dendreon Bavarian Nordic Sanofi-Aventis Astra-Zeneca Novacea Abbott 
Feature Study† 
IMPACT Prostvac Tax 327 minimally symptomatic subgroup Zibotentan ASCENT-2 Atrasentan 
Treatment arm PV D3P/D1P/MP Z15 Z10 CD1 PD3 
No. of patients 341 171 82 40 550 98 107 107 477 476 408 401 
Median OS, mo 25.8 21.7 25.1 16.6 21.3 23.5 24.5 17.3 17.8 20.2 20.5 20.3 
Prognostic features             
Median age, y 72 70 71.5 79 NR 70 70 72 70.4 70.9 73 72 
Narcotic free, % 100 100 100 100 NR 100 100 100 NR NR 100 100 
Prior chemotherapy, % 19.6 15.2 NR NR 
PSA (ng/mL), median 51.7 47.2 36 45 NR 72 55 64 73.1 64 69.8 79.6 
LDH (u/L), median 194 193 194 205 NR NR NR NR 205 202 186 188 
Alk Phos (u/L), median 99 109 100 115 NR NR NR NR 126 113 NR NR 
Gleason 
score≤7, % 75.4 75.4 100 100 NR NR NR NR NR NR NR NR 
ECOG 0–1, % 100 100 100 100 NR NR NR NR 93 95 98 97 
Hemoglobin 
(g/dL), median 12.9 12.7 13.0 12.7 NR NR NR NR 12.5 12.6 13.4 13.2 
Visceral 
disease, % NR NR NR NR NR NR NR NR 
Study funding Dendreon Bavarian Nordic Sanofi-Aventis Astra-Zeneca Novacea Abbott 

* Alk Phos = alkaline phosphatase; ECOG = Eastern Cooperative Oncology Group performance status scale; LDH = lactate dehydrogenase; NR = not reported; OS = overall survival; PSA = prostate-specific antigen.

† In the IMPACT trial, sipuleucel-T (S) was compared with a control intervention (C). In the prostvac trial, recombinant vaccinia vector-PSA-TRICOM (2×10 8 pfu) followed by recombinant Fowlpox-PSA-TRICOM boost (1×10 9 pfu) + recombinant granulocyte-macrophage colony-stimulating factor adjuvant (PV) was administered to patients and was compared with patients who received the control intervention (C). Patients in the Tax 327 trial were administered 75mg/m 2 docetaxel every 3 weeks + 5mg prednisone twice daily (D3P) and were compared with both patients who received 30mg/m 2 docetaxel weekly + 5mg prednisone twice daily (D1P) and those who received 12mg/m 2 mitoxantrone every 3 weeks + 5mg prednisone twice daily (MP). No previous therapy with chemotoxic agents with the exeption of estramustine, which was allowed. The clinical trial of zibotentan compared patients who recieved 15mg zibotentan daily (Z15) with those who received 10mg zibotentan daily (Z10) and those who received an oral placebo daily (P). In the ASCENT-2 trial, the treatment arms were high-dose calcitriol daily + 36mg/m 2 docetaxel every 3 weeks + 8mg oral dexamethasone 12 hours, 3 hours, and 1 hour before docetaxel infusion for 3 of 4 weeks (CD1) vs prednisone twice daily + 75mg/m 2 docetaxel every 3 weeks and 8mg oral dexamethasone 12 hours, 3 hours, and 1 hour before docetaxel infusion (PD3). Prior chemotherapy (only estramustine monotherapy) was allowed. The atrasentan trial compared 10mg atrasentan daily (A) vs oral placebo daily (P). The median Gleason score in both treatment arms was 7; percentage of patients with Gleason score of 7 or lower was not reported. ECOG was not reported; the value listed for ECOG 0–1 represents the percentage of patients with Karnofsky Performance Status 100–80.

Observation 3: Potential Harm From the IMPACT Study Interventions

Huber et al. ( 1 ) failed to account for the fact that the intravascular pool of mononuclear cells represents a small fraction of the total body pool and that these populations rapidly reequilibrate ( 10 ). The 1.5–2.0 volume leukapheresis procedure in IMPACT removed approximately 7×10 9 lymphocytes. Given that the total body pool of lymphocytes is estimated between 5×10 11 and 6×10 12 cells ( 11–13 ), leukapheresis removed only 0.1%–1.4% of the total number of lymphocytes. This small percentage would not be expected to have any substantive effect on the lymphocyte repertoire.

An extensive body of literature has shown no detrimental effects of repeated apheresis procedures on healthy donors ( 14 ), and the median white blood cell, neutrophil, lymphocyte, and monocyte counts in the sipuleucel-T studies were within normal ranges at 2, 10, and 22 weeks following the third leukapheresis procedure in both the sipuleucel-T and the control groups ( 15 ). Furthermore, cells undergoing homeostatic proliferation actually tend to be more, rather than less, immunoreactive, as evidenced by multiple cancer immunotherapy protocols that induce lymphopenia before immunization and/or adoptive T-cell transfer to augment immune activation and clinical efficacy.

Finally, infection-related adverse events were not increased among the control arm and were consistent with what would be expected in an elderly population over an extended period of follow-up ( 15 ). The storage of the cells from the control group did not lead to infusion of dead cells, because the median viabilities were greater than 95% for both sipuleucel-T and control groups (Dendreon unpublished data on file).

