Citations

695 Background: Recent results from COSMIC 313 trial and updated findings from other contemporary trials have added to the existing body of evidence for 1L mRCC. Therefore, we present the most up-to-date results from our living, interactive systematic review (LISR) to facilitate the choice of optimal therapy in 1L mRCC setting. Methods: This LISR and network meta-analysis is maintained using a novel living evidence synthesis (LIvE) framework. The framework facilitates the identification of new or updated studies using an automated ‘living’ search which is followed by screening and extraction in a semi-automated fashion within a machine learning assisted graphical user interface. Relevant data is parsed and analyzed to compute mixed treatment comparisons and certainty of evidence is adjudicated using a rule-based algorithm. Detailed methods have been published before (PMID: 33824031). Results: As of October 1st 2022, this LISR includes 16 clinical trials (30 references). Mixed treatment comparisons showed statistically significant PFS benefit with lenvatinib-pembrolizumab (LenPem; rank 1) when compared to cabozantinib-nivolumab (CabNivo; rank 3; hazard ratio [HR]: 0.69, 95% confidence interval: 0.52-0.93), CaboNivo-ipilimumab (CaboNivoIpi; rank 4; HR: 0.62; 0.43-0.89), avelumab-axitinib (AveAxi; rank 5; HR: 0.56; 0.43-0.75), PemAxi (rank 6; HR: 0.55; 0.42-0.72), atezolizumab-bevacizumab (AteBev; rank 7; HR: 0.46; 0.35-0.59), and NivoIpi (rank 8; HR: 0.45; 0.35-0.59). No significant differences were observed between CaboNivoIpi and other combination therapies for PFS improvement. Similarly, for OS, LenPem (rank 1), PemAxi (rank 2) and CaboNivo (rank 3) were ranked as potentially more efficacious treatment options than other counterparts. However, no statistically significant difference was observed for OS benefit with mixed treatment comparisons. The odds of achieving an ORR were higher with LenPem (rank 1; odds ratio [OR]: 2.44; 1.43-4.17), and CaboNivo (rank 2; OR: 1.77; 1.04-3.03) when compared to CaboNivoIpi (rank 6). NivoIpi (rank 1), LenPem (rank 2), CaboNivoIpi (rank 3) were ranked potentially as more efficacious treatments for achieving a CR. In terms of grade 3 or higher treatment related adverse events, NivoIpi (rank 3) was ranked as potentially the safest option among other combinations while CaboNivoIpi (rank 12), LenPem (rank 11), and CaboNivo (rank 10) were more likely to increase the risk of toxicity compared to most other treatments. Conclusions: Triplet combination of CaboNivoIpi may not provide additional survival benefit compared to other immunotherapy combinations and may increase toxicity. Patient-level considerations such as treatment toxicity, and quality of life should be factored in when opting intensified 1L therapies in mRCC patients.

694 Background: The treatment landscape of localized renal cell carcinoma (RCC) is rapidly evolving. Recent trials have demonstrated contrasting efficacy with adjuvant immunotherapy. Therefore, we sought to assess the mixed treatment comparisons among different adjuvant treatment options using updated data from trials and quantified the absolute effect with these treatments stratified by risk categories. Methods: This living network meta-analysis was conducted using the living interactive evidence (LIvE) synthesis framework. We used stratified baseline risks of disease progression from observational data and at 5, 10, 15 years from the Leibovich risk stratification system (based on risk scores ranging from 0 to ≥15). Corresponding intervention risks were then approximated using relative effect estimates (from NMA) and baseline risks. The difference between CIRs and baseline risks were calculated to present absolute risk differences in each risk category. Results: This NMA included eight RCTs with 8480 participants and seven unique treatment options. Pembrolizumab (pembro; rank 1) was associated with improved disease-free survival (DFS) when compared to atezolizumab (atezo; rank 6; hazard ratio: 0.68; 0.49;0.93), and nivolumab-ipilimumab (nivoipi; rank 5; 0.68; 0.48-0.97). However, no statistically significant difference was observed between pembro and atezo for overall survival (0.53; 0.28-1.01). Survival data for nivoIpi was not reported. No new statistically significant differences were observed since last update. The absolute benefit of atezo and nivoipi was minimal with higher T and N patients (Table). The results were similar with increasing Leibovich risk scores. Conclusions: Current evidence favors the use of a risk adapted approach when offering adjuvant immunotherapy. Adjuvant pembrolizumab remains a preferred treatment in patients with RCC who underwent nephrectomy. [Table: see text]

692 Background: Sarcomatoid mRCC exhibits poor prognosis and limited response to vascular endothelial growth factor pathway inhibition. Therefore, we assessed the efficacy of ICI combination therapy in this patient population using data from contemporary trials. Methods: MEDLINE and EMBASE were searched to identify phase III randomized controlled trials (RCTs) comparing the efficacy of ICI combinations with sunitinib monotherapy in patients with sarcomatoid mRCC. Patient important outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and complete response (CR). Precomputed hazard ratios (HR) with 95% confidence intervals (CI) for survival outcomes and binary outcome data for response rates (expressed as relative risk [RR] were meta-analyzed using a DerSimonian-Lairds random-effects method. Mixed treatment comparisons among different ICI combinations were made using a network-meta-analysis within the Bayesian framework. The surface under the cumulative ranking curves (SUCRA) were computed to assess the relative treatment rankings. Results: Six RCTs with a total of 618 patients were considered eligible for inclusion. ICI combination therapy was significantly associated with improved OS (HR: 0.56; 95% CI: 0.43-0.72) and PFS (HR: 0.50; 0.40-0.62), increased ORR (RR: 2.42; 1.92-3.06), and CR (RR: 4.23; 2.00-8.93) when compared to sunitinib in patients with sarcomatoid mRCC (Table). The results were consistent with Hartung-Knapp adjustment. Mixed treatment comparisons using current data revealed no statistically significant differences among different ICI combinations. However, the combination of nivolumab-ipilimumab was consistently ranked higher (rank 2 for OS, ORR, and CR) and may potentially be more efficacious than other counterparts. Conclusions: Current evidence suggests improved survival, delayed disease progression and increased response rates with the use of ICI combination therapy in patients with sarcomatoid mRCC. [Table: see text]

531 Background: Neoadjuvant cisplatin-based chemotherapy (NAC) is established in the management of MIBC. Pathologic complete response (pCR, ypT0N0) and downstaging (<ypT2N0) are associated with long term survival in patients with MIBC. Several trials have evaluated neoadjuvant immunotherapy (NAI) and chemoimmunotherapy (NACI) for MIBC. We aimed to conduct a meta-analysis of available trials to compare the incidence of pathological response with NAC, NAI and NACI in MIBC patients undergoing radical cystectomy. Methods: Phase II/III clinical trials assessing neoadjuvant systemic therapies (NAC, NAI, or NACI) in patients with MIBC undergoing radical cystectomy were identified through a systematic search of MEDLINE and EMBASE. Outcomes of interest included pCR and pathological downstaging. A DerSimonian and Laird random-effect meta-analysis was conducted to estimate pooled incidence of events using the Freeman-Tukey transformation. Clopper-Pearson method was used to estimate the associated 95% confidence intervals (CI). Results: Of the 5357 records initially identified, 28 trials with a total of 2138 patients were considered eligible for inclusion. Neoadjuvant chemotherapy was assessed in 15 trials (1535 patients), NAI in 5 (288 patients), and NACI in 8 (315 patients). The pooled incidence of patients experiencing a pCR was 30.91% (95% CI: 26.54%-35.45%) with NAC, 30.92% (23.22%-39.14%) with NAI, and 42.25% (36.6%-48.0%) with NACI. The difference in pCR among these therapies was statistically significant (p <0.05). Similarly, the pooled incidence of achieving pathological downstaging was 40.91% (34.26%-47.72%) with NAC, 38.84% (26.73%-51.64%) with NAI, and 62.88% (57.22%-68.39%) with NACI. Consistently, there was statistically significant effect modification by the choice of neoadjuvant systemic therapy (p <0.01). The results were consistent across different clinically important subgroups (Table). Conclusions: NACI may achieve better pCR and pathological downstaging than NAC and NAI alone in MIBC patients which may potentially be associated with long-term survival. Definitive data from phase III trials are pending. [Table: see text]

40 Background: Previously we have reported enrollment disparities in PCa clinical trials. Funding source can influence minority representation in clinical trials. Hence, we aimed to evaluate the impact of source of funding on enrollment disparities in PCa clinical trials. Methods: MEDLINE and EMBASE were searched to identify phase II/III PCa trials. All relevant trials reporting age by 65 years were considered eligible for inclusion. Trials recruiting from the United States (US) were considered eligible for analysis by race and ethnicity. The trial proportions of age, or racial/ethnic subgroup category and the global incidence in the corresponding age subgroup (from the global burden of disease database), or the US-population-based incidence in the corresponding racial/ethnic subgroup (from SEER 21 database) were used to compute enrollment incidence ratio (EIR) at each trial. EIRs with corresponding 95% confidence intervals (CI) were then meta-analyzed using a random-effects model and stratified by sources of funding (industry, US-government, and others [academic and non-US govt]). A univariate meta-regression was conducted to assess the temporal changes in EIR by each funding category. Results: Of 127 trials recruiting from the US, 89 (70%) reported race, and 35 (27%) reported ethnicity. Among those, 57 (64%), 14 (16%), and 18 (20%) trials reported industry, US-government, and other sources of funding, respectively. Of those reporting ethnicity, 23 (66%), 4 (11%), and 8 (23%) trials reported industry, US-government, and other sources of funding, respectively. Among the 287 eligible trials, 49 trials (17%) reported age by 65 years. Of those, 36 (73%), 6 (12%), and 7 (13%) reported industry, US-government, and other sources of funding, respectively. In terms of racial/ethnic enrollment, Black patients were significantly under-represented in industry funded trials (0.33; 0.27-0.41). No significant disparity was observed in US-government funded trials (0.75: 0.57-1.00). The P-value of interaction was <0.0001. Hispanics were significantly under-represented in industry funded clinical trials (0.56; 0.43-0.74). The number of US-government funded trials reporting Hispanics were small (<10) which precluded any meaningful statistics. No significant disparity was observed in terms of older adults (EIR: 1.00; 95% CI: 0.95; 1.05) overall and by funding sources. Black patients’ representation in industry funded PCa trials has significantly decreased over the last three decades. No significant change was observed in US-government funded PCa trials over the last three decades (P:0.004). Conclusions: Black and Hispanic men with PCa are likely to be under-represented in industry sponsored clinical trials. Black patients’ representation in industry sponsored trials has declined over time, thus widening the cancer-care inequities in these patients.

195 Background: Preliminary data suggests that patients with metastatic castration-sensitive prostate cancer (mCSPC) who achieve deep prostate-specific antigen (PSA) response may have improved survival. This finding may have implications for developing treatment de-escalation strategies. Thus, we assessed the overall survival by deep PSA response in mCSPC patients receiving intensified treatments. Methods: MEDLINE and EMBASE were systematically searched from each database’s inception through 1st October 2022. Trials assessing androgen deprivation therapy intensification (doublets, triplets) and reporting overall survival (OS) by deep PSA response were considered eligible for inclusion. Deep PSA response was defined as the PSA level of less than 0.1 or 0.2 ng/ml within eight months after initiation of intensified treatment. Precomputed effect estimates of OS (deep PSA response vs no deep PSA response) were pooled using an inverse-variance approach after logarithmic transformation; a random-effects meta-analysis was conducted within the Bayesian framework using empirical informative priors for heterogeneity parameter as specified by Turner et al. Summary effect was expressed as hazard ratios (HR) with the corresponding 95% credible intervals (CrI). A sensitivity analysis was conducted using the Der Simonian-Lairds random-effects meta-analysis with Hartung-Knapp (HK) adjustment. Results: Five RCTs (PEACE-1, ARASENS, CHAARTED, LATITUDE, TITAN) with 2533 patients were included in this systematic review. A total of 1335 patients experienced a deep PSA response, while 1218 did not achieve a deep PSA response after the initiation of intensified treatment. The pooled incidence of deep PSA response was 49.45% (95% confidence interval: 37.75-61.18). Bayesian meta-analysis showed significantly improved OS in overall mCSPC patient population who achieved a deep PSA response after intensified treatment with either triplet or doublet therapy as compared to those who did not achieve a deep PSA response (HR: 0.39; 95% CI: 0.30-0.50) as shown. The results were consistent with HK adjustment. Conclusions: Excellent overall survival in patients with deep PSA response may offer an opportunity to guide treatment de-escalation trials in carefully selected mCSPC patients. [Table: see text]

193 Background: We maintain a network meta-analysis for the treatment of mCSPC using a living interactive evidence (LIvE) synthesis framework. Recently, the STAMPEDE trial presented evidence regarding a new triplet regimen (enzalutamide-abiraterone-androgen deprivation therapy [E+AAP+ADT]). Hence, in this report we provide the most-up-to-date evidence to inform the choice of optimal therapy in mCSPC patients. Methods: Phase III randomized controlled trials (RCTs) assessing treatment intensification with androgen pathway inhibitors (API), docetaxel (D), or both in patients with mCSPC were included. Mixed treatment comparisons for overall-survival (OS) and progression-free survival (PFS) were made across randomized comparisons using a frequentist network-meta-analysis. Additionally, subgroup data from three trials (ENZAMET, TITAN, ARCHES) by the receipt of docetaxel were abstracted to evaluate the comparative effectiveness of different triplet regimens. Treatment effects were expressed as hazard ratio (HR) and 95% confidence intervals (CI). Relative treatment rankings were evaluated using P-scores and assessed in congruency with the pairwise estimates. Results: This report includes 10 clinical trials (30 references) and over 11500 patients updated as of 1st October 2022. Using randomized data in overall patient population, AAP+D+ADT (rank 1; HR: 0.50; 95% CI: 0.35-0.72) and E+AAP+ADT (rank 4; HR: 0.76; 0.62-0.93) significantly improved PFS compared to D+ADT (rank 7) but not when compared to E+ADT (rank 2) and APA+ADT (rank 3). Similarly, darolutamide (DARO)+D+ADT (rank 1; HR: 0.68; 0.57-0.81), AAP+D+ADT (rank 2; HR: 0.75; 0.59-0.95) significantly improved OS when compared to D+ADT (rank 7). Efficacy by volume of disease and timing of metastatic presentation was consistent with prior update. Using subgroup data by the receipt of docetaxel, a total of five triplet regimens (DARO+D+ADT, AAP+D+ADT, E+D+ADT, apalutamide (APA)+D+ADT, and E+AAP+ADT) were evaluable for comparisons. E+D+ADT (rank 3) improved PFS compared to D+ADT (rank 9; HR: 0.52; 0.41-0.66) and E+AAP+ADT (rank 6; HR: 0.70; 0.52-0.94). Compared to AAP+ADT (rank 7), E+D+ADT (HR: 0.64; 0.49-0.84) and AAP+D+ADT (rank 2; 0.62; 0.42-0.91) significant improved PFS. However, no significant differences were observed among E+D+ADT, AAP+D+ADT, and APA+D+ADT. Similarly, DARO+D+ADT (rank 1) improved OS compared to APA+D+ADT (HR: 0.47; 0.24-0.93). Conclusions: Current evidence favors the use of emerging triplet regimens over docetaxel doublet but not API doublets in overall population. Among different triplets, E+AAP+ADT may not delay progression compared to docetaxel triplets. Hence, access to treatment, toxicity, disease volume and timing of metastases should be carefully considered in mCSPC patients.

116 Background: The impact of socioeconomic status on genitourinary (GU) cancer mortality in the United States (US) is unclear. Hence, we evaluated the association of the socioeconomic status with GU cancer mortality across the US counties. Methods: County-level age-adjusted mortality rates (AAMR) per 100,000 person-years (PY) for populations diagnosed with GU cancers were abstracted from the wide-ranging online data for epidemiological research (WONDER) database. The agency for toxic substances and disease registry (ATSDR) was queried to obtain county-level social vulnerability indices from 2014-2018. Percentile ranking scores (PRS: ranging from 0-1) were computed for each US county and further categorized into quartiles (Q: 1st: 0-0.25 [least vulnerable]; 4th: 0.75-1.00 [most vulnerable]). AAMRs were then linked with quartile rankings. A population-weighted, Poisson regression analysis was conducted to compute rate ratios (RR) of AAMRs between 4th and 1st Q with the corresponding 95% confidence intervals (CI). Results: A total 3142 US counties were included in this analysis. The AAMR for GU cancers was 22.6 overall deaths (OD) and 4.20 premature deaths (PD; defined as death at age <65 years) per 100,000 PY. GU cancer-related mortality increased in a stepwise fashion from the 1st Q to the 4th Q (OD: 21.6 vs 24.1; PD: 3.48 vs 5.19). In terms of OD by specific GU cancers, significantly higher AAMRs were observed in the 4th Q compared to the 1st Q for patients with prostate cancer (RR; 1.19 [95% CI;1.14-1.24]), and renal cell carcinoma (RCC; 1.12 [1.04-1.21]) but not for those with lower urothelial tract cancers (0.92 [0.87-0.96]). Among subgroups, non-Hispanic Blacks (1.19 [1.07-1.33]), and Hispanics (1.28 [1.08-1.51]) with prostate cancer and men with RCC (1.11; 1.03-1.19) in the 4th Q experienced significantly higher overall mortality when compared to those in the 1st Q. With regards to PD, significantly higher AAMRs were observed in the 4th Q vs 1st Q for patients with prostate cancer (1.54 [1.34-1.77]), and RCC (1.28 [1.12-1.45]). Consistently, men with RCC in the 4th Q also experienced higher premature mortality when compared to the 1st Q. Sparsity of mortality data among different ethnic/racial subgroups across the US counties precluded any formal assessment of disparity by specific GU cancers. A sensitivity analysis, conducted using the weighted linear regression approach, showed consistent results. Conclusions: Population level data suggest that socially vulnerable populations, especially Non-Hispanic Black and Hispanic men with prostate cancer, and men with renal cell carcinoma may be at an increased risk of cancer-related mortality. Hence, there is a dire need to address this mortality gap across different socioeconomic subgroups to ensure health-care equity. Investigations at the patient level are required to further ascertain these findings.

Accurate clinical staging of bladder cancer aids in optimizing the process of clinical decision-making, thereby tailoring the effective treatment and management of patients. While several radiomics approaches have been developed to facilitate the process of clinical diagnosis and staging of bladder cancer using grayscale computed tomography (CT) scans, the performances of these models have been low, with little validation and no clear consensus on specific imaging signatures. We propose a hybrid framework comprising pre-trained deep neural networks for feature extraction, in combination with statistical machine learning techniques for classification, which is capable of performing the following classification tasks: (1) bladder cancer tissue vs. normal tissue, (2) muscle-invasive bladder cancer (MIBC) vs. non-muscle-invasive bladder cancer (NMIBC), and (3) post-treatment changes (PTC) vs. MIBC.

Importance The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown. Objective To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups. Data Sources For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database’s inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a “living” auto search was created with weekly updates to identify new evidence as it became available. Study Selection Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC. Data Extraction and Synthesis Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022. Main Outcomes and Measures Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life. Results This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT. Conclusions and Relevance The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.