Fay, André P.

PURPOSE To describe a newly established international registry recruiting diverse patients with advanced prostate cancer across academic and community practices to address unmet needs in this population. PATIENTS AND METHODS Initiated in 2017, IRONMAN (International Registry for Men with Advanced Prostate Cancer) is a prospective cohort of patients with advanced prostate cancer. The study will enroll 5,000 patients with metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC), recruited from Australia, the Bahamas, Barbados, Brazil, Canada, Ireland, Jamaica, Kenya, Nigeria, Norway, South Africa, Spain, Sweden, Switzerland, the United Kingdom, and the United States. The study is collecting datatypes to study variation in care and treatment of advanced prostate cancer across countries and across academic, community-based, and government practices with a focus on clinical outcomes, patient-reported outcomes, epidemiologic data, biologic subtypes, and clinician questionnaires. RESULTS Through July 2022, 2,682 eligible patients were enrolled in 11 of 12 active countries. Sixty-six percent of patients have mHSPC, and 34% have CRPC. On the basis of self-report, 11% of patients are Black and 9% are Hispanic. Five Veterans Affairs Medical Centers are enrolling patients. Globally, 23% of patients report being veterans of military service. CONCLUSION To our knowledge, this is the first international cohort of people newly diagnosed with advanced prostate cancer designed to describe variations in patient management, experiences, and outcomes. IRONMAN aims to identify optimal treatment sequences to improve survival, understand patient-reported outcomes, and explore novel biomarkers to understand treatment resistance mechanisms. Insights from IRONMAN will inform and guide future clinical management of people with mHSPC and CRPC. This cohort study will provide real-world evidence to facilitate a better understanding of the survivorship of people with advanced prostate cancer.

424 Background: Programmed death-1 (PD-1) receptor negatively regulates T cell-mediated responses.PD-1 ligand (PD-L1) is aberrantly expressed in clear cell renal cell carcinoma (ccRCC) and is associated with worse prognosis. Levels of PD-L1 expressions in non-ccRCC and its association with clinicopathological features and survival are unknown. Methods: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 97 patients with chromophobe (CHR), papillary (PAP), translocation Xp11.2 (TrL) RCC and oncoytoma (ONC) and were included in the analysis. PD-L1 expression was evaluated by immunohistochemistry using a mouse monoclonal anti-PD-L1 antibody (405.9A11). The assay was validated using FFPE cell line controls known to be positive or negative for PD-L1 expression by flow cytometry. PD-L1 tumor positivity (PD-L1+) was defined as ≥5% tumor cell membrane staining. For PD-L1 expression in immune cells, a combined score based on the intensity of infiltrate and percentage of positive cells was used. Baseline characteristics including stage/grade, and survival data were collected. Comparisons between PD-L1 expression and clinicopathological features were evaluated using chisq or wilcoxon rank sum tests. Cox model tests for association of PD-L1 expression with OS in univariate and multivariable analysis. Results: Among 97 patients, 12 (12.4%) were considered PD-L1+ in tumor cells: 2/36 (5%) of CHR RCC, 5/50 (10%) of PAP RCC, 3/7 (43%) of TrL RCC, and 2/4 (50%) of ONC. PD-L1 positivity in tumor cells was significantly associated with higher stage (p=0.026) and grade (p=0.046), as well as lower OS on univariate (p=0.02) but not multivariate analysis (p=0.29). On the other hand, PD-L1 positivity by immune cells was observed in 50 (51.5%) patients: 13/36 (36%) of CHR RCC, 30/50 (60%) of PAP RCC, 6/7 (86%) of TrL RCC, and 1/4 (25%) of ONC. PD-L1 positivity in immune cells did not correlate with stage (p=0.7), grade (p=0.1) or OS (p=0.8). Conclusions: PD-L1 expression is variable in non-ccRCC and depends on histology and tumor vs. immune cells scoring. Only PD-L1 positivity in tumors cells was associated with aggressive features. Patients with non-ccRCC should not be automatically excluded from trials of agents that target the PD-1/PD-L1 pathway.

