Chapter 7eProstate Cancer / 87

This is just another example of how androgen deprivation is associated with

an increased risk of long-term adverse events. Add colorectal carcinoma to

osteoporosis, diabetes, and, possibly, cardiovascular events. While men in this

age group should already be undergoing routine screening, I believe that

urologists should be reinforcing this message with all our patients.

A. S. Kibel, MD

Advanced Disease

Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer

Kantoff PW, for the IMPACT Study Investigators (Harvard Med School,

Boston, MA; et al)

N Engl J Med 363:411-422, 2010

Background.dSipuleucel-T, an autologous active cellular immuno-therapy, has shown evidence of efficacy in reducing the risk of deathamong men with metastatic castration-resistant prostate cancer.

Methods.dIn this double-blind, placebo-controlled, multicenter phase3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive eithersipuleucel-T (341 patients) or placebo (171 patients) administered intrave-nously every 2 weeks, for a total of three infusions. The primary end pointwas overall survival, analyzed by means of a stratified Cox regressionmodel adjusted for baseline levels of serum prostate-specific antigen(PSA) and lactate dehydrogenase.

Results.dIn the sipuleucel-T group, there was a relative reduction of22% in the risk of death as compared with the placebo group (hazardratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P¼ 0.03). Thisreduction represented a 4.1-month improvement in median survival(25.8 months in the sipuleucel-T group vs. 21.7 months in the placebogroup). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect wasalso observed with the use of an unadjusted Cox model and a log-ranktest (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P¼ 0.02) and after adjust-ment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95%CI, 0.62 to 0.98; P¼ 0.03). The time to objective disease progression wassimilar in the two study groups. Immune responses to the immunizingantigen were observed in patients who received sipuleucel-T. Adverseevents that were more frequently reported in the sipuleucel-T groupthan in the placebo group included chills, fever, and headache.

Conclusions.dThe use of sipuleucel-T prolonged overall survivalamong men with metastatic castration-resistant prostate cancer. No effecton the time to disease progression was observed. (Funded by Dendreon;ClinicalTrials.gov number, NCT00065442.)

:

A few years ago we were desperate for new treatments for advanced prostate

cancer. Now, overnight we have multiple new options. This randomized trial

88 / Urology

demonstrated that immunotherapy improves survival in patients with castration-

resistant prostate carcinoma. The findings in this study are consistent with

prior underpowered studies that demonstrated an overall survival advantage

for sipuleucel-T. Interestingly, this prior work did not demonstrate an improve-

ment in progression-free survival. This most recent study was large enough to

finally put this question to rest. There clearly was an overall survival advantage

and, once again, no improvement in progression-free survival. The hazard

ratio demonstrated an improvement of approximately 22%, which was statisti-

cally significant. This translated to just over a 4-month improvement in survival.

This is not a curative therapy. As can be seen from Fig 2 in the original article,

most of these patients eventually died. However, it is hard to argue with the

results. Overall survival is the ultimate end point of any clinical trial. The poor

survival in both arms of the trial reflects the fact that these are patients who

have received prior therapies and have progressed through them and reached

the end stage of their disease. I think it would be interesting to see how this

drug performs earlier in the disease progression when the immune system is

more robust. I think the most encouraging thing is that this treatment, along

with others, heralds a new age in the treatment of metastatic prostate cancer

and gives hope to our patients that we will eventually provide a substantial

improvement in both their quantity and quality of life.

A. S. Kibel, MD

Antiandrogen monotherapy in patients with localized or locally advanced

prostate cancer: final results from the bicalutamide Early Prostate Cancer

programme at a median follow-up of 9.7 years

Iversen P, on behalf of the Casodex Early Prostate Cancer Trialists’ Group

(Rigshospitalet, Copenhagen, Denmark; et al)

BJU Int 105:1074-1081, 2010

Objective.dTo evaluate the efficacy and tolerability of bicalutamide150 mg once-daily as immediate hormonal therapy in patients with pros-tate cancer or as adjuvant to radical prostatectomy or radiotherapy.Patients and Methods.dIn all, 8113 patients with localized (T1-2,

N0/Nx) or locally advanced (T3-4, any N; or any T, N+) prostate cancer(all M0) were enrolled in three complementary, double-blind, placebo-controlled trials. Patients were randomized to receive standard care pluseither oral bicalutamide 150 mg once-daily or oral placebo. Primaryendpoints were progression-free survival (PFS) and overall survival (OS).Data were collated from individual trials and evaluated in a combinedanalysis.Results.dOverall, at a median follow-up of 9.7 years, bicalutamide

significantly improved PFS (hazard ratio 0.85, 95% confidence interval0.79e0.91; P¼ 0.001). Compared with placebo there was no differencein OS (hazard ratio 1.01, P¼ 0.77). Patients who derived benefit frombicalutamide in terms of PFS were those with locally advanced disease,with OS significantly favouring bicalutamide in patients with locally