Riaz, Irbaz Bin

BackgroundDespite routine evaluation of cytogenetics in myeloma, little is known regarding the impact of high‐dose therapy (HDT) consolidation on overall survival (OS) or progression‐free survival (PFS) in patients who have high‐risk cytogenetics. The authors performed a meta‐analysis of randomized controlled trials (RCTs) to assess the heterogeneity of HDT efficacy according to cytogenetic risk.MethodsAll RCTs in patients who had newly diagnosed myeloma from 2000 to 2021 that compared upfront HDT versus standard‐dose therapy (SDT) consolidation were included. The primary objective was to assess the difference in HDT efficacy between standard‐risk and high‐risk cytogenetics in terms of the OS or PFS log(hazard ratio) (HR). The pooled OS and PFS HR was calculated according to cytogenetic‐risk subgroup using a random‐effects model, and heterogeneity (I2) (the percentage of total observed variability explained by between‐study differences) was assessed using an interaction test.ResultsAfter screening 3307 citations, 6 RCTs were included for PFS analysis, and 4 were included for OS analysis. The median follow‐up ranged from 3.1 to 7.8 years. The pooled OS HR for HDT versus SDT consolidation in patients with standard‐risk and high‐risk cytogenetics was 0.90 (95% confidence interval [CI], 0.70‐1.17; I2 = 0%) and 0.66 (95% CI, 0.45‐0.97; I2 = 0%), respectively. The difference in HDT efficacy in terms of OS between standard‐risk and high‐risk patients was statistically significant in favor of the high‐risk group (P for interaction = .03). The pooled PFS HR for HDT versus SDT was 0.65 (95% CI 0.56‐0.76; I2 = 0%) versus 0.52 (95% CI, 0.33‐0.83; I2 = 55%), respectively. The difference in HDT efficacy in terms of PFS between standard‐risk and high‐risk patients was not significant (P for interaction = .25).ConclusionsThe magnitude of OS benefit with upfront HDT is cytogenetics‐dependent. Patients with high‐risk cytogenetics should preferably receive upfront rather than delayed HDT consolidation.Lay Summary Upfront autologous stem cell transplantation improves overall survival in patients with newly diagnosed myeloma harboring high‐risk cytogenetics.

518 Background: Cisplatin (C) based neoadjuvant chemotherapy (NAC) has been the mainstay treatment for muscle invasive bladder cancer (MIBC). However, the optimal choice of NAC is not well-established. We therefore conducted a network-meta-analysis (NMA) to assess comparative efficacy of different treatment options. Methods: Several electronic databases (MEDLINE, and EMBASE) and conference proceedings were systematically used to identify randomized trials evaluating first-line treatments in neoadjuvant MIBC. Outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and pathologic complete response (pCR). DerSimonian-Laird random-effects meta-analysis was used to compute direct comparisons between NAC and local therapy (LT) only. Fixed effect NMA was conducted within the frequentist framework for mixed treatment comparisons. P-scores were used to assess relative treatment rankings. All statistical analyses were conducted in R (v 4.1.1). Results: This systematic review included 23 trials (25 references) with a total of 5313 patients with 10 unique treatments. Direct comparisons showed significant benefit in PFS (HR: 0.82; 95% CI: 0.71-0.94), and in OS (HR: 0.85; 95% CI: 0.78-0.92) with NAC when compared to LT only. However, the likelihood of achieving an objective response (RR: 1.18; 95% CI: 0.72-1.95: I2: 85%) or CR (RR: 1.51; 95% CI: 0.87-2.61; I2: 79%) was not different between the two arms. Data available in 15 trials contributed to the network for PFS outcome while only eight trials contributed to OS outcome. Mixed treatment comparisons showed significantly improved PFS with nintedanib-gemcitabine-cisplatin (NinGC; HR: 0.42; 95% CI: 0.20-0.87) and dose-dense-methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC; HR: 0.61; 95% CI: 0.43-0.88) compared to LT only. Consistent benefit was observed when NinGC (HR: 0.48; 95% CI: 0.24-0.97) and ddMVAC (HR: 0.70; 95% CI: 0.51-0.96) were compared to GC only. However, no significant differences were observed between NinGC (rank 1) and ddMVAC (rank 2) or among other mixed treatment comparisons. Similarly, OS was significantly improved with NinGC (rank 1) relative to MVAC (HR: 0.41; 95% CI: 0.17-0.97), MVC (HR: 0.37; 95% CI: 0.16-0.88), MC (HR: 0.38; 95% CI: 0.16-0.92), AC (HR: 0.36; 95% CI: 0.15-0.91), and GC (HR: 0.39; 95% CI: 0.17-0.90). While similar results were observed with ddMVAC (rank 2) when compared to MVC (HR: 0.63; 95% CI: 0.42-0.94), MC (HR: 0.64; 95% CI: 0.42-0.98), and GC (HR: 0.66; 95% CI: 0.47-0.92), no significant differences were observed with ddMVAC when compared to MVAC (HR: 0.62; 95% CI: 0.38-1.01) and NinGC (HR: 1.70; 95% CI: 0.69-4.19). Conclusions: Current evidence shows improved PFS and OS with the use of neoadjuvant ddMVAC and Nin-GC in patients with MIBC relative to other treatment options.

481 Background: EV is an anti-Nectin-4 antibody-drug conjugate that has been approved by the US FDA for mUC progressing on platinum and PD1/L1 inhibitor therapy and in cisplatin-ineligible pts following prior therapy. However, prognostic and predictive biomarkers in the setting of EV therapy are unclear. We aimed to investigate baseline and early changes in commonly available clinical and laboratory tests that could help predict survival and toxicities in patients with mUC treated with EV. Methods: Data from patients with mUC who were treated with EV at Dana Farber Cancer Institute between 2017 and 2021 were reviewed retrospectively. We assessed the association of demographic (age, sex), clinical (ECOG-performance status [PS], sites of metastasis) and laboratory variables (hemoglobin, RDW, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, platelet count and serum albumin) at baseline as well as after 4-7 weeks of treatment with Overall Survival (OS) by constructing univariate and multivariable Cox proportional-hazards models. Any variables significantly associated with OS at the univariate level (using an alpha-level of 0.1 to determine statistical significance) were then entered into the multivariable model. Predictors were eliminated from the final multivariable models by a backward selection process, retaining only those with a p-value of ≤ 0.05. Results: A total of 49 patients who received EV were included in the analysis. The median age was 72 years (range 48-88) and 36 (73.5%) were male. The median OS was 13.3 months (range: 2.7-38.7) and grade 3-4 toxicities were seen in 11 pts (22.4%). In the final multivariable models, lower serum albumin at 4-7 weeks (HR = 0.18; 95% CI = 0.05-0.71; p = 0.015), and baseline ECOG-PS of 1 vs. 0 (HR = 2.56; 95% CI = 1.05-6.21; p = 0.038) were significantly associated with worse OS (Table). Patients with higher serum albumin levels at 4-7 weeks also had significantly lower odds of experiencing grade 3-4 adverse events on EV (OR = 0.05; 95% CI = 0.002-0.52; p = 0.02). Conclusions: Lower serum albumin appeared to predict worse survival and severe toxicities in mUC pts receiving EV. This information may guide therapy and assist in the prevention of toxicities. Additionally, ECOG-PS was prognostic while the location of metastatic disease was not prognostic in the setting of EV.[Table: see text]

360 Background: Pembrolizumab has been established as an effective treatment option in adjuvant renal cell carcinoma after the publication of KEYNOTE-564. However, the magnitude of benefit based on different risk categories is not well defined. Methods: We included full-text publications of phase II/III randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors or tyrosine kinase inhibitors (TKIs) in adjuvant renal cell carcinoma after a systematic search. The outcomes of interest included disease free survival (DFS), overall survival (OS), all grade or grade ≥3 treatment related, and all cause adverse events. Mixed treatment comparisons were computed through a fixed-effect multivariate meta-regression within the frequent framework. Relative treatment rankings were assessed using P-scores. 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 (CIRs) 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 baseline category. Results: This NMA included six RCTs with a total of 7525 participants and five unique treatment options. Mixed treatment comparisons showed significant DFS and OS benefit with pembrolizumab (rank 1) when compared against sunitinib (DFS HR 0.74 [0.55-0.99]; OS HR 0.51 [0.27-0.94]). However, there were no significant differences with pembrolizumab compared to pazopanib (DFS HR 0.81 [0.60- 1.09]; OS HR 0.54[0.29-1.01]) and axitinib (DFS HR 0.78 [0.54-1.14]; OS HR 0.52 [0.24-1.16]). The safety profiles were comparable. Absolute benefit of TKIs in adjuvant setting was minimal whereas this benefit increased with higher T and N patients in patients treated with pembrolizumab (Table). Similarly, the treatment benefit increased with higher Leibovich’s risk scores at 5, 10 and 15 years of follow up. Conclusions: The current analysis suggests that a risk adapted approach may be useful when considering adjuvant pembrolizumab in RCC patients.[Table: see text]

136 Background: Intensification of initial treatment of in patients with metastatic castration-sensitive prostate cancer (mCSPC) with androgen pathway inhibition (API) in addition to docetaxel (DOC) and androgen deprivation therapy (ADT) has shown promise to improve clinical outcomes. Thus, we synthesize the data from modern clinical trials to estimate overall estimates of progression and survival outcomes. Methods: A systematic search of electronic databases (MEDLINE and EMBASE) was conducted to include phase III randomized controlled trials (RCTs) evaluating triplet therapy (API+DOC+ADT) against doublet therapy (DOC+ADT) in mCSPC. Outcomes of interest included overall survival (OS) and radiographic progression-free survival (rPFS). A DerSimonian-Laird random-effects meta-analysis was performed to pool precomputed hazard ratios (HRs) and confidence intervals (CIs) after logarithmic transformation using inverse-variance weighting approach. Cochran’s Q statistical test was used to assess statistically significant heterogeneity not explained by chance, while I2 statistical test was used to quantify the total observed variability, due to between-study heterogeneity. I2 values >50% indicated substantial heterogeneity. A summary of findings table was constructed to translate relative estimates to absolute risks. Results: A total of 1,531 patients in four RCTs with direct comparative data between triplet and doublet therapies, were included in this meta-analysis. PEACE-1 was the only RCT directly assessing this question (AAP+DOC+ADT). ENZA+DOC+ADT was evaluated as a subgroup in two RCTs (ENZAMET; ARCHES), APA+DOC+ADT was evaluated as a subgroup in one (TITAN). To be able to pool studies, the relative efficacy of control arm in ENZAMET (first generation bicalutamide + ADT) was considered equivalent to ADT based on prior literature. A total of 672 rPFS events were observed (34%; 261 events in triplet therapy, 54%; 411 events in doublet therapy). The difference was statistically significant (HR: 0.49; 95% CI: 0.42-0.58; I2: 0%). Similarly, 469 OS events were observed (28%; 217 events in triplet therapy, 33%; 252 events in doublet therapy). The difference was statistically significant (HR: 0.80; 95% CI: 0.67-0.96; I2: 0%). The summary of findings is outlined in the table. Conclusions: The results of this meta-analysis support an improvement in rPFS and OS in favor of triplet therapy over doublet therapy for mCRPC. However, comparative effectiveness of different triplet regimens may be different and needs further exploration.[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.

132 Background: Treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) is rapidly evolving. Recent updates of relevant trials and presentation of PEACE-1 results warranted mixed treatment comparisons to inform the choice of treatment in mCSPC. Methods: MEDLINE and EMBASE, along with conference proceedings were searched using a systematic search strategy to identify relevant abstracts and full-text publications of phase II/III randomized controlled trials (RCTs) assessing first-line treatment options in mCSPC. Outcomes of interest included overall survival (OS), radiographic progression-free survival (rPFS), and grade ≥3 adverse events (AEs). Direct comparisons were made using DerSimonian-Laird random-effects meta-analysis. Fixed-effect frequentist NMA was conducted to compute network estimates using a multivariate meta-regression approach. Relative treatment rankings were assessed in congruency with direct estimates using P-scores. Secondary NMAs were conducted in several substrata (young, and old; Gleason score < 8 and ≥8; performance status 0 and 1-2, low and high volume of disease). Results: This NMA included nine trials (23 references) with nine unique treatments. rPFS was improved with abiraterone acetate and prednisone-docetaxel-androgen deprivation therapy combination (AAP-D-ADT; rank 1) when compared against most treatment options including AAP-ADT (HR: 0.58, 95% CI: 0.44-0.76; rank 5), apalutamide (APA)-ADT (HR: 0.63, 95% CI: 0.46-0.87; rank 4), TAK-ADT (HR: 0.55, 95% CI: 0.36-0.84; rank 6), and enzalutamide(E)-AAP-ADT (HR: 0.70, 95% CI: 0.51-0.97; rank 3), however no significant differences were observed between AAP-D-ADT, and E+ADT (rank 2). Improved OS was observed with AAP-D-ADT (HR: 0.75, 95% CI: 0.59-0.95; rank 2), E-AAP-ADT (HR: 0.68; 95% CI: 0.48-0.97; rank 1), and AAP-ADT (HR: 0.82, 95% CI: 0.70-0.96; rank 3) compared to D+ADT (rank 6). However, most of the mixed treatment comparisons were statistically insignificant in terms of OS. Similarly, in patients with high volume of disease, AAP+D+ADT (rank 1) was observed to significantly improve rPFS compared to AAP-ADT, APA-ADT, E-ADT, and D-ADT; however, no significant differences were observed among treatment comparisons with regards to OS improvement. E+ADT (rank 1) improved rPFS compared to other treatment in low volume disease but was not different for OS. No significant differences were observed among different treatment options when compared across prespecified subgroups. Moreover, AAP+D+ADT was ranked as the least safe with significantly increased risk of grade 3 AEs relative to other treatments. Conclusions: Current NMA suggests that triplet therapy options were ranked as most likely to improve rPFS and OS at the cost of increased toxicity. Doublet combinations may still be preferred for older patients with low volume of disease.

26 Background: The underrepresentation of minority populations in clinical trials negatively impacts cancer and widens inequities. We aimed to quantify the enrollment disparities in prostate cancer (PC) clinical trials over the last three decades. Methods: MEDLINE and Embase were searched to identify primary reports of prostate cancer RCTs (1989-2020). Data for trial characteristics, the proportion of trials reporting race, ethnicity and age, and the proportion of patients by race, ethnicity and age enrolled in trials were summarized using descriptive statistics. Enrollment incidence ratios (EIR), which compare trial enrollment against global estimates of incidence in age-related subgroups (acquired from the Global Burden of Disease database) and U.S. population-based estimates of racial/ethnic subgroups (acquired from the SEER 18 incidence database) were calculated. Individual trial EIRs were pooled using random-effects meta-analyses to account for the substantial heterogeneity between trials. Multivariable meta-regression was used to explore associations between key trial characteristics and EIR. Annual percentage changes (APC) over the last three decades in enrollment disparities were analyzed using the Joinpoint Regression Analysis. Results: 281 trials from 1989 to 2020 with 99,588 patients were included in this analysis. 107 trials reported race (38%), of which only 25 trials (9%) reported data on all 5 U.S. racial categories (Black, White, Asian, Pacific Islander and Native American. 255 (91%) trials reported mean or median but only 71 trials (25%) specifically reported the enrollment proportion of older adults (age > 65 years). Clinical outcomes by race and age were reported in 9 (8%) and 37 (14%) trials, respectively. Results from meta-analyses showed that Black patients (summary EIR: 0.42 [95% CI: 0.35 - 0.51]), Hispanics (summary EIR: 0.50 [95% CI: 0.37 - 0.68]) and older adults (summary EIR: 0.95 [95% CI: 0.91 - 0.99]) were underrepresented in trials relative to their population estimates. Significantly fewer Black participants (EIR for Black patients = 0.42, EIR for White patients = 0.99; p < 0.0001), Hispanic participants (EIR for Hispanics = 0.50, EIR for non-Hispanics = 1.00; p = 0.001) and older adults (EIR for older adults = 0.95, EIR for younger adults = 1.06; p = 0.037) were enrolled. Representation of Black patients decreased significantly from 1989-2019 (APC: -4.25), while Hispanic representation increased significantly from 2000-2020 (APC: 5.89). Meta-regression showed Black patients were particularly underrepresented in larger-size trials (p < 0.0001). Conclusions: Black representation in PC clinical trials is less than 50% of their expected share based on cancer incidence and it has consistently decreased over last three decades, contributing to the disparities experienced by the population.

e20037 Background: Several treatment options are available for relapsed refractory multiple myeloma(RRMM). However, in the absence of direct-comparative trials, it is unclear how to choose optimal therapy in RRMM. We conducted a network meta-analysis (NMA) to assess the comparative efficacy of different treatment options in RRMM. Methods: Standard electronic databases were searched for abstract and full-text publications of phase 2/3 randomized controlled trials (RCTs) assessing treatment regimens in RRMM. Progression free survival (PFS) , overall survival (OS), complete response (CR), and very good partial response (VGPR) were analyzed. Mixed treatment comparisons were made using fixed-effect network meta-analysis (NMA) within the frequentist framework due to sparse direct evidence. Sensitivity analyses were conducted using the Bayesian approach. Publication bias was assessed by visual inspection of comparison-adjusted funnel plots. P-score plots were used to assess relative rankings of the treatments. R statistical software v 4.0.3 was used to conduct the analyses. Results: After a review of 1137 citations, A total of 37 relevant studies were included in systematic review and 30 studies were analyzed in the network meta-analysis (29 contributed for PFS; 18 for OS; 23 for CR; 25 for VGPR). Mixed treatment comparisons showed high likelihood of PFS benefit with triplet regimens; Isatuximab-Carfilzomib-Dexamethasone (Isa-Kd; P-score: 0.98), followed by Daratumumab-Carfilzomib-Dexamethasone (DKd; P-score: 0.93), Daratumumab-Bortezomib-Dexamethasone (DVd P-score: 0.92), Elotuzumab-Pomalidomide-Dexamethasone (EPd); P-score: 0.84), and Isatuximab-Pomalidomide-Dexamethasone (Isa-Pd; P-score: 0.80) when compared to monotherapy and different doublet regimens. Isa-Kd and DKd continued to show significant PFS advantage when compared to Kd doublet. High likelihood of OS benefit was observed with Carfilzomib-Lenalidomide-Dexamethasone (KRd); P-score: 0.86) followed by Kd (P-score: 0.83), and DVd (P-score: 0.82). However, trials did not consistently report data for OS and most of the mixed treatment comparisons were statistically insignificant. Similar results were observed for CR and VGPR with triplet regimens showing better likelihood for achieving CR and VGPR. Conclusions: This NMA provide most updated evidence on different treatment options in RRMM and can serve as a contemporary guidance in the absence of head-to-head trials. The weight of current evidence favors the use of triplet regimens. Isa-Kd, DKd, DVd, EPd and Isa-Pd showed no statistically significant difference in terms of PFS in RRMM.