Synergistic Toxicities from Multiple Therapies for Synchronous Malignancies.

Patients may present with multiple malignancies in the setting of particular environmental and occupational exposures. These patients often require combination systemic therapy, which has not yet been studied for concurrent use. While toxicities for specific chemotherapies and immunotherapies may be well known, the possibility of exaggerated toxicity due to combination therapy exists and is understudied. Several trials are underway that may shed further light on how combination therapies affect patient toxicity. This case report outlines the unfortunate development of severe edema and rash, refractory to traditional methods of management, from combining immunotherapy and chemotherapy.

Comparative Effectiveness of Immune Checkpoint Inhibitors in Patients with Platinum Refractory Advanced Urothelial Carcinoma.

PURPOSE: Five programmed cell death protein 1 or its ligand (L1) inhibitors are approved for treatment of platinum refractory, locally advanced/unresectable or metastatic urothelial carcinoma. However, their comparative effectiveness is unknown. We compared time to initiation of third therapy or death, and overall survival with different programmed cell death protein 1/L1 inhibitors in patients with platinum refractory metastatic urothelial carcinoma. MATERIALS AND METHODS: Patient-level data were extracted from a real-world de-identified database. Comparative effectiveness was inferred via Cox proportional hazards model, weighted by matching weights. Each patient's propensity for each treatment was modeled via random forest, based on potential drivers of treatment selection. A propensity score for each therapy was used to calculate a matching weight, targeting the same estimand as 1:1 matching of treatment groups with balance among potential confounders. Eligibility criteria included diagnosis of metastatic urothelial carcinoma, receipt of first line treatment with a platinum based chemotherapy, followed by initiation of single agent programmed cell death protein 1/L1 inhibitor after disease progression from August 1, 2016 through May 1, 2019. RESULTS: Overall, 609 patients were eligible for analysis. Median time to initiation of third therapy or death with atezolizumab, nivolumab and pembrolizumab was 4.2, 5.3 and 4.5 months, respectively, and median overall survival was 6.4, 8.0 and 8.3 months, respectively. Matching weighted analyses did not show strong evidence of differences among programmed cell death protein 1/L1 inhibitors in terms of time to initiation of third therapy or death and overall survival. CONCLUSIONS: In this large real-world cohort, effectiveness in terms of time to initiation of third therapy or death and overall survival with programmed cell death protein 1/L1 inhibitors in patients with platinum refractory locally advanced/unresectable or metastatic urothelial carcinoma was similar.

Recent developments in the treatment of non-metastatic castration resistant prostate cancer.

Non-metastatic castration resistant prostate cancer (nmCRPC) is defined as a disease state withlack of radiographic evidence of metastatic disease, a confirmed rising PSA level on continuous ADT and maintaining a castrate level of testosterone following definitive therapy. Prior to the publication of PROSPER, SPARTAN and ARAMIS, no trials have demonstrated a clinical benefit for these patients. Recently enzalutamide, apalutamide, and darolutamide respectively, were tested in this disease setting with metastasis free survival (MFS) as the primary endpoint for each trial. In this review article, we define key terms related to the discussion of nmCRPC, examine the clinical trial design, and safety profile for each of these three key clinical trials and present updated overall survival (OS) results from these studies. Also we specifically discuss the key clinical trial results including the primary endpoint of MFS for each trial as well as quality of life effects of these three androgen receptor antagonists. Finally, this article examines the potential impact of molecular imaging testing on the applicability of these clinical trial results.

Association of SPOP Mutations with Outcomes in Men with De Novo Metastatic Castration-sensitive Prostate Cancer.

