“The recent report of results of RTOG 9601 by Shipley et al in The New England Journal of Medicine—reviewed in this issue of The ASCO Post—strongly supports the variably used practice of adding ‘androgen blockade’ to salvage radiation therapy in men with a rising prostate-specific antigen (PSA) after radical prostatectomy. The findings show a clear reduction in prostate cancer–specific and overall mortality with the addition of 2 years of bicalutamide to salvage radiation therapy. Another likely (although not demonstrated) benefit is the reduction in the need to treat patients with subsequent life-long continuous or intermittent androgen blockade at the expense of treating all men with 2 years of bicalutamide.”
“The addition of hormonal therapy to radiation treatment following surgery significantly improved survival in patients with recurrent prostate cancer, according to the results of a study published in The New England Journal of Medicine.
“In the multicenter trial—which initially enrolled 760 men with biochemical recurrence after radical prostatectomy—patients were randomly assigned to treatment with bicalutamide or placebo for 2 years, along with 6.5 weeks of radiation therapy.”
“After surgery to remove the prostate, more than 30 percent of men have a recurrence, and until now there has not been clear evidence about the best way to stop the disease from killing them. Most are given radiation, but prescribing drugs to counter the effects of male hormones has been inconsistent.”
Written by Emma Shtivelman, PhD and Dov Shiffman, PhD
The American Society of Clinical Oncology (ASCO) meeting of 2016 is behind us, but oncologists, patients, and journalists are still analyzing the most interesting presentations made there. Below, we describe some of the more prominent results in triple negative breast cancer (TNBC), both promising and disappointing.
“The oral androgen receptor inhibitor enzalutamide significantly reduced the risk for prostate cancer progression or death compared with bicalutamide in patients with castration-resistant prostate cancer, according to findings from the STRIVE trial.
“Enzalutamide (Xtandi, Astellas) has been found to improve survival in men with castration-resistant prostate cancer prior to and following chemotherapy. It binds the androgen receptor in the same way as bicalutamide does, but with greater affinity, according to researchers.
“Since bicalutamide is the standard treatment for this population of patients, researchers conducted this phase 2 trial to compare the two treatments.”
“Patients with castration-resistant prostate cancer treated with enzalutamide demonstrated significantly longer PFS than those treated with bicalutamide, according to topline results of the phase 2 STRIVE trial released by Astellas.
“The trial included 396 patients with castration-resistant prostate cancer. About two-thirds of the patients (n = 257; 64.8%) had metastatic disease. The other 139 patients had nonmetastatic disease that progressed after surgical castration or treatment with a luteinizing hormone-releasing hormone analogue therapy.
“Researchers randomly assigned patients to 160 mg once-daily enzalutamide (Xtandi; Astellas, Medivation) — an androgen receptor antagonist — or 50 mg once-daily bicalutamide, an oral non-steroidal antiandrogen. PFS served as the primary endpoint.
“Patients assigned enzalutamide demonstrated a significant improvement in median PFS (19.4 months vs. 5.7 months; HR = 0.24; 95% CI, 0.18-0.32), according to a press release issued by Astellas. Median time on treatment also was longer in the enzalutamide group (14.7 months vs. 8.4 months).”
The gist: In a clinical trial with metastatic, castration-resistant prostate cancer (CRPC) patients, the drug enzalutamide outperformed bicaluatmide. Men who took enzalutamide had about 10 more months without their disease worsening than men who took bicalutamide.
“Medivation, Inc. MDVN, -3.90% and Astellas Pharma Inc. today announced topline results from the Phase 2 TERRAIN trial comparing enzalutamide with bicalutamide in men with metastatic castration-resistant prostate cancer. The study achieved its primary endpoint demonstrating a statistically significant increase in progression-free survival (PFS) for enzalutamide compared to bicalutamide (Hazard Ratio = 0.44; 95% Confidence Interval, 0.34-0.57; p < 0.0001). Median PFS was 15.7 months in the enzalutamide group compared to 5.8 months in the bicalutamide group.
“The median time on treatment in TERRAIN was 11.7 months in the enzalutamide group versus 5.8 months in the bicalutamide group. Serious adverse events were reported in 31.1% of enzalutamide-treated patients and 23.3% of bicalutamide-treated patients. Grade 3 or higher cardiac adverse events were reported in 5.5% of enzalutamide-treated patients versus 2.1% of bicalutamide-treated patients. Two seizures were reported in the enzalutamide group and one in the bicalutamide group. The most common side effects occurring during treatment and more common in the enzalutamide-treated versus bicalutamide-treated patients included fatigue, hot flush, hypertension, diarrhea, weight decreased and pain in extremity.
” ‘The results of this study showed that enzalutamide provides a longer duration of disease control in the studied patient population compared to bicalutamide,’ said Neal Shore, MD, co-principal investigator of the TERRAIN study and Medical Director, Carolina Urologic Research Center. ‘This robust data set adds to an impressive and consistent body of data for enzalutamide across multiple studies and stages of prostate cancer.’ “
Lee E, Madarc A, Davida G, Garabediand MJ, et al. PNAS. Sep 9, 2013.
“Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective approach to treating prostate cancer. Here we provide proof-of-concept that a small-molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin–signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both β-catenin/T-cell factor and β-catenin/AR protein interaction, reflecting the fact that T-cell factor and AR have overlapping binding sites on β-catenin. Given that AR interacts with, and is transcriptionally regulated by β-catenin, C3 treatment also resulted in decreased occupancy of β-catenin on the AR promoter and diminished AR and AR/β-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and β-catenin cofactor, coactivator-associated arginine methyltransferase 1 (CARM1), providing insight into the unrecognized function of β-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model and blocked renewal of bicalutamide-resistant sphere-forming cells, indicating the therapeutic potential of this approach.”
A recent trial suggests that the standard duration of hormonal therapy is longer than necessary for many patients. In the study, men with localized, but high-risk prostate cancer who were treated with hormonal therapy for 18 months lived just as long as those treated for 36 months. The phase III trial was conducted at multiple hospitals in Quebec, Canada. Dr. Abdenour Nabid of Sherbrooke University Hospital Center in Sherbrooke, Quebec, is lead author of the study. He presented these results last month at the American Society of Clinical Oncology Genitourinary (ASCO GU) Symposium in Orlando, Florida. Continue reading…