Enzalutamide Prolongs Overall Survival in
Prostate Cancer after Chemotherapy
Background: The once-daily oral androgen receptor signaling inhibitor enzalutamide differs from current antiandrogen therapies by its ability to inhibit nuclear translocation of the androgen receptor and its coactivator recruitment, in addition to other benefits in prostate cancer. This novel agent is administered without the need for concomitant prednisone, which has been postulated to activate androgen-receptor signaling.
Design: In this phase 3, double-blind, placebo-controlled clinical trial, enzalutamide significantly prolonged survival in patients with castration-resistant prostate cancer (CRPC) after standard chemotherapy. A total of 1199 men with CRPC who had received chemotherapy were randomized in a 2:1 ratio to oral enzalutamide 160 mg daily or to placebo. The primary end point was overall survival (OS).
Results: Based on the study design, the trial was stopped when 520 deaths occurred, and an interim analysis was conducted. At that point, the OS was not reached with enzalutamide. The median OS was 18.4 months in the group receiving enzalutamide (confidence interval [CI], 18.3-not reached) compared with 13.6 months with placebo (CI, 11.3-15.8). Enzalutamide was significantly (P <.001) superior to placebo in all the secondary end points. These secondary measures showed that 54% of patients who received enzalutamide had reduced prostate-specific antigen (PSA) levels by more than 50% versus by 2% in the placebo group; the quality-of-life response rate was 43% with enzalutamide versus 18% with placebo; time to PSA progression was 8.3 months versus 3.0 months, respectively; radiographic progression-free survival was 8.3 months versus 2.9 months (hazard ratio, 0.40), respectively; and time to first skeletal-related event was 16.7 months versus 13.3 months (hazard ratio, 0.69), respectively.
The rates of adverse events (AEs) were similar in the 2 groups, with the exception of higher rates of fatigue, diarrhea, and hot flashes reported with enzalutamide than with placebo. In addition, 5 patients (0.6%) had seizures while taking enzalutamide. Of note, AEs of grade ≥3 occurred 8.4 months earlier with placebo than with enzalutamide—the median time to such events was 4.2 months with placebo and 12.6 months with enzalu-tamide. Enzalutamide is currently being investigated in clinical trials of men with earlier-stage prostate cancer.
Takeaway: The results are impressive and show that enzalutamide is as effective as other second-line therapies for advanced CRPC. Of note, prednisone, a known stimulator of androgen receptor and receptor signaling, is not required with this drug, thereby avoiding its AEs. Another valuable result was that the clinical benefits occurred in the presence of castrate levels of testosterone and that androgen-receptor signaling and overexpression play an important role in CRPC. It may be rational to combine enzalutamide and antiandrogens in CRPC, but follow-up studies are needed. Enzalutamide may be added to the other drugs that prolong survival in CRPC. It is clear that enzalutamide has a safer toxicity profile than the cytotoxic drugs mitoxantrone and docetaxel, but it should be used with caution in patients with a history of seizures or those receiving drugs that lower the seizure threshold.
Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.
Anastrozole-Fulvestrant Combination Improves
Overall Survival in Metastatic Breast Cancer
Background: Fulvestrant downgrades the estrogen receptor and may therefore improve survival in postmenopausal women with hormone-receptor (HR)-positive metastatic breast cancer.
Design: The Southwest Oncology Group (SWOG) study randomized 707 postmenopausal patients with previously untreated HR-positive metastatic breast cancer to anastrozole alone or to a combination of anastrozole plus fulvestrant. All patients received 1 mg of anastrozole; those in the combination group also received a 500-mg loading dose of fulvestrant on day 1, followed by 250 mg on days 14, 28, and every 28 days thereafter. Patients in the anastrozole-alone group whose disease progressed were strongly encouraged to cross over to receive fulvestrant alone. Early in 2011, when the 500 mg of fulvestrant was approved by the US Food and Drug Administration, all patients were allowed to receive the 500-mg dose.
Results: In the SWOG study, the median progression-free survival (PFS) was 15.0 months with the combination therapy and 13.5 months with anastrozole alone, representing a significant difference (P = .007); the overall survival (OS) was 41.3 months with anastrozole alone and 47.7 months with the combination therapy, also a significant difference (P = .049), although 41% of these patients crossed over to fulvestrant after progression. This is the first study of first-line hormone therapy used for HR-positive metastatic breast cancer that shows an improvement in OS. It is also the first study to show the superiority of concurrent therapy with 2 hormonal modulators over monotherapy, especially an improvement in OS. Toxic effects were mild and similar between the 2 groups. However, more patients who received the combination therapy discontinued treatment because of toxicity.
