Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial.

The RANGE study (NCT02426125) evaluated ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with platinum-refractory advanced urothelial carcinoma (UC). Here, we use programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) and transcriptome analysis to evaluate the association of immune and angiogenesis pathways, and molecular subtypes, with overall survival (OS) in UC. Higher PD-L1 IHC and immune pathway scores, but not angiogenesis scores, are associated with greater ramucirumab OS benefit. Additionally, Basal subtypes, which have higher PD-L1 IHC and immune/angiogenesis pathway scores, show greater ramucirumab OS benefit compared to Luminal subtypes, which have relatively lower scores. Multivariable analysis suggests patients from East Asia as having lower immune/angiogenesis signature scores, which correlates with decreased ramucirumab OS benefit. Our data highlight the utility of multiple biomarkers including PD-L1, molecular subtype, and immune phenotype in identifying patients with UC who might derive the greatest benefit from treatment with ramucirumab.

Effectiveness of first-line abiraterone versus enzalutamide among patients ≥80 years of age with metastatic castration-resistant prostate cancer: A retrospective propensity score-weighted comparative cohort study.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) disproportionately affects the elderly. There is limited data assessing the efficacy and tolerability of abiraterone acetate (AA) versus enzalutamide in this population. OBJECTIVE: To compare the clinical efficacy and tolerability of AA versus enzalutamide in patients ≥ 80 years with mCRPC. DESIGN, SETTING AND PARTICIPANTS: A retrospective propensity-weighted comparative cohort study of first-line AA versus enzalutamide among patients with mCRPC aged ≥80 years. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Inverse probability treatment weights based on propensity scores were generated to assess the treatment effect of AA versus enzalutamide on time to PSA progression (TTPP), time to progression (TTP) (first of PSA/radiographic/clinical progression) and overall survival using a weighted Cox proportional hazards model. PSA response rate (PSA RR) was compared between groups using Χ2. RESULTS AND LIMITATIONS: One hundred fifty-three patients received AA, and 125 received enzalutamide. Enzalutamide was associated with higher PSA RR (61.6% vs 43.8%, P < 0.004), and TTP (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.50-0.88, P = 0.01) but not TTPP (HR 0.73, 95% CI 0.53-1.01, P = 0.06). There were significantly more dose reductions with enzalutamide (22.9% vs 44.8%, P > 0.001) but there was no interaction between median proportion of full dose received and TTPP or TTP for either drug. Rates of treatment discontinuation (for reasons other than progression) were also significantly different between AA and enzalutamide (28.8% vs 40.8%, respectively, P = 0.04). The most common reason for dose reductions and discontinuation of enzalutamide was fatigue (30.4% and 5.6%, respectively). CONCLUSIONS: Despite more dose reductions and a higher treatment discontinuation rate, enzalutamide was associated with a higher PSA RR and longer time to progression, than AA. Given that clinical outcomes were not adversely impacted by decreased treatment exposure, dose modification may be a useful treatment strategy to balance toxicity and tolerance.

Developing a Highly Specific Biomarker for Germ Cell Malignancies: Plasma miR371 Expression Across the Germ Cell Malignancy Spectrum.

PURPOSE: Our objective was to evaluate operating characteristics, particularly specificity and positive predictive value (PPV), by mapping plasma miR371 expression to actual clinical events in patients with a history of germ cell tumor. PATIENTS AND METHODS: One hundred eleven male patients with a history of or newly diagnosed germ cell tumors were evaluable. Biospecimens obtained before confirmed clinical events were analyzed for miR371 expression with blinding of providers and laboratory personnel to analytic results or clinical status, respectively. Cases (patients with clinically confirmed active germ cell malignancy [aGCM]) and controls (patients with no clinically confirmed aGCM) were assigned over the course of the management. Patients were assigned risk status (high, low, or moderate) based on the composite clinical picture at time points in management. RESULTS: Considering all cases and controls and results of prospectively obtained biosamples analyzed for miR371 expression, 46 (35%) of 132 samples had clinically confirmed aGCM over the course of management; 44 (96%) of these 46 patients had plasma miR371 expression (true positives) with no false positives. Two (4%) of 46 patients had no miRNA expression despite pathologic confirmation of aGCM (false negatives). Plasma miR371 expression in confirmed aGCM had a specificity, sensitivity, positive predictive value, and negative predictive value of 100%, 96%, 100%, and 98%, respectively. Interpretation of sensitivity and negative predictive value is limited by modest follow-up. Specificity and sensitivity were 100% and 98%, 100% and 92%, and 100% and 97% in the low-, moderate-, and high-risk groups, respectively, with a median follow-up time of 15 months. CONCLUSION: Plasma miR371 expression predicts aGCM with high specificity and positive predictive value. Although other operating characteristics of miR371 await longer follow-up for more complete definition, the findings of a highly specific liquid biopsy strongly support moving forward with large-scale, real-world clinical trials to further define full operating characteristics and to identify clinical utility and areas of patient benefit.

Lack of Effectiveness of Postchemotherapy Lymphadenectomy in Bladder Cancer Patients with Clinical Evidence of Metastatic Pelvic or Retroperitoneal Lymph Nodes Only: A Propensity Score-based Analysis.

BACKGROUND: Limited data is available on the role, and extent of, postchemotherapy lymphadenectomy (PC-LND) in patients with clinical evidence of pelvic (cN1-3) or retroperitoneal (RP) lymph node spread from urothelial bladder carcinoma. OBJECTIVE: To compare the outcomes of operated versus nonoperated patients after first-line chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: Data from 34 centers was collected, totaling 522 patients, treated between January 2000 and June 2015. Criteria for patient selection were the following: bladder primary tumor, lymph node metastases (pelvic±RP) only, first-line platinum-based chemotherapy given. INTERVENTION: LND (with cystectomy) versus observation after first-line chemotherapy for metastatic urothelial bladder carcinoma. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Overall survival (OS) was the primary endpoint. Multiple propensity score techniques were adopted, including 1:1 propensity score matching and inverse probability of treatment weighting. Additionally, the inverse probability of treatment weighting analysis was performed with the inclusion of the covariates, that is, with doubly robust estimation. RESULTS AND LIMITATIONS: Overall, 242 (46.4%) patients received PC-LND and 280 (53.6%) observation after chemotherapy. There were 177 (33.9%) and 345 (66.1%) patients with either RP or pelvic LND only, respectively. Doubly robust estimation-adjusted comparison was not significant for improved OS for PC-LND (hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.31, p=0.479), confirmed by matched analysis (HR: 0.91, 95% CI: 0.60-1.36, p=0.628). This was also observed in the RP subgroup (HR: 1.12, 95% CI: 0.68-1.84). The retrospective nature of the data and the heterogeneous patient population were the major limitations. CONCLUSIONS: Although there were substantial differences between the two groups, after accounting for major confounders we report a nonsignificant OS difference with PC-LND compared with observation only. These findings may be hypothesis-generating for future prospective trials. PATIENT SUMMARY: We found no differences in survival by adding postchemotherapy lymphadenectomy in patients with pelvic or retroperitoneal lymph node metastatic bladder cancer. The indication to perform postchemotherapy lymphadenectomy in the most suitable patients requires additional studies.

Clinical Outcomes of Perioperative Chemotherapy in Patients With Locally Advanced Penile Squamous-Cell Carcinoma: Results of a Multicenter Analysis.

BACKGROUND: The prognosis of patients with locally advanced penile squamous-cell carcinoma is primarily related to the extent of lymph node metastases. Surgery alone yields suboptimal results, and there is a paucity of data on these patients' outcomes. PATIENTS AND METHODS: This retrospective study evaluated patients who received neoadjuvant or adjuvant chemotherapy from 1990 onward at 12 centers. Cox models were used to investigate prognostic factors for relapse-free survival and overall survival (OS). RESULTS: Among the 201 included patients, 39 (19.4%) had disease of T3-4 and N0 clinical stage; the remaining patients had clinical lymph node involvement (cN+). Ninety-four patients received neoadjuvant chemotherapy (group 1), 78 received adjuvant chemotherapy (group 2), and 21 received both (group 3). Eight patients for whom the timing of perioperative chemotherapy administration was unavailable were included in the Cox analyses. Forty-three patients (21.4%) received chemoradiation. Multivariate analysis for OS (n = 172) revealed bilateral disease (P = .035) as a negative prognostic factor, while pelvic cN+ tended to be nonsignificantly associated with decreased OS (P = .076). One-year relapse-free survival was 35.6%, 60.6%, and 45.1% in the 3 groups, respectively. One-year OS was 61.3%, 82.2%, and 75%, respectively. No significant differences were seen on univariable analyses for OS between the groups (P = .45). Platinum type of chemotherapy and chemoradiation were not significantly associated with any outcome analyzed. CONCLUSION: Benchmark survival estimates for patients receiving perioperative chemotherapy for locally advanced penile squamous-cell carcinoma have been provided, with no substantial differences observed between neoadjuvant and adjuvant administration. This analysis may result in improved patient information, although prospective studies are warranted.