Abiraterone Improves Overall Survival in Patients with Metastatic Prostate Cancer
Background: Androgen deprivation has long been the standard of care for men with advanced prostate cancer, demonstrating efficacy in preventing or delaying the recurrence of metastases in this patient population. The selective androgen biosynthesis inhibitor abiraterone acetate, administered either alone or in combination with low-dose prednisone, has demonstrated significant antitumor activity in men with advanced prostate cancer, regardless of any previous chemotherapy treatment. However, whether abiraterone prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer whose disease progressed after docetaxelbased chemotherapy was not previously known.
Design: This phase 3 multinational, double-blind, placebo-controlled trial included patients from 147 sites in 13 countries; they were followed from May 2008 through July 2009. A total of 1195 patients who had previously received docetaxel chemotherapy were randomly assigned in a 2:1 ratio to 2 groups to receive 1000 mg daily of abiraterone acetate (administered as four 250-mg tablets) plus prednisone 5 mg twice daily (N = 797), or placebo plus prednisone (N = 398). The primary end point was OS; the secondary end points included time to prostate-specific antigen (PSA) progression; progressionfree survival (PFS), determined from radiologic findings; and PSA response rate.
Summary: The primary and secondary end points in this study all showed significantly improved outcomes in the active treatment group compared with the placebo group. After a median follow-up period of 12.8 months, patients receiving abiraterone demonstrated significantly longer OS (14.8 months) than those receiving placebo (10.9 months; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.54-0.77; P <.001). For the interim analysis, the data were unblinded, because these results exceeded the preplanned criteria for study termination. Secondary end points also showed improvement with abiraterone compared with placebo: the PFS period was longer with abiraterone compared with placebo (5.6 months vs 3.6 months, respectively; P <.001), as was time to PSA progression (10.2 months vs 6.6 months, respectively; P<.001), and the PSA response rate was greater (29% vs 6%, respectively; P <.001). Treatment with abiraterone had a low frequency of treatment-related toxic effects. Patients receiving abiraterone plus prednisone, however, had more mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, than those receiving placebo plus prednisone.
Takeaway: This phase 3 study of a novel testosterone biosynthetic inhibitor demonstrated a significant im - provement in OS, PFS, and PSA responses in patients with castrate-resistant prostate cancer who had been previously treated with docetaxel. Furthermore, adverse events were low grade and largely minimized by concurrent low-dose prednisone therapy. The results of this study provide a proof of the principle that metastatic castrate-resistant prostate cancer is still driven by endogenous androgens. Therefore, hormonal therapy can be considered for a patient in whom previous chemotherapy has failed. The next study that should be conducted would involve a comparison between firstline therapy with abiraterone acetate versus docetaxelbased chemotherapy in the setting of castrate-resistant prostate cancer.
de Bono JS, et al. N Engl J Med. 2011;364:1995-2005.
Comparing Denosumab and Zoledronic Acid for Treatment of Bone Metastases in Men with Castration-Resistant Prostate Cancer
Background: The development of bone metastases is common in men with advanced prostate cancer. Researchers have therefore been investigating therapies for the treatment or prevention of bone metastases in this patient population. In a new study, denosumab, a human monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL), was compared in a phase 3 study with zoledronic acid for the prevention of skeletalrelated events (SREs) in men with bone metastases caused by castration-resistant prostate cancer.
Design: Men from 342 centers in 39 countries with castration-resistant prostate cancer and no previous exposure to intravenous (IV) bisphosphonates were randomly assigned to receive 120 mg of subcutaneous denosumab plus IV placebo or 4 mg of IV zoledronic acid plus subcutaneous placebo every 4 weeks. The primary end point was the time to a first on-study SRE (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), which was assessed first for noninferiority and then for superiority as a secondary end point. An intention-to-treat analysis was performed to assess efficacy, and safety was assessed according to the incidence of treatment-emergent adverse events and changes in hematology and laboratory findings.
Summary: Among 1901 patients who were assigned to treatment and were eligible for the efficacy analysis, 950 received denosumab and 951 received zoledronic acid. The median duration on study at the primary analysis cutoff date was 12.2 months (interquartile range, 5.9-18.5) for patients given denosumab and 11.2 months (5.6-17.4) for those given zoledronic acid. The median time to a first on-study SRE was 20.7 months (95% CI, 18.8-24.9) with denosumab versus 17.1 months (15.0-19.4) with zoledronic acid (HR, 0.82; 95% CI, 0.71-0.95; P = .0002 for noninferiority; P = .008 for superiority). Adverse events occurred in 916 patients (97%) given denosumab and 918 (97%) given zoledronic acid, and serious adverse events occurred in 594 (63%) and 568 patients (60%), respectively. More episodes of hypocalcemia occurred with denosumab (121 [13%]) than with zoledronic acid (55 [6%]; P <.0001). The occurrence of osteonecrosis of the jaw was not significant (22 [2%] vs 12 [1%], respectively; P = .09).