Takeaway: Although this study shows a significant difference in PFS for the combination of anastrozole and fulvestrant, the difference was only 1.5 months. The anastrozole group was allowed to cross over to low-dose fulvestrant, which did not improve OS versus the combination group. Three other studies have shown that high-dose fulvestrant after an aromatase inhibitor improved OS. In an unplanned subset analysis in the current study, the greatest benefit was seen in patients previously untreated with tamoxifen. This study contrasts with another recent study that showed no benefit from the combination of low-dose fulvestrant plus anastrozole (Bergh J, et al. J Clin Oncol. 2012;30:1919-1925). Mehta and colleagues suggest that further studies should be performed, combining an aromatase inhibitor and high-dose fulvestrant in comparison to an aromatase inhibitor or high-dose fulvestrant alone. Therefore, this study has too many confounding variables, and it is unclear whether the combination of low-dose fulvestrant plus anastrozole cannot be recommended at this time.
Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367:435-444.
Adding Cetuximab to Chemotherapy Improves
Outcomes in Patients with KRAS G13D Mutation
Background: Although epidermal growth factor receptor (EGFR) monoclonal antibodies were initially indicated for the treatment of EGFR-expressing metastatic colorectal cancer (mCRC), studies conducted in patients with mCRC have failed to show benefits of the EGFR monoclonal antibodies cetuximab and panitumumab for patients with KRAS mutations. About 40% of patients have a KRAS mutation; most frequent mutations are G12D (13%), G12V (9%), and G13D (8%).
Design: This new analysis of pooled data from previously published studies evaluated progression-free survival (PFS), overall survival (OS), and response to therapy using published results from 1378 patients in the 2 randomized clinical trials, CRYSTAL and OPUS. Among the 533 patients (39%) with KRAS mutations, 83 (16%) had the G13D mutation, 125 (23%) had the G12V mutation, and 325 (61%) had other mutations.
Results: Previous comparisons between patients with KRAS wild-type tumors and patients with KRAS mutations have not differentiated between subtypes of KRAS mutations, but this analysis shows significant variations in treatment effects in terms of the response rate and duration of PFS in patients with the KRAS G13D mutation compared with all the other mutations (including KRAS G12V). There was no significant OS difference between the groups; median OS was 15.4 months with the combination versus 14.7 months with chemotherapy alone (hazard ratio, 0.89; P = .68) in patients with the G13D mutation. Patients with G12V and other mutations did not benefit from the combination. However, in the subgroups of patients with the KRAS G13D mutation, PFS improved significantly by adding cetuximab to standard chemotherapy, leading to a median PFS of 7.4 months with the combination compared with 6.0 months with placebo (hazard ratio, 0.47; P = .039); similarly, tumor response rate was 40.5% versus 22.0%, respectively (odds ratio [OR], 3.38; P = .042). Of note, patients with the KRAS G13D mutation who received chemotherapy alone had worse outcomes than those with other mutations receiving chemotherapy alone (response rate, 22.0% vs 43.2%; OR, 0.40; P = .032).
Takeaway: This study confirms the results from a previous report by the same authors, indicating that the type of KRAS mutation plays a role in the response of the EGFR inhibitors cetuximab and pantimumab. The results show that tumor response and PFS were significantly better with cetuximab plus FOLFOX or FOLFIRI in patients with mCRC and KRAS G13D mutation compared with chemotherapy alone. These outcomes were comparable to those of patients with the KRAS wild-type. Of note, patients with KRAS G13D treated with chemotherapy alone had a worse response rate and PFS than patients with other KRAS mutations. However, patients with the G12V mutation treated with the combination had worse OS compared with the wild-type mutation group. Further research is ongoing to determine the mechanism associated with these differences. The lesson is that KRAS mutation subtypes affect the tumor biology of CRC and should be considered in treatment planning. This study suggests that KRAS screening should be broadened to include KRAS subtypes.
Tejpar S, Celik I, Schlichting M, et al. Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol. 2012;30:3570-3577.