Conclusions

The control arm intervention for the sipuleucel-T trials was chosen after careful consideration and discussion with the FDA. Having patients in the control arm undergo leukapheresis procedures and subsequent infusion of a cellular product that was identical in appearance to sipuleucel-T substantially strengthened the study design and the interpretability of the results.

The sipuleucel-T data have undergone rigorous review, including an FDA advisory committee, FDA review, a Center for Medicare and Medicaid Services national coverage determination, a Technology Assessment, and the peer review of multiple publications. The issues raised by Huber et al. were considered during these reviews and not given credence.

References

1.
Huber
ML
Haynes
L
Parker
C
Iversen
P
Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer
J Natl Cancer Inst
 
2012
;104(4):
273–279.
2.
Halabi
S
Vogelzang
NJ
Kornblith
AB
et al
Pain predicts overall survival in men with metastatic castration-refractory prostate cancer
J Clin Oncol
 
2008
;
26
(
15
):
2544
2549
3.
Halabi
S
Vogelzang
NJ
Ou
SS
Kelly
WK
Small
EJ
Clinical outcomes by age in men with hormone refractory prostate cancer: a pooled analysis of 8 Cancer and Leukemia Group B (CALGB) studies
J Urol
 
2006
;
176
(
1
):
81
86
4.
Kantoff
PW
Higano
CS
Shore
ND
et al
Sipuleucel-T immunotherapy for castration-resistant prostate cancer
N Engl J Med
 
2010
;
363
(
5
):
411
422
5.
Higano
CS
Schellhammer
PF
Small
EJ
et al
Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer
Cancer
 
2009
;
115
(
16
):
3670
3679
6.
Fan
C,
George
B
Bross
P
FDA Clinical Review
:
Sipuleucel-T
. Silver Spring, MD: FDA;
2010
http://www.fda.gov/downloads/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm214540.pdf. Accessed
January 30, 2012
7.
Scher
HI
Jia
X
Chi
K
et al
Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer
J Clin Oncol
 
2011
;
29
(
16
):
2191
2198
8.
Berthold
DR
Pond
GR
Roessner
M
et al
Treatment of hormone-refractory prostate cancer with docetaxel or mitoxantrone: relationships between prostate-specific antigen, pain, and quality of life response and survival in the TAX-327 study
Clin Cancer Res
 
2008
;
14
(
9
):
2763
2767
9.
Anderson
J
Minimal pain hormone refractory prostate cancer: optimising care [online]
. Published November6
2008
http://www.peerviewpress.com/evidence-based-decisions-management-advanced-prostate-cancer-0#. Accessed
January 30, 2012
10.
Sprent
J
Cho
JH
Boyman
O
Surh
CD
T cell homeostasis
Immunol Cell Biol
 
2008
;
86
(
4
):
312
319
11.
Osgood
EE
Number and distribution of human hemic cells
Blood
 
1954
;
9
(
12
):
1141
1154
12.
Di Mascio
M
Paik
CH
Carrasquillo
JA
et al
Noninvasive in vivo imaging of CD4 cells in simian-human immunodeficiency virus (SHIV)-infected nonhuman primates
Blood
 
2009
;
114
(
2
):
328
337
13.
Trepel
F
Number and distribution of lymphocytes in man. A critical analysis
Klin Wochenschr
 
1974
;
52
(
11
):
511
515
14.
Strauss
RG
Effects on donors of repeated leukocyte losses during plateletpheresis
J Clin Apher
 
1994
;
9
(
2
):
130
134
15.
Hall
SJ
Klotz
L
Pantuck
AJ
et al
Integrated safety data from 4 randomized, double-blind, controlled trials of autologous cellular immunotherapy with sipuleucel-T in patients with prostate cancer
J Urol
 
2011
;
186
(
3
):
877
881

Funding

No author has received financial support for the submitted work. The IMPACT trial was funded by Dendreon Corp.

Notes

P. W. Kantoff served as a paid consultant for Bellicum, BN-IT, Janssen, Bayer, Sanofi-Aventis, and Dendreon Corp. C. S. Higano has served as a paid consultant for Amgen, Astra Zeneca, Bayer, Bristol-Myers Squibb, Medivation, Millennium, Sanofi-Aventis, Teva, and Dendreon Corp; received research funding from Amgen, Bayer, Cell Genesys, Cougar, Imclone, Medivation, Millennium, Sanofi-Aventis, Teva, and Dendreon Corp; received honoraria from Amgen, Astra Zeneca, Bayer, Bristol-Myers Squibb, Medivation, Millennium, Sanofi-Aventis, Teva, and Dendreon Corp; her spouse is cofounder of Cell Therapeutics, Inc. E. J. Small has received honoraria from Celgene Corp, F Hoffman-La Roche Ltd, J&J Pharma Serv, LLC, Millennium, and Dendreon Corp and has received other remuneration from Dendreon Corp. J. B. Whitmore and M. W. Frohlich are employees of Dendreon Corp. P. F. Schellhammer has received honoraria from Amgen, Astra Zeneca, Bayer, and Dendreon Corp. The authors thank Johnathan C. Maher, PhD, of Dendreon Corp for contributing to the writing and editing of the submitted work. All authors contributed to the conception and design of the manuscript, data analysis and interpretation, writing and editing of the manuscript, and approved the final version for submission.