Recently, mutations in speckle-type pox virus and zinc finger protein (SPOP) gene (mutant SPOP [mtSPOP]) have been associated with improved outcomes to abiraterone in the castration-resistant setting. We hypothesized that mtSPOP would be associated with improved outcomes to systemic therapy in men with de novo metastatic castration-sensitive prostate cancer (d-mCSPC). Retrospective data of newly diagnosed d-mCSPC patients were collected from four institutions. Eligibility criteria included standard androgen deprivation therapy without intensification, and SPOP mutational status (mtSPOP or wild-type SPOP [wtSPOP]) determination by targeted next-generation sequencing from tumor biopsies. A total of 121 men (25 mtSPOP [21%] and 96 wtSPOP [79%]) were included. After adjusting for covariates, mtSPOP was significantly associated with better median progression-free survival (35 vs 13 mo; adjusted hazard ratio [HR] 0.47; p = 0.016) and overall survival (97 vs 69 mo; adjusted HR 0.32; p = 0.027), with similar HR and p value on the univariate analysis. These findings, upon external validation, may assist with counseling and prognostication in the clinic, and inform the design of future clinical trials in this setting. PATIENT SUMMARY: : Presence of tumor mutation in speckle-type pox virus and zinc finger protein (SPOP) gene was associated with improved survival outcomes in men with de novo metastatic castration-sensitive prostate cancer receiving standard androgen deprivation therapy.

Impact of performance status on treatment outcomes: A real-world study of advanced urothelial cancer treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) represent an appealing treatment for patients with advanced urothelial cancer (aUC) and a poor performance status (PS). However, the benefit of ICIs for patients with a poor PS remains unknown. It was hypothesized that a poor Eastern Cooperative Oncology Group (ECOG) PS (≥2 vs 0-1) would correlate with shorter overall survival (OS) in patients receiving ICIs. METHODS: In this retrospective cohort study, clinicopathologic, treatment, and outcome data were collected for patients with aUC who were treated with ICIs at 18 institutions (2013-2019). The overall response rate (ORR) and OS were compared for patients with an ECOG PS of 0 to 1 and patients with an ECOG PS ≥ 2 at ICI initiation. The association between a new ICI in the last 30 and 90 days of life (DOL) and death location was also tested. RESULTS: Of the 519 patients treated with ICIs, 395 and 384 were included in OS and ORR analyses, respectively, with 26% and 24% having a PS ≥ 2. OS was higher in those with a PS of 0 to 1 than those with a PS ≥ 2 who were treated in the first line (median, 15.2 vs 7.2 months; hazard ratio [HR], 0.62; P = .01) but not in subsequent lines (median, 9.8 vs 8.2 months; HR, 0.78; P = .27). ORRs were similar for patients with a PS of 0 to 1 and patients with a PS ≥ 2 in both lines. Of the 288 patients who died, 10% and 32% started ICIs in the last 30 and 90 DOL, respectively. ICI initiation in the last 30 DOL was associated with increased odds of death in a hospital (odds ratio, 2.89; P = .04). CONCLUSIONS: Despite comparable ORRs, ICIs may not overcome the negative prognostic role of a poor PS, particularly in the first-line setting, and the initiation of ICIs in the last 30 DOL was associated with hospital death location.

First-line Treatment of Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis.