Takeaway: Denosumab is a human monoclonal antibody that binds to RANKL, leading to inhibition of osteoclast-mediated bone destruction. In this study, denosumab therapy delayed the time to first SREs by 18% compared with zoledronic acid. Furthermore, the decrease in markers of bone turnover was greater with denosumab than with zoledronic acid. However, OS and time to progression were not different between the groups. The authors concluded that denosumab is better than zoledronic acid for preventing SREs. This is the first monoclonal antibody shown to be an effective agent in bone metastases caused by castrate-resistant prostate cancer. Its role in this setting would be further defined by the results of a comparative pharmacoeconomics study.
Fizazi K, et al. Lancet. 2011;377:813-822.
Sipuleucel-T Immunotherapy Extends Overall Survival for Patients with Castration-Resistant Prostate Cancer
Background: Sipuleucel-T, an autologous active cellular immunotherapy, has demonstrated efficacy in reducing the risk of death among men with metastatic castration- resistant prostate cancer. Previous research, however, has not confirmed improved OS with the drug.
Design: Researchers in the double-blind, placebocontrolled, multicenter Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) study randomly assigned 512 patients in a 2:1 ratio to receive either sipu - leucel-T or placebo administered intravenously every 2 weeks for a total of 3 infusions. The primary end point was OS, determined from a stratified Cox regression model adjusted for baseline levels of serum PSA and lactate dehydrogenase.
Summary: The relative risk of death among 341 patients given sipuleucel-T was 22% lower than that among 171 patients given placebo (HR, 0.78; 95% CI, 0.61-0.98; P = .03), translating to a 4.1-month longer median survival (25.8 months vs 21.7 months, respectively). In addition, the 36-month survival probability was 31.7% and 23.0%, respectively. The treatment effect was also demonstrated in an unadjusted Cox model and a log-rank test (HR, 0.77; 95% CI, 0.61-0.97; P = .02) and after adjustment for the use of docetaxel after the study therapy (HR, 0.78; 95% CI, 0.62-0.98; P = .03). The time to objective disease progression was similar in the 2 study groups. Patients who received sipuleucel-T also demonstrated immune responses to the immunizing antigen. Adverse events that occurred more frequently among patients given sipuleucel-T than among those given placebo included chills, fever, and headache.
Takeaway: Vaccine immunotherapy has been studied but has not been proved beneficial until this study. Compared with placebo, sipuleucel-T improved OS by 4 months in patients with castrate-resistant prostate cancer and was consistent among all subgroups of prognostic factors. About half of the patients in the placebo group crossed over to the cancer vaccine group. OS was almost 24 months with the active treatment compared with 12 months in the placebo group. Adverse effects were minimal and well tolerated, mainly consisting of infusion reactions. This study establishes sipuleucel-T as a useful agent, especially in the setting of asymptomatic advanced prostate cancer. Because several therapies are now available that are effective in this setting, placebocontrolled trials in patients with castrate-resistant prostate cancer may no longer be ethical.
Kantoff PW, et al. N Engl J Med. 2010;363:411-422.
Improving Survival with Ipilimumab in Metastatic Melanoma
Background: In phase 3 randomized trials involving patients with metastatic melanoma, no therapy has been demonstrated to extend OS to 1 year or beyond. Ipilimumab, a fully human monoclonal antibody that potentiates an antitumor T-cell response by blocking cytotoxic T-lymphocyte–associated antigen, has shown activity as monotherapy in phase 2 studies. Previous research suggests glycoprotein 100 (gp100) peptide vaccine, which also induces immune response but has limited antitumor activity as monotherapy, may improve the efficacy of high-dose interleukin-2 in patients with metastatic melanoma. In this phase 3 study, ipilimumab, administered with and without gp100, was compared with gp100 alone in patients who had previously undergone therapy for metastatic melanoma.
Design: In a randomized, double-blind, phase 3 study, HLA-A*0201–positive patients with unresectable stage III or IV melanoma that had progressed during previous therapy for metastatic disease were enrolled between September 2004 and August 2008 at 125 centers in 13 countries in North America, South America, Europe, and Africa. All were randomly assigned in a 3:1:1 ratio to receive either ipilimumab (3 mg/kg body weight) plus gp100, ipilimumab alone, or gp100 alone every 3 weeks for a total of 4 treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was OS.
Summary: Among a total of 676 patients, 403 received ipilimumab plus gp100, 137 received ipilim - umab alone, and 136 received gp100 alone. The median OS was 10.0 months among patients who received ipilimumab plus gp100, versus 6.4 months among those who received gp100 alone (HR for death, 0.68; P <.001) and 10.1 months among those given ipilimumab alone (HR for death in the comparison with gp100 alone, 0.66; P = .003). OS did not differ between patients who received ipilimumab alone and those given the combination (HR with ipilimumab plus gp100, 1.04; P = .76). Grade 3 or 4 immune-related adverse events occurred in 10% to 15% of patients who received ipilimumab and in 3% who received gp100 alone. Fourteen deaths were related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.
