Zafar, Muhammad Daim Bin

6557 Background: Trials that inadequately include underrepresented minority (URM) populations widen inequities in cancer care. We assessed reporting patterns, representation, and trends of URM representation in breast cancer (BC) trials. Methods: We analyzed all phase 2/3 trials for age disparity and trials recruiting from the US for racial/ethnic disparity amongst BC RCTs (1990-2021). Enrollment-incidence ratios (EIR), which compare trial proportions (TP) from age subgroups against global estimates of incidence in the corresponding age group (from Global Burden of Disease) and racial/ethnic subgroups against US-population-based incidence in the corresponding racial/ethnic group (from SEER 22), were calculated. Individual-trial EIRs were pooled using random-effects meta-analyses. EIRs of <0.80 indicated meaningful underrepresentation, while EIRs >1.20 indicated meaningful overrepresentation. Meta-regression was used to explore associations between key trial characteristics and EIR, and trends in EIR over the last three decades. Results: Of 842 global trials with 490,657 participants, 232 (27.6%) reported the number of participants in specific age strata and 144 (17.1%) reported outcomes by age. Only 60 trials recruited exclusively from the US. Of these, 41 (68.3%) reported race and 24 (40.0%) reported ethnicity, and 2 (3.3%) analyzed outcomes by race. Older adults aged ≥65 years (TP: 24.3%; EIR: 0.53 [95% CI: 0.47-0.60]) and Hispanic women (TP: 5.3%; 0.54; 0.40-0.75) were underrepresented across global trials and US-only trials respectively. Black women were significantly underrepresented in trials that led to FDA approval (0.38; 0.25-0.58) but not in US-only trials. Stratified analysis by BC subtype (with subtype-specific population incidence) showed underrepresentation of Black women in US-only trials for HER2+ BC (0.66; 0.47-0.93), Hispanic women in ER+ BC (0.42; 0.20-0.90), Asians in triple-negative BC (0.24; 0.11-0.53), and older women in HER2+ BC (0.35; 0.31-0.40) and triple-negative BC (0.36; 0.29-0.45). From 1990-2021, the representation of older women declined significantly (meta-regression coefficient for EIR: -0.4 per 10 years), while Black and Hispanic representation showed no significant change. Black (p = 0.02) and Hispanic representation (p = 0.05) worsened significantly in larger trials. Conclusions: Published reports of BC trials do not consistently report the inclusion of URM. Older and Hispanic women were consistently underrepresented, whereas Black women were underrepresented in large, practice-changing trials. [Table: see text]

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]

499 Background: The impact of socioeconomic status on gastrointestinal (GI) cancer mortality in the United States (US) is not well-established. We hypothesized that socially vulnerable populations have disproportionately higher mortality rates. Hence, we assessed the association of the social vulnerability index (SVI) with GI cancer mortality across US counties. Methods: Social vulnerability indices were obtained from the agency for toxic substances and disease registry (ATSDR) from 2014-2018 to compute percentile ranking scores (PRS: ranging from 0-1) for each US county. PRS were further categorized into quartiles (Q: 1st: 0-0.25 [least vulnerable]; 4th:0.75-1.00 [most vulnerable]). The wide-ranging online data for epidemiological research (WONDER) database was queried to abstract county-level age-adjusted mortality rates (AAMR) per 100,000 person-years (PY) for populations diagnosed with GI cancers. AAMRs were then linked with quartile rankings. Rate ratios (RR) of AAMRs between 4th and 1st Q were subsequently estimated with 95% confidence intervals using population-weighted, Poisson regression. Results: A total of 3142 counties were included in this analysis. The AAMR for overall deaths (OD) and premature deaths (PD; defined as death at age <65) in the GI cancer population was 53.8 and 17.7 per 100,000 PY. A gradient increase in GI cancer-related mortality was observed from 1st Q to 4th Q (OD: 49.2 vs 59.3; PD: 14.1 vs 21.3). This stepwise increase in AAMR over the quartiles was consistent across gender, different racial/ethnic subgroups, and rural/urban categories of counties. The AAMRs for OD were significantly higher in the 4th Q as compared to the 1st Q for gastric (RR: 1.67 [95% CI, 1.51-1.86]), hepatocellular including intrahepatic biliary (1.52 [1.45-1.61]), colorectal (1.21 [1.16-1.26]) and biliary (1.17 [1.06-1.28]) cancer. Similarly, significantly higher AAMRs for PD were observed in 4th Q vs1st Q for gastric (1.81 [1.60-2.05]), hepatocellular including intrahepatic biliary (1.78 [1.58-2.00]), biliary (1.64 [1.35-1.99]), colorectal (1.29 [1.21-1.39]) and pancreatic (1.16 [1.07-1.25]) cancer. However, no significant differences were observed for esophageal and small intestinal cancers. Men with gastric (1.58 [1.41-1.78]) and hepatocellular cancer (1.54 [1.43-1.66]), non-Hispanic Black population (1.54 [1.31-1.80]) with hepatocellular cancer, and Hispanic population with colorectal cancer (1.50 [1.31-1.72]) were observed to have higher overall mortality in the 4th Q compared to the 1st Q. The findings were similar for premature mortality. Conclusions: Population-level data suggests that the US counties with higher socio-economic adversities may be at an increased risk of GI cancer-related mortality. Investigations using patient-level data are required to probe the impact of socioeconomic vulnerabilities on cancer-related mortality.