CONTEXT: No head-to-head clinical trials compare contemporary first-line therapies for metastatic renal cell carcinoma (mRCC). A network meta-analysis provides an approach for quantitative analysis. OBJECTIVE: To indirectly compare the efficacy and safety of first-line treatments for mRCC in the intention-to-treat (ITT) population and by clinical risk group. EVIDENCE ACQUISITION: An updated systematic review from database inception to February 17, 2019 identified all parallel-group randomized controlled trials assessing first-line therapy for mRCC. "Clinically relevant" studies were selected for a network meta-analysis. Progression-free survival (PFS) was the primary outcome. Overall survival (OS), overall response rate (ORR), and grade 3 and 4 adverse events (AEs) were secondary outcomes. EVIDENCE SYNTHESIS: We identified 12 relevant trials: 12 reported outcomes for PFS, nine for OS, 10 for ORR, and nine for AEs. In the ITT population, cabozantinib (surface under the cumulative ranking curves [SUCRA] 84%), avelumab plus axitinib (SUCRA 68%), and pembrolizumab plus axitinib (SUCRA 82%) were superior to the other agents for PFS; pembrolizumab plus axitinib appeared superior for OS (SUCRA 95%); and atezolizumab demonstrated the lowest likelihood of AEs (SUCRA 100%). Findings were similar in the intermediate/poor-risk subgroup. Based on the limited data available, avelumab plus axitinib may be preferred in patients with favorable-risk disease. CONCLUSIONS: The optimal first-line treatment for mRCC appears to differ by efficacy endpoint, toxicity, and clinical risk group. Direct comparative studies remain important in guiding treatment choice. PATIENT SUMMARY: Head-to-head comparisons do not exist for the newest treatments of metastatic renal cell carcinoma (mRCC). In an indirect comparison, we found that pembrolizumab plus axitinib and cabozantinib are good options for most patients with mRCC.

Management of Nonmetastatic Castration-Resistant Prostate Cancer: Recent Advances and Future Direction.

OPINION STATEMENT: Nonmetastatic castration-resistant prostate cancer (nmCRPC) comprises a relatively narrow niche of advanced prostate cancer, but the treatment landscape for men with nmCRPC has drastically changed over the past year. Prior to the SPARTAN and PROSPER trials, men with nmCRPC were commonly treated with first-generation androgen receptor antagonists, such as bicalutamide or flutamide, or with estrogens or ketoconazole, none of which were associated with any proven survival benefit. The SPARTAN trial evaluated apalutamide versus placebo for men with nmCRPC and found that apalutamide significantly improved metastasis-free survival (MFS), the primary endpoint of this trial. Similarly, the PROSPER trial showed that enzalutamide significantly improved MFS compared with placebo for men with nmCRPC. In both trials, the data for overall survival was immature at the time of analysis. The SPARTAN and PROSPER trials led to the approval of apalutamide and enzalutamide, respectively, for men with nmCRPC. More recently, the phase 3 trial ARAMIS showed that darolutamide, a novel androgen receptor antagonist, also improves MFS compared with placebo for men with nmCRPC, and this trial is expected to garner regulatory approval for darolutamide in the nmCRPC setting. Novel imaging modalities are becoming more prevalent for the diagnostic evaluation of men with prostate cancer and are more sensitive than conventional bone or CT scans for detection of oligometastatic disease that previously was undetected. These modalities are likely to reduce the incidence and prevalence of nmCRPC in the near future. Ultimately, the treatment options for men with nmCRPC have significantly improved over the past 2 years.

Treatment Decisions for Metastatic Clear Cell Renal Cell Carcinoma in Older Patients: The Role of TKIs and Immune Checkpoint Inhibitors.

Given the underrepresentation of older patients in registration trials for metastatic renal cell carcinoma (mRCC), data to support the use of any particular systemic therapy over others, based on age, is limited. This is further complicated by clinical trials not commonly reporting adverse events by age. Thus, recommendations on treatment of older patients with mRCC are generally extrapolated from data on younger patients enrolled in these trials, which may not be ideal as many older patients are frail, have age-related organ dysfunction, or have multiple medical co-morbidities. In the last decade, the treatment landscape for mRCC has drastically changed with the approval of more than ten targeted therapies, as well as immune checkpoint inhibitors. Thus, treatment selection and sequencing of treatments can be especially challenging for clinicians. We begin this review by analyzing the available efficacy and toxicity data of these treatments in younger and older patients. We also discuss a network meta-analysis that compares the efficacy of these agents in older patients with mRCC. Utilizing this data, we suggest that nivolumab plus ipilimumab and cabozantinib may be favored for first-line treatment of specific populations of older patients. For salvage treatment, we suggest that cabozantinib may be the preferred agent for older patients.