Takeaway: This randomized, 3:1:1 ratio trial showed that ipilimumab, with or without gp100, improved OS by 32% to 34% compared with gp100 alone. This is the first agent to show such an improvement in OS in metastatic melanoma. Furthermore, gp100 did not improve patient outcomes compared with ipilimumab alone. The primary adverse effects associated with ipi - limumab are immune-mediated, manifested as gastrointestinal tract or dermatologic reactions (ie, rash, pruritus, or vitiligo). A total of 14 patients (2.1%) had their mortality associated with ipilimumab therapy, 7 of which were related to immune-mediated adverse events affecting the gastrointestinal tract: colitis and septicemia associated with bowel perforation—inflammatory colitis, bowel perforation, or multiorgan failure—peritonitis. Ipilimumab may be considered for patients in whom previous therapies have failed.
Hodi FS, et al. N Engl J Med. 2010;363:711-723.
Beta-Blocker Therapy Linked to Reduced Progression of Thick Melanoma
Background: The association between beta-adrenoceptor antagonist (beta-blocker) therapy and the overall risk of cancer or of specific, prevalent cancers, such as breast cancer, has not been established. However, the results of a new study suggest that beta-blockers may reduce the risk of prostate cancer, and findings from preclinical studies indicate that beta-blockers inhibit tumor growth and metastasis in animal models of melanoma.
Design: Researchers at a dermatology clinic in Florence, Italy, prospectively reviewed clinical records from 1993 through 2009 of all patients with histologically confirmed malignant melanoma (Breslow thickness >1 mm). Disease progression was indicated by evidence of sentinel lymph node metastasis and lymphatic, intransit, or visceral metastasis. Deaths by any cause and those due to melanoma were recorded, and medication use patterns were determined from patient interviews during the first visit and at each 6-month follow-up visit and from the patients’ general practitioner once a year during the study period. Patients who had reported betablocker use for at least 1 year were considered to have undergone treatment. Median OS and median diseasefree survival (DFS) were calculated, and a Cox proportional hazards model was used to evaluate the influence of treatment on DFS and OS, adjusting for significant confounders.
Summary: Of 121 consecutive patients documented with a thick melanoma, 30 had been undergoing beta-blocker therapy for 1 year or more, whereas the other 91 had not undergone treatment. After a median follow-up period of 2.5 years, tumor progression was observed in 3.3% of patients prescribed beta-blockers and in 34.1% of those who were not. The Cox model on disease progression indicated a 36% (95% CI, 11%-54%; P = .002) risk reduction for each year of beta-blocker use. No deaths were observed among those taking betablockers, but among those who were not taking betablockers, 24 had died.
Takeaway: This retrospective study produced an inter esting outcome—beta-blocker therapy for more than 1 year significantly decreased the death rate from thick (>1 mm in Breslow thickness) melanoma. The mechanism for this effect is not yet well understood, but it has been suggested that its antiangiogenic properties, as well as its ability to decrease stress mediators, including norepinephrine, may be responsible for this effect. This study was limited by a small number of patients and by its observational methodology. The results of this study, however, suggest that a prospective randomized trial in malignant melanoma is indicated.
De Giorgi V, et al. Arch Intern Med. 2011;171:779-781.
Bisphosphonates May Reduce the Risk of Colorectal Cancer in Postmenopausal Women
Background: Bisphosphonates are often used to treat osteoporosis and bone metastases caused by breast cancer and, in fact, have been shown recently to reduce the risk of that type of cancer, possibly by acting through the mevalonate pathway. Their effect on the risk of other cancers, however, is unknown.
Design: Computerized health service pharmacy records were examined to evaluate the dose-response relationship between the duration of long-term bisphosphonate use and the risk of colorectal cancer (CRC) among 933 pairs of postmenopausal women and age-, sex-, clinic-, and ethnic group–matched individuals recruited between 2000 and 2006 in the ongoing population- based, case-controlled Molecular Epidemiology of Colorectal Cancer Study in Israel.
Summary: Bisphosphonate therapy lasting for more than 1 year before diagnosis, but not for less than 1 year, was associated with a significantly reduced relative risk of CRC (relative risk, 0.50; 95% CI, 0.35-0.71), even after adjustment for possible confounders or effect modifiers such as vegetable consumption, sports activity, family history of CRC, body mass index, and the use of lowdose aspirin, statins, vitamin D, or postmenopausal hormones (relative risk, 0.41; 95% CI, 0.25-0.67). Bisphosphonate therapy combined with statin use, however, did not lower the risk for CRC further.
Takeaway: Bisphosphonates have been associated with a low risk for breast cancer. Inhibition of angiogenesis and of tumor-cell adhesion and promotion of apoptosis are other antitumor mechanisms that have been suggested for the benefits associated with bisphosphonates. This retrospective study of bisphosphonate therapy for more than 1 year significantly decreased the risk for CRC by 59%. Alendronate was used in almost 95% of patients in the bisphosphonate group. Patient adherence was estimated to be 89% to 96% and depended on the dosing schedule. These data suggest that bisphosphonates should be considered for future cancer prevention studies.
Rennert G, et al. J Clin Oncol. 2011;29:1146-1150.