Citations

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.

6549 Background: Representation and outcomes of women, older adults, and racial minorities in ICI trials has not been previously described. Methods: MEDLINE and Embase were searched to identify ICI RCTs. Data for trial characteristics, proportion of trials reporting race, age and sex as well as the proportion of patients by race, age and sex enrolled in ICI trials was collected. Descriptive statistics were reported for trials reporting minority representation and proportion of included patients by race, age and sex. Disparities in representation were calculated using enrollment incidence disparity (EID) and enrollment incidence ratios (EIR) by comparing trial enrollment against U.S. population-based estimates acquired from the SEER 18 incidence database. The relationship of EID to key trial characteristics were compared using standard parametric and non-parametric statistical tests. Trends in EIR were analyzed using the Joinpoint Regression Analysis software. Results: 108 ICI trials from 2009 to 2020 with 48,360 patients were included in this analysis. All RCTs reported sex (101/101). 78 trials reported race (72%), of which only 41 trials (38%) reported data on all 5 U.S. racial categories (Black, White, Asian, Pacific Islander and Native American). Participation of Black patients was reported in 66 trials (61%), White participants in 78 trials (72%), Asians in 69 trials (64%), Native Americans and Pacific Islanders in 41 trials (38%), and Hispanics in 24 trials (22%). Age categories were inconsistently defined, and 80 trials (74%) reported the proportion of patient by age categories. Subgroup analyses of clinical outcomes by race, age and sex were reported in 17 (22%), 62 (79%) and 57 (73%) trials respectively. Women (trial proportion [TP]: 32%; EIR: 0.77), patients aged ≥ 65 years (TP: 42%; EIR: 0.74), Black participants (TP: 1.8%; EIR: 0.17) and Hispanic participants (TP: 5.9%; EIR: 0.67) were largely underrepresented, and Asians were overrepresented (TP: 15.9%; EIR: 2.64). Black patients were underrepresented across all cancer types. Similarly, women, older adults ( > 65 years of age) and Hispanic patients were consistently underrepresented across cancer types with few exceptions. Representation of older adults increased significantly from 2010-2020 (APC: 2.72), while representation of Black patients decreased significantly from 2009-2020 (APC: -23.37). Black patients were found to be significantly underrepresented in phase III trials (p = 0.0005), trials with OS as the primary endpoint (p = 0.004), and PD1 inhibitor trials (p = 0.002). Hispanics were significantly underrepresented in PD1 inhibitor trials (p = 0.003). Conclusions: There is both suboptimal reporting about participation and underrepresentation of women, racial minorities (particularly Black patients) and older adults in ICI trials as compared to their cancer incidence.

PURPOSE Multiple large clinical trials have investigated adjuvant tyrosine kinase inhibitors (TKIs) to reduce the risk of cancer recurrence and progression to metastasis in high-risk renal cell carcinoma. We sought to maintain living and interactive evidence on this topic, until a high level of certainty is reached for key clinical outcomes such that further updates become unnecessary and unlikely to change clinical practice. METHODS We created a living interactive evidence synthesis platform to maintain a continuously updated meta-analysis on TKI monotherapy in adjuvant renal cell carcinoma. We implemented an automated search strategy with weekly updates to identify randomized phase 2 and 3 clinical trials. Study selection, appraisal, and data extraction were done in duplicate. Cumulative meta-analysis was performed using Analyzer Module in Living Interactive Evidence platform. For each outcome (overall survival [OS], disease-free survival [DFS], and all-cause and treatment-related adverse events), we assessed certainty of evidence using GRADE approach and conducted trial sequential analysis. RESULTS This final update includes five randomized trials including recently updated data from PROTECT trial. Meta-analysis shows that adjuvant TKI monotherapy offers no benefit in OS (hazard ratio, 1.01; 95% CI, 0.91 to 1.12, high certainty) or DFS (hazard ratio, 0.92; 95% CI, 0.86 to 1.00, high certainty) and significantly increases adverse event risk. Lack of benefit was consistent across subgroups including highest-risk patients (test for subgroup differences: P = .32). Optimal information size criteria were met, and there was high certainty of evidence for lack of DFS and OS benefit for adjuvant TKIs. CONCLUSION There is no guidance on when to stop maintaining a living review. In this example, we used trial sequential analysis and high certainty of evidence (future clinical trials unlikely to change current conclusions) as a benchmark to conclude a living review in view of convincing evidence.

335 Background: Systematic reviews are outdated quickly when the evidence is rapidly evolving as the process is laborious and there is little incentive for primary author team of an index SRMA to update the evidence. Consequently, there is an epidemic of redundant SRMAs performed by different teams—sometimes with conflicted results—for treatment of first line mRCC. Methods: We have created a living, interactive systematic review (LISR)and network meta-analysis(LINMA) for the treatment of first line mRCC using an Artificial intelligence (AI) assisted framework for evidence synthesis (Living, Interactive evidence synthesis framework) (LIvE) . The framework is implemented in five-layered architecture (application layer, shared module layer, core service layer, middleware layer, and storage layer) which work together to automate the identification of new studies and analysis and semi-automate the screening and data extraction. Dynamic features such as interactive tables, figures and evidence maps are enabled using Python and JavaScript programming languages. Results: We have maintained a living, interactive evidence profile for the first line treatment mRCC since September 2019 ( LIVING WEBSITE) . Living search strategy identifies new studies as they become available. As of October 13, 2020 LISR, includes data 14 clinical trials ( PRISMA ). Baseline characteristics are summarized in an interactive table ( TABLE) . Cabozantinib& Nivolumab (Cabo-Nivo) is the highest ranked drug for improving Overall Response (OR), Progression Free Survival (PFS) and Overall Survival (OS) whereas Ipilimumab in combination with Nivolumab (Ipi-Nivo) is highest ranked drug for achieving complete response (CR). Ipi-Nivo and Atezolizumab & Bevacizumab (Ate-Bev) ranked highest and Cabo-Nivo ranked lowest for treatment related Adverse events (TRAEs). Results of network meta-analysis are summarized as interactive tables and plots ( NMA ), summary of findings tables ