Abiraterone plus Low-Dose Prednisone before Chemotherapy Improves Outcomes of Patients with Metastatic Prostate Cancer
Background: Metastatic castration-resistant prostate cancer (CRPC) is associated with rapid deterioration and leads to mortality within 2 to 4 years. The treatment options available for patients who have not received chemotherapy have been proved to produce response in these patients, but new options are needed that could lead to tumor regression or prolong life. Previous studies have shown that the use of abiraterone plus low-dose prednisone in patients with CRPC who have received chemotherapy improves survival; this combination was subsequently approved by the US Food and Drug Administration for this patient population. Early-phase clinical trials in patients with CRPC who have not received chemotherapy have shown increased response rates with this combination.
Design: This phase 3 clinical trial was designed to evaluate the effects of the combination of abiraterone plus low-dose prednisone on radiographic progression-free survival (PFS) and overall survival (OS) and other measures of disease progression in patients with advanced or metastatic disease before chemotherapy. Between April 2009 and June 2012, a total of 1088 patients were randomized in a 1:1 ratio to receive 1000 mg of abiraterone plus prednisone 5 mg twice daily (ie, low dose) or placebo plus prednisone. The primary end points were radiographic PFS and OS.
Discussion: By the time of the first interim analysis on December 20, 2010, the combination of abiraterone plus low-dose prednisone resulted in a 57% reduction in the risk of radiographic progression or death. The study was unblinded after this analysis, when 43% of the expected deaths occurred. The median radiographic PFS was 16.5 months with the active combination versus 8.3 months with placebo (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.45-0.62; P <.001). At a median follow-up of 22 months, OS was improved with abiraterone plus low-dose prednisone versus 27.2 months with placebo plus prednisone. In addition, a 25% reduction in mortality risk was seen with the active combination (HR, 0.75; 95% CI, 0.61-0.93; P = .01), showing a strong trend of improved survival. The PFS was favorable across all subgroups with the active combination. The addition of abiraterone to low-dose prednisone was associated with favorable PFS across all subgroups compared with prednisone and with placebo. Furthermore, the abiraterone plus prednisone combination was superior to prednisone plus placebo in terms of time to initiation of cytotoxic chemotherapy, pain medication use, prostate-specific antigen progression, and performance status. As can be expected, grade 3 or grade 4 adverse events and abnormalities on liver function were more frequent with the abiraterone plus prednisone combination.
Takeaway: Having a noncytotoxic pharmacotherapy is an important advance in the treatment of metastatic prostate cancer. Not only did combination abiraterone and prednisone improve PFS, but it also led to a delay in the use of subsequent chemotherapy or analgesic therapy, effects that clearly improved patients’ quality of life. Furthermore, abiraterone plus prednisone was well tolerated and safe for long-term use, in contrast to systemic chemotherapy which can cause life-threatening adverse effects and poor quality of life. Of note is that abiraterone acetate is hydrolyzed to the active metabolite abiraterone and is then further metabolized to inactive metabolites abiraterone sulphate and N-oxide abiraterone sulphate by CYP3A4 and SULT2A1. Therefore, there are many potential drug interactions with abiraterone, including CYP2D6 and CYP2D8 substrates and CYP3A4 substrates.
Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-148.
Adding Rituximab to Chlorambucil Improves Event-Free Survival in Patients with MALT Lymphoma
Background: Approximately 8% of patients with non- Hodgkin lymphoma have extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). The condition can occur in any extranodal location, although the stomach is the most frequent site. Although eradication of Helicobacter pylori has been shown to be successful in treating localized gastric involvement, no consensus exists about the optimal treatment for patients with extensive MALT lymphoma.
Design: The first phase of the IELSG-19 (Randomized Trial of Chlorambucil Versus Chlorambucil plus Rituximab Versus Rituximab in MALT Lymphoma), international, multicenter, phase 3 clinical trial, from January 2003 to October 2005, randomized 252 patients with MALT lymphoma in a 1:1 ratio to chlorambucil alone (arm A) or to chlorambucil plus rituximab (arm B). All patients were aged >18 years and had a diagnosis of CD20-positive MALT lymphoma at any extranodal site. Patients did not receive any previous therapy other than for the purpose of H pylori eradication. After October 2005, a third arm receiving rituximab therapy alone (arm C) was added. This report is based on the results of the first phase only, which included only 2 arms.
Results: After a median follow-up of 62 months, the median event-free survival (EFS) in the 2 arms combined had not been reached. At 5 years, the EFS in the patients receiving rituximab plus chlorambucil was significantly better than the patients receiving chlorambucil alone (68% vs 50%, respectively; 95% confidence interval [CI], 59%-76% vs 41%-60%, respectively; P = .002). Adding rituximab to chlorambucil led to a significant improvement in EFS (hazard ratio, 0.52; 95% CI, 0.34-0.79). A total of 22 patients had an event that was not related to progression or to death. Although the overall response rate was similar in the 2 arms, the combination of rituximab plus chlorambucil resulted in a greater rate of complete remission compared with chlorambucil alone (78% vs 65%, respectively). The 5-year overall survival rate was 89% in the 2 arms. Both treatments were also well tolerated, and no unexpected toxicities were reported in any arm.
Takeaway: There is no standardized treatment for advanced cases of extranodal MALT lymphomas. The National Comprehensive Cancer Network guidelines recommend chemotherapy regimens that are effective for follicular lymphoma, including R-CHOP/R-CVP, bendamustine plus rituximab, single-agent alkylating agents (cyclophosphamide or chlorambucil), or rituximab alone. This study shows that rituximab added to chlorambucil improves EFS and the response rate compared with chlorambucil alone. It is likely that the addition of rituximab to other alkylators, such as cyclophosphamide, would be equivalent in efficacy to chlorambucil plus rituximab. These regimens are particularly useful for elderly patients. It will be interesting to see the results of the third arm of this trial and whether combination therapy with chlorambucil plus rituximab is better than single-agent rituximab.
Zucca E, Conconi A, Laszlo D, et al. Addition of rituximab to chlorambucil produces superior event-free survival in the treatment of patients with extranodal marginal-zone B-cell lymphoma: 5-year analysis of the IELSG-19 randomized study. J Clin Oncol. 2013;31:565-572.
T-DM1 Significantly Prolongs Survival in Patients with HER2 Advanced Breast Cancer
Background: Approximately 20% of patients with advanced breast cancer exhibit amplification of the epidermal growth factor, HER2, which is associated with shortened survival. The combination of cytotoxic chemotherapy and HER2-targeted agents is an effective therapy for these cases. The antibody drug conjugate trastuzumab emtansine (T-DM1) includes anti–HER2-targeted antitumor properties with the cytotoxic activity of DM1, a microtubule-inhibitor agent.
Design: In this international phase 3 clinical trial known as EMILIA, 991 patients with advanced HER2-positive breast cancer were randomized in a 1:1 ratio to T-DM1 3.6 mg/kg intravenously every 21 days or to 1250 mg of oral lapatinib plus oral capecitabine. Dose adjustments, including reductions and delays, as well as discontinuation because of adverse events, were done per protocol. All patients had previously received trastuzumab and a taxane. The primary end points were progression-free survival (PFS) and overall survival (OS). The secondary end points were objective response rate and time to symptom progression.
Results: The median PFS (as assessed by an independent review) was 9.6 months with T-DM1 compared with 6.4 months with the combination of lapatinib and capecitabine, with a hazard ratio (HR) for disease progression or death of 0.65 (95% confidence interval [CI], 0.55-0.77; P <.001). At the second interim analysis, the median OS was 30.9 months with T-DM1 versus 25.1 months for the combination of lapatinib plus capecitabine (HR for all-cause death, 0.68; 95% CI, 0.55-0.85; P <.001). The objective response rate was also higher with T-DM1 than with the combination (43.6% vs 30.8%, respectively; P <.001). All of the results for the other secondary end points also favored T-DM1. Overall, the new agent was less toxic than the combination of lapatinib and capecitabine in this setting. Grade 3 or 4 events were more frequent with the combination than with T-DM1.
Takeaway: T-DM1 is the first immunoconjugate drug approved by the US Food and Drug Administration for the treatment of any cancer. A very potent cytotoxic drug, a maytansine-like agent, emtansine is linked to the targeted drug trastuzumab. This immunoconjugate is approved for HER2-positive, metastatic breast cancer in patients who were previously treated with trastuzumab or a taxane alone or in combination. This pivotal randomized trial of T-DM1 versus the second-line combination of lapatinib plus capecitabine in patients with locally advanced or metastatic breast cancer produced a very impressive 50% prolongation of PFS, a 5-month improvement in OS, and a 32% reduction in mortality. The toxicity profile of T-DM1 was significantly better than the cytotoxic combination. This new drug may now be considered a first-line treatment for recurrent advanced HER2-positive breast cancer. As an aside, this study provides evidence for the proof of concept by linking a very toxic cytotoxic compound to a targeted linking agent. It is expected that more immunoconjugates will be forthcoming in the treatment of patients with cancer.
Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.