Raina, Ammad

4594 Background: Cisplatin based neoadjuvant chemotherapy (NAC) followed by definitive therapy improves survival in patients with muscle invasive bladder cancer (MIBC). However, the clinical benefit of NAC might vary with the choice of definitive therapy. Therefore, we assessed the absolute benefit of NAC followed by radical cystectomy or radical radiotherapy separately using the totality of evidence. Methods: MEDLINE and EMBASE were systematically searched to identify randomized trials assessing cisplatin based neoadjuvant chemotherapy followed by either radical cystectomy or definitive radiotherapy in patients with MIBC. Outcomes of interest included overall survival (OS) and disease-free survival (DFS). Treatment effects were expressed as hazard ratios (HR) with 95% confidence interval (CI). Incidence rate ratios were calculated to estimate time to event outcomes for trials not reporting HR. A random-effects DerSimonian-Laird meta-analysis was conducted. Absolute effects were then obtained using baseline risks from the control arm of RCTs. Results: Of 4887 studies identified, 13 trials with 2529 patients were included in this meta-analysis. Most trials included patients with T2-4 and N0 patients and only 3 trials included patients with node positive disease. Total of 180 (47%) DFS events were observed with NAC+RC compared to 213 (56%) events in RC alone (HR: 0.72; 95% CI: 0.59-0.89) and 346 (58%) OS events were observed with NAC+ RC compared to 385 (52%) events in RC alone (HR: 0.80; 95% CI: 0.69-0.92). Total of 186 (70%) DFS events were observed with NAC + radiotherapy compared to 205 (71%) events in radiotherapy alone (HR: 0.91; 95% CI: 0.74-1.12) and 263 (58%) OS events were observed with NAC+ radiotherapy compared to 294 (61%) events in radiotherapy alone (HR:0.93; 95% CI: 0.79-1.08). Conclusions: The choice of definitive therapy after cisplatin-based NAC impacts survival in patients with MIBC. RC after NAC improved DFS (114 fewer events per 1000 events) and OS (76 fewer per 1000 events) whereas radiotherapy after NAC showed no survival benefit. [Table: see text]

134 Background: Recent trials have suggested poly ADP-ribose polymerase inhibitors (PARPi) sensitivity in patients with treatment-refractory metastatic castration-resistant prostate cancer (mCRPC) harboring mutations in DNA damage and response repair genes (DDR). However, the efficacy profile might differ with different genes and is still being explored in multiple studies. Methods: We systematically searched several electronic databases (MEDLINE, EMBASE), and conference proceedings to include abstracts and full-text publications of phase II/III trials evaluating PARPi in treatment-refractory mCRPC with DDR gene alterations. Outcomes of interest included objective response rate (ORR), complete response (CR), prostate specific antigen (PSA) 50% response, circulating tumor cells conversion (CTCc) from ≥ 5 to < 5 cells, composite response (CoR) and risk of progression. Data was pooled using Inverse-variance approach. A DerSimonian and Laird random-effect meta-analysis was conducted to estimate pooled proportion (PP) of events using the Freeman-Tukey transformation in each gene. Clopper-Pearson method was used to estimate the associated 95% confidence intervals (CI). Results: This systematic review and meta-analysis included five unique trials with 648 patients and four PARPi (niraparib, olaparib, rucaparib, talazoparib). Objective response to PARPi was observed in 44.7% of patients with mutations in either BRCA1 or 2 or both (95% CI: 36.0%-53.6%; I2: 0%), 23.5% with ATM (95% CI: 3.91%-51.0%; I2: 65%), 25.0% with CDK12 (95% CI: 8.66%-49.1%), and 45.3% with PALB2 alterations (95% CI: 14.8%-77.5%; I2: 0%). Consistent results were observed for CR outcome. PSA50% response to PARPi was observed in 60.3% of patients with BRCA1/2 mutations (95% CI: 50.3%-70.0%; I2: 57%), 5.54% (95% CI: 0.01-16.6; I2: 0%) with ATM, and 70.1% (95% CI: 35.6%-96.6%; I2: 0%) with PALB2 mutations while no PSA 50% response was observed in patients with CDK12 mutations (PP: 0.00%; 95% CI: 0%-16.84%). Moreover, CTCc was observed in 68.3% of patients with BRCA1/2 mutations (95% CI: 45.0%-87.8%; I2: 77), 34.2% (95% CI: 11.2-61.3%; I2: 45%) with ATM, 41.7% (95% CI: 15.2%-72.3%) with CDK12, and 48.5% (95% CI: 6.39%-92.9%; I2: 49%) with PALB2. CoR was observed in 76.5% patients with BRCA1/2 mutations (95% CI: 65.4%-86.1%; I2: 22%), 30.4% (95% CI: 16.0%-46.9%) with ATM, 25% (95% CI: 8.66%-49.1%) with CDK12, and 63.9% (95% CI: 31.0%-91.8%; I2: 0%) with PALB2 mutations. Similarly, the risk of progression was 50.9% in patients with BRCA1/2 mutations (95% CI: 37.7%-63.9%), 70.9% (95% CI: 60.0%-80.40%; I2: 0%) with ATM, and 75% (95% CI: 19.4-99.3%) with PALB2. Conclusions: Current evidence is sparse regarding efficacy by specific genes. Limited data favors the use of PARPi in mCRPC patients harboring mutations in BRCA1/2 and PALB2 genes.

e17539 Background: Chemotherapy with Docetaxel (D) or androgen pathway inhibition (API) with Abiraterone Acetate plus prednisone (AAP), Aplautamide(APA) and Enzalutamide(E) are acceptable, FDA approved treatment options for mCSPC. It is not clear whether the magnitude of benefit varies by the choice of initial agent [chemotherapy vs API] or by volume of disease [High vs Low]. Data is now available from all registration trials by volume status and motivated this analysis to inform initial treatment choice in mCSPC. Methods: We systematically searched MEDLINE(Ovid), Embase, and Scopus for randomized controlled trials of chemotherapy(D) or APIs (AAP, APA, ENZ) that had available hazard ratios (HRs) for overall survival (OS) and Progression Free Survival (PFS) according to patient’s volume of disease. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled overall survival HR and 95% CI by chemotherapy and APIs and by high volume(HVD) and low volume(LVD) using a random effect model, and tested for heterogeneity to assess the null hypothesis that no difference in the survival advantage exists by choice of initial agent and volume of disease. Results: Of 4456 studies identified in our search, there were 8 eligible randomized controlled trials that were included in the analysis. Both D and APIs significantly improved PFS [HR 0.48; 0.45-0.51] and OS [0.72; 0.64-0.81] when added to ADT, however the latter was associated with significantly higher improvement in PFS( P < 0.01) and OS (P = 0.03). In patients treated with D, patients with HVD derive significantly more benefit as compared to LVD( P = 0.046) and patients treated with APIs both HVD and LVD patients derive similar benefit( P = 0.80) (Table). Conclusions: mCSPC patients derive higher magnitude of survival benefit when treated with APIs as compared to D; however, D may be preferred in HVD patients. [Table: see text]

708 Background: Patients with high risk non-metastatic renal cell cancer (RCC) are at significant risk of recurrence following nephrectomy. Previously, we reported no benefit of adjuvant tyrosine kinase inhibitor (TKI) treatment in high-risk patients. Since our most recent publication, efficacy results from the multicenter double-blind SORCE trial have become available. We updated our meta-analysis to include these additional data and performed a cumulative meta-analysis. Methods: PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials were searched to identify relevant RCTs. A generic variance-weighted random effects model was used to derive estimates for efficacy. Heterogeneity was assessed using the Cochran Q statistic and was quantified using the I2 test. The primary outcome was disease-free survival (DFS), defined as the interval between randomization and the first recurrence, the occurrence of metastasis or a secondary cancer, or death due to any cause. Statistical analysis was performed using Comprehensive Meta-Analysis version 3 (Biostat). Results: Five phase 3 trials were identified, enrolling 6531 patients. Two trials compared sunitinib with placebo (S-TRAC and ECOG-ACRIN), two compared sorafenib with placebo (ECOG-ACRIN and SORCE) and one trial each compared pazopanib (PROTECT) and axitinib (ATLAS) vs placebo. Cumulative evidence suggests that adjuvant therapy with TKIs showed no significant improvement in (DFS) hazard ratio [HR] of 0.93 (95% CI, 0.85-1.02), compared to placebo. There was no significant heterogeneity among included trials ( I2= 52%, P= .41). Overall, the trials were at low risk of bias. Conclusions: Adjuvant vascular endothelial growth factor tyrosine kinase inhibitors in high-risk renal cell carcinoma did not improve DFS as compared to placebo. Improved patient selection using better prognostic biomarkers or scoring systems may identify subsets of patients who can benefit from adjuvant treatments. Toxicity estimates will be updated as data from SORCE trial publication becomes available.

PURPOSE: Gender disparity persists in academic medicine. Female faculty are underrepresented in leadership positions and have lower research output. We studied gender differences in faculty rank and departmental leadership and contributing factors among academic hematologists and oncologists in the United States. METHODS: For clinical faculty at 146 hematology or oncology fellowship programs listed in the Fellowship and Residency Electronic Interactive Database, we collected data on demographics, academic rank, and research output using the Doximity and Scopus databases. We compared unadjusted characteristics of men and women by using 2-sided t tests and χ2 tests where appropriate. To predict probability of full professorship or leadership position among men versus women, we performed multivariable logistic regression analysis adjusted for clinical experience in years, number of publications, h-index, clinical trial investigator status, National Institutes of Health funding, and workplace ranking (top 20 v not). RESULTS: Two thousand one hundred sixty academic hematologists and oncologists were included. Women composed 21.9% (n = 142) of full professors, 35.7% (n = 169) of associate professors, and 45.4% (n = 415) of assistant professors. Thirty percent (n = 70) of departmental leaders were women. Female faculty, compared with male faculty, had a lower mean h-index (12.1 v 20.9, respectively; P < .001) and fewer years of professional experience since fellowship (10 v 16 years, respectively; P < .001). After adjusting for duration of clinical experience, academic productivity, and workplace ranking, the odds of obtaining professorship (odds ratio [OR], 1.05; 95% CI, 0.71 to 1.57; P = .85) or divisional leadership (OR, 0.57; 95% CI, 0.20 to 1.58; P = .28) for female physicians were not different compared with male physicians. CONCLUSION: Gender disparity exists in senior ranks of academic hematology and oncology; however, gender is not a significant predictor in achieving professorship or department leadership position.

Introduction: We have previously reported underrepresentation of female faculty at senior academic ranks in hematology/oncology (H/O). In this analysis we aimed to investigate the influence of sex in attaining leadership positions amongst academic hematologists/oncologists in United States. Methods: Faculty members were identified at 146 H/O fellowship programs listed on fellowship and residency electronic interactive database (FREIDA.) Data was collected on demographics, academic rank and research output using Doximity and Scopus databases. We compared the unadjusted characteristics of men and women by using two-sided t-tests and χ2 tests where appropriate. In primary analysis, logistic regression models were used to evaluate sex differences on probability of having full professorship (versus assistant and associate professorship) and of achieving leadership positions including division chief, Program Director (PD) and Associate Program Director (APD). Adjusted models included the following variables: clinical experience in years, number of publications, h-index, appointment at top 20 hospital, clinical trial investigator status and National Institutes of Health funding. Stratified analysis was performed adjusting for duration of clinical experience (≤15 vs >15 years) Results: Fewer women were full Professors (21.9% vs 78.1%), division chiefs (16.7% vs 83.3%), and PDs (30.5% vs 69.5) but the number was similar for Associate Program Directors (47.1% vs 52.9%). In a univariate unadjusted model, women were less likely to be full professors compared to men (OR 0.39; 95% confidence interval [CI], 0.31-0.48; P<.001). However, in the multivariable adjusted model no statistically significant sex difference in full professorship was found (OR 1.05; 95% CI 0.71, 1.57; P=.85; Table). The likelihood of full professorship was positively associated with clinical experience in years, number of first/last author publications, h-index, and being a primary investigator on at least one clinical trial.In a univariate unadjusted model, women were less likely to be division chiefs as compared to males (OR 0.35; 95% CI, 0.16, 0.80; P=.01). However, in the multivariable adjusted model, there was no statistically significant sex difference in achieving the position of division chief (OR 0.57; 95% CI 0.20, 1.58; P=.28; Table). No significant difference was found between females and males for being program directors or associate program directors in both univariate and multivariate analysis. Similarly, a stratified analysis adjusting for duration of clinical experience (≤15 vs >15 years) found no significant sex differences in attaining leadership position (Table) Conclusion: We found that women are underrepresented at higher academic ranks and in leadership positions in hematology/oncology, but that sex is not a significant negative predictor to women obtaining leadership positions after correcting for traditional predictors of academic success. However, "non-traditional" and therefore less measurable and analyzable factors such as networking, mentorship, sponsorship, gender bias, balancing work and home responsibilities and many others may contribute and should be further investigated. Disclosures No relevant conflicts of interest to declare.

e12545 Background: Palbociclib(P), Ribociclib(R) and Abemaciclib(A) in combination with Endocrine therapy (ET) have demonstrated progression free survival (PFS) in patients with metastatic hormone receptor positive, HER2-negative breast cancer as compared to ET alone. In the absence of head to head clinical trials and to provide clinical guidance, we performed an indirect comparison for P, R and A using network Meta-Analysis (NMA). Methods: MEDLINE, EMBASE and the Cochrane Library were searched to identify RCTs comparing P+ET, R+ET, A+ ET vs ET alone. NMA for PFS and toxicity endpoints was conducted using a multivariate random-effects meta-regression, using a consistency model, as described by White and colleagues. We used a frequentist approach and provided a point estimate from the network and a 95% CI from the frequency distribution of the estimate. We also estimated the relative ranking of the different treatments for each outcome using the distribution of the ranking probabilities and the surface under the cumulative ranking curves (SUCRA). Risk of bias was assessed using Cochrane Collaboration tool. Results: 8 RCTs were identified including 4580 patients. Risk of bias was low. 5 RCTs tested CDK 4/6 inhibitors in endocrine naive and 2 in the refractory setting, while MONALESSA-3 included patients both with endocrine naive and endocrine resistant disease. In the endocrine naïve patients, PFS for P was similar when compared indirectly with R (HR, 0.95, 95% CI 0.67-1.35) or A (HR, 1.00, 95% CI 0.62-1.61). Similarly, indirect comparison between R vs A did not show any statistical significant (HR, 0.95, 95% CI 0.62-1.45). In endocrine refractory patients, P showed no difference when compared indirectly to A (HR 1.12, 95% CI 0.67-1.87) or R (HR 0.98, 95% CI 0.52-1.86). R vs A did not show any statistically significant PFS either (HR, 1.14, 95% CI 1.61-4.51). P was ranked first in terms of PFS in frontline setting (SUCRA of 70.5) while R ranked first in the refractory setting (SUCRA of 39.5). QT prolongation was reported for R only. P caused more neutropenia while A caused more fatigue, anemia and diarrhea, although the results were not statistically significant. Conclusions: The efficacy of using either palbociclib, ribociclib or abemaciclib in combination with ET was similar in terms of PFS in either endocrine naïve or resistant disease. Palbociclib causes more neutropenia, abemaciclib causes more fatigue, anemia and diarrhea while ribociclib causes QT prolongation.

e12057 Background: Several RCTs have evaluated a shorter duration of T ( < 12 months) with hopes of similar efficacy, reduced cardiotoxicity, cost and burden of treatment. Of the 5 major studies, PERSPHONE showed that 6 months was non-inferior compared to 12 months. However, four additional studies of shorter duration failed to demonstrate non-inferiority. Therefore, we performed an updated systematic review and a meta-analysis to assess the optimal duration of adjuvant T. Methods: MEDLINE, EMBASE, Cochrane, Scopus and conference proceedings were searched to identify RCTs comparing one year of adjuvant T with a shorter duration in early-stage HER2+ breast cancer. The DerSimonian-Laird random-effects Meta-Analysis was performed using CMAv3 software to derive pooled Hazard Ratio (HR) estimates for overall survival (OS, Disease-Free Survival (DFS) and Odds Ratio(OR) estimates of cardiac toxicity. Q-test was used to assess between-study heterogeneity; I2 statistic was computed to express the percentage of the total observed variability due to study heterogeneity. The risk for bias was assessed using the Cochrane Collaboration’s tool. Results: We screened 1772 citations and identified 5 studies(n = 11,377) for analysis. 5691 patients were randomized to 12 months of adjuvant T while 5686 were randomized to a shorter duration (3 studies evaluated 6 vs 12 months, 2 studies evaluated 9 weeks vs 12 months). OS (HR, 1.16, 95% CI 1.03-1.31, P= 0.015,I2 0.00, p= 0.837) and DFS (HR, 1.14, 95% CI 1.02-1.26 , P = 0.016,I2 14.90, p= 0.319) were significantly worse in patients receiving shorter duration T as compared to 12 months. Cardiotoxicity was significantly higher in the 12 month group vs shorter duration (OR, 2.10, 95% CI 1.58-2.80, p = 0.000 ,I2 51.182, p= 0.085). Grade 3/4 cardiac events and cardiac events leading to discontinuation of therapy were significantly higher in patients receiving 12 months (HR 2.06, 95% CI 1.60-2.63, P = 0.000, I2 3.967, p= 0.384). There was no significant heterogeneity among studies. Risk of bias was low. Conclusions: Twelve months of adjuvant T is associated with significantly better DFS and OS compared to a shorter duration. As such, 12 months should remain the standard of care for most patients. There is an unmet need to identify lower risk groups which might do well with from shorter duration of HER2-directed therapy.