422 Background: There is significant variability in the response to VEGF-TT in mRCC with no validated predictive biomarkers. We hypothesized that whole exome analysis might identify markers of response and resistance to VEGF-TT in mRCC. Methods: mRCC patients who received first-line sunitinib or pazopanib and were in two extreme phenotypes of response were identified. Extreme responders (ER) were defined as PR or CR for ≥3 years (n=10) and primary refractory patients (PRP) were defined as PD within the first 3 months of therapy (n=10). WES was performed in pre-treatment specimens and established Broad Institute analytical pipelines were utilized to identify point mutations and copy number alterations across the exome. ER (n=4) and PRP (n=4) who were part of TCGA project for clear-cell RCC were included in this analysis. Nonsense, missense and indel mutations in established or novel RCC genes were investigated. Results: IMDC prognostic scores were not significantly different between the two groups. VHL mutations were observed at similar frequency in ER and PRP, overall 57%. Mutations in PBRM1 were identified in 7 ER (50%) vs. 1 PRP (7%) (p=0.03). In addition, mutations in TP53 were only found in PRP (p=0.09). No other gene had mutations that were associated with either response or primary refractory disease (Table). Conclusions: In this pilot study, PBRM1 mutations were associated with extreme response to VEGF-TT. However, this was exploratory, and multivariable analysis was not performed. Analysis of additional patient samples is ongoing to confirm or refute this association. If true it suggests that epigenetic effects of PBRM1 mutation may contribute to response to VEGF-TT in mRCC. [Table: see text]

616 Background: Polybromo-1 (PBRM1) and BRCA1 associated protein-1 (BAP1) are genes commonly mutated in clear cell RCC (ccRCC) and have been associated with clinical outcome. This work aims to evaluate the impact of PBRM1 and BAP1 expression by IHC in mRCC patients treated with VEGF-TT. Methods: PBRM1 and BAP1 expression was evaluated by IHC in a TMA including 146 mRCC patients. PBRM1 and BAP1 IHC scores were dichotomized as a binary variable: negative (-) or positive (+) (weak positivity was excluded). The associations of PBRM1 or BAP1 expression with baseline clinico-pathological characteristics were evaluated, as well as with overall survival (OS) and time to treatment failure (TTF) usingCox proportional hazards models. Results: Out of 146 patients, 116 and 109 samples had available results for PBRM1 and BAP1 staining, respectively. Overall, 90% (n = 131) patients had ccRCC. 70/116 samples (60%) were PBRM1- and 26/109 patients (24%) were BAP1-. Only 12% (n = 13) of patients had simultaneous negative PBRM1 and BAP1. While there was no association between PBRM1 expression status and clinical factors, BAP1- samples were associated with poor IMDC prognostic risk score (p = 0.004) and higher Fuhrman grade (p = 0.012). PBRM1+ patients showed a trend towards an increased risk of death and a shorter TTF compared to PBRM1- patients (OS: HR = 1.38, 95%CI: 0.92-2.07, p = 0.1; TTF: HR = 1.39, 95%CI: 0.94-2.06, p = 0.1). BAP1 expression was not independently associated with OS or TTF. Conclusions: Loss of PBRM1, but not BAP1 expression showed a trend towards longer TTF and OS in mRCC patients treated with VEGF-TT.

Abstract Purpose: We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC). Experimental Design: We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response. Results: Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response. Conclusions: In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445–52. ©2016 AACR. See related commentary by Voss and Hsieh, p. 2320

Abstract Purpose: The interaction of programmed death-1 ligand (PD-L1) with its receptor (PD-1) on T cells inactivates antitumor immune responses. PD-L1 expression has been associated with poor outcomes in renal cell carcinoma (RCC) but has not been investigated in advanced RCC patients receiving VEGF-targeted therapy. Experimental Design: Formalin-fixed paraffin-embedded specimens were collected at baseline from patients in the COMPARZ trial. Tumor cell PD-L1 expression by IHC was evaluated using H-score (HS). Dual PD-L1/CD68 staining was used to differentiate PD-L1 tumor expression from tumor-associated macrophages. Intratumor CD8-positive T cells were quantified morphometrically. Associations between biomarkers and survival were investigated using the log-rank test. Results: HS data were available from 453 of 1,110 patients. Sixty-four percent of patients had negative PD-L1 expression (HS = 0). Patients with HS > 55 (n = 59, 13%) had significantly shorter overall survival (OS) than those with HS ≤ 55 in both pazopanib and sunitinib arms (median 15.1 vs. 35.6 and 15.3 vs. 27.8 months, respectively, P = 0.03). In both arms, median OS was shortest in patients with HS > 55 and intratumor CD8-positive T-cell counts > 300 (9.6 and 11.9 months with pazopanib and sunitinib, respectively). Median OS in patients with HS ≤ 55 and CD8-positive T-cell counts ≤ 300 was 36.8 and 28.0 months with pazopanib and sunitinib, respectively. Progression-free survival results were similar to OS results. Conclusions: Increased tumor cell PD-L1, or PD-L1 plus tumor CD8-positive T-cell counts, were associated with shorter survival in patients with metastatic RCC receiving VEGF-targeted agents. These findings may have implications for future design of randomized clinical trials in advanced RCC. Clin Cancer Res; 21(5); 1071–7. ©2014 AACR.