5083 Background: ARASENS and PEACE-1 trials suggests treatment intensification with novel hormonal therapy (NHT) in addition to androgen deprivation therapy (ADT) and docetaxel (DOC) provides survival benefit as compared to DOC+ADT in patients with metastatic castration sensitive prostate cancer (mCSPC). However, the performance of triplet therapy as compared to NHT+ADT remains unexplored. Methods: MEDLINE, EMBASE and recent conference proceedings were searched to include phase III trials evaluating triplet therapy in patients with mCSPC and reporting treatment effects in subgroup of patients with and without docetaxel. Outcomes included overall survival (OS) and radiographic progression free survival (rPFS). Precomputed hazard ratios (HRs) and confidence intervals (CIs) from non-randomized subgroup comparisons were pooled after logarithmic transformation using inverse-variance weighting approach. A DerSimonian-Laird random-effects meta-analysis was then performed to assess subgroup differences. Interaction between subgroups was assessed using P-value of heterogeneity. Mixed treatment comparisons were computed using a fixed-effect model within the frequentist framework using subgroup effect estimates from eligible trials. Results: This meta-analysis included five clinical trials (ARASENS, PEACE-1, ENZAMET, ARCHES and TITAN) with a total of 5804 patients (docetaxel: 2836; no docetaxel: 2836). Subgroup analysis showed statistically significant difference between treatment effects in patients who received docetaxel (NHT + DOC + ADT; HR: 0.74; 95% CI: 0.66-0.84; I2: 0%) and those who did not (NHT + ADT; HR: 0.61; 95% CI: 0.53-0.70; I2: 0%) for OS (p-value of interaction: 0.04). However, no statistically significant interaction was observed in terms of rPFS (p-value: 0.46). Mixed treatment comparisons showed improved OS with NHT + DOC + ADT (HR: 0.74; 95% CI: 0.66-0.84) as compared to DOC + ADT, but not when compared to NHT + ADT (HR: 0.97; 95% CI: 0.78-1.20). NHT + ADT significantly improved OS compared to DOC + ADT (HR: 0.77; 95% CI: 0.64-0.92). Consistently, significant rPFS improvement was observed with NHT + DOC + ADT when compared DOC + ADT (HR: 0.49; 95% CI: 0.42-0.57) but not when compared to NHT + ADT (HR: 0.82; 0.65-1.04). NHT + ADT was observed to improve rPFS compared to DOC + ADT (HR: 0.60; 95% CI: 0.50-0.72). Conclusions: This exploratory and hypothesis generating analysis suggests that addition of docetaxel (triplet therapy) may not delay progression or prolong survival compared to NHT-based doublets. These findings provide direction for future clinical trials in this space and suggest an equipoise to the question of how triplet regimens compare with NHT-doublets. The results should be interpreted with caution as this analysis does not account for potential confounding relationships such as volume of disease.

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.