Amy M. Sion, PharmD BCOP
Clinical Pharmacy Specialist
Oncology Research/Genitourinary Oncology
Medical University of South Carolina
Charleston, SC
The 2018 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium took place February 8–10 in San Francisco, CA, hosting more than 3,000 attendees from all over the world. The symposium had three full-day sessions focusing on important developments and contributions to research on prostate, renal cell, and urothelial cancers. An additional session was dedicated to the management of adrenal and germ-cell cancers. The following is a summary of noteworthy abstracts and presentations given at the meeting.
Apalutamide, a Novel Nonsteroidal Antiandrogen for Nonmetastatic Prostate Cancer
The results of the SPARTAN trial, a phase 3 double-blind randomized study of apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) were presented by Eric Small of the University of California–San Francisco. The primary end point of this study was metastases-free survival (MFS), followed by these secondary end points: time to metastases, progression-free survival (PFS), time to symptomatic progression, overall survival (OS), and time to cytotoxic chemotherapy. To be eligible for enrollment, patients were required to have nmCRPC and a prostate-specific antigen (PSA) doubling time of 10 months or less. A total of 1,207 patients were randomized 2:1 to receive apalutamide 240 mg daily (n = 806) or placebo (n = 401), in combination with investigator’s choice of androgen-deprivation therapy (ADT).
In the apalutamide group, the median MFS was 40.5 months, versus 16.2 months in the placebo group (hazard ratio [HR] = 0.28; 95% confidence interval [CI], 0.23–0.35, p < .0001), demonstrating a 72% risk reduction in metastatic progression or death across all subgroups. Time to metastases (HR = 0.27, p < .0001) and PFS (HR = 0.29, p < .0001) were also significantly improved in the apalutamide arm. Notably, patients who progressed on apalutamide and received subsequent treatment with an agent approved by the U.S. Food and Drug Administration (FDA) for treating metastatic CRPC had a 51% risk reduction in progression (biochemical or clinical) when compared to the patients who had placebo-only prior treatment.
In the intention-to-treat (ITT) population, when compared to placebo, apalutamide had a higher frequency of adverse events, including fatigue, rash, weight loss, arthralgia, falls and fractures, and hypothyroidism. However, the incidence of grade 3 or higher adverse events was similar in both treatment arms.
On the basis of the data from this trial, the FDA approved apalutamide for the treatment of nmCRPC on February 14, 2018. The approval of this agent provides a new therapeutic option to improve metastases-free survival in men with nonmetastatic castration-resistant disease.
The POUT Trial in Upper-Tract Urothelial Cancer
In the last 2 years, we have seen the approval of five checkpoint inhibitors (both programmed cell death-1 [PD-1] and programmed death-ligand 1 [PD-L1] inhibitors) for urothelial cancer, changing the way we treat this patient population. However, many questions about treatment modalities in urothelial cancer are still unanswered; one is the use of adjuvant systemic chemotherapy for invasive upper-tract urothelial carcinoma (UTUC). The standard treatment in these patients is nephroureterectomy followed by surveillance, but to this point, adjuvant chemotherapy is supported only by limited retrospective studies, which have provided insufficient evidence for the development of consensus guidelines.
Alison Birtle of Lancashire Teaching Hospitals in Great Britain presented the results from the POUT trial, a phase 3 randomized trial of perioperative chemotherapy versus surveillance in upper-tract urothelial cancer. Patients with invasive UTUC were randomized within 90 days following nephroureterectomy to either surveillance or platinum-based chemotherapy. Chemotherapy consisted of gemcitabine 1,000 mg/m2 on days 1 and 8 with cisplatin 70 mg/m2 on day 1. Carboplatin was allowed only if the glomerular filtration rate (GFR) was 30–49 ml/min, but substitution was not permitted for any other comorbidity(ies). Patients with GFR <30 ml/min were excluded, as well as patients with muscle-invasive bladder cancer or distant metastases. The primary end point of the study was disease-free survival (DFS). Notable secondary end points were metastases-free survival (MFS) and overall survival (OS).
As of November 2017, 261 patients were randomized to chemotherapy (n = 131) or surveillance (n = 129). Baseline characteristics were well matched in both arms, and 63.8% of the total patient population was determined to be eligible for cisplatin-based treatment. Grade 3 or higher adverse events were increased in the chemotherapy versus surveillance arm (62.1% vs. 24.8%, respectively). In a comparison of chemotherapy and surveillance at the 3-year point, DFS was significantly improved (HR = 0.49, CI 95%, 0.31–0.76, p = .001). Similarly, 3-year MFS was also significantly improved in patients receiving chemotherapy (HR = 0.49, CI 95%, 0.30-0.78, p = .002). Overall survival data were immature, but preliminary analysis suggests a trend toward better survival in the treatment arm.
This is the first prospective trial to show a role for adjuvant chemotherapy within 90 days following nephroureterectomy in patients with UTUC. The results demonstrate that adjuvant systemic therapy is efficacious and improves DFS and MFS outcomes. The postoperative chemotherapy should thus be considered to be the standard of care in patients with UTUC who are eligible for platinum-based treatment.
The Future of Immuno-Oncology in Renal Cell Carcinoma
Bernard Escudier from Gustave Roussy Cancer Center in France presented “The Future of Immuno-Oncology in Renal Cell Carcinoma,” the keynote lecture on renal cell cancer. The current approved use of the PD-1 inhibitor nivolumab is as a second-line agent following failure of an anti–vascular endothelial growth factor (VEGF) agent for metastatic renal cell carcinoma (mRCC). This approval was a result of the pivotal CheckMate-025 trial. Analysis of data from this study showed that patients in the nivolumab arm (n = 410) had improvement in overall response rate, but 35% of these patients also had progressive disease. Consequently, new clinical trials are under way to see whether clinical outcomes can be improved by combining immunotherapy with anti-VEGF agents or using dual immunotherapy (CTLA-4 and PD-1/PD-L1 inhibitors).
Dr. Escudier presented data from the CheckMate-214 trial, which compared combination treatment with ipilimumab and nivolumab to single-agent sunitinib for advanced renal cell cancer. Overall survival in the combination group was not reached, compared to 26 months (HR = 0.63, CI 99.8%, 0.44–0.89, p < .0001) in the sunitinib group. Overall response rate in the combination arm was 42% versus 27% in the single-agent arm (p < .0001). Interestingly, this efficacy was seen only in intermediate- and poor-risk patients. On the basis of these results, the FDA has granted priority review for the use of the combination of nivolumab and ipilimumab as a front-line treatment for intermediate- and poor-risk patients with advanced renal cell carcinoma. If approval is granted as a first-line regimen, this will significantly alter the current practice using VEGF inhibitors as first-line treatment for RCC; however, the anti-VEGF agents will continue to have a role in first-line treatment for good-risk patients. Further, it is hoped that genomic/biomarker testing will provide insight into the differing responses between good- and intermediate- or poor-risk patients.
Phase 3 study results examining the combination of VEGF inhibition and PD-1/PD-L1 blockade also are expected shortly, including three independent trials comparing single-agent sunitinib to avelumab/axitinib, lenvatinib + everolimus/pembrolizumab, and pembrolizumab/axitinib, respectively. Further, preliminary results from the phase 3 IMmotion 151 trial were presented at the meeting. This study was designed to assess differences in progression-free survival (PFS) between three treatment arms: atezolizumab + bevacizumab, atezolizumab monotherapy, and sunitinib in untreated metastatic renal cell carcinoma. Early results showed longer PFS for the atezolizumab + bevacizumab group, but this correlated only to tumors with positive PD-L1 expression (≥1% expression on immune cells). These data suggest that combination therapy may be superior to single-agent anti-VEGF or anti–PD-1/PD-L1 therapy for advanced renal cell carcinoma, but results from the above-mentioned studies are needed to confirm this efficacy.
The 2019 ASCO GU Cancers Symposium will be held February 14–16 in San Francisco, CA. For more information on the symposium visit www.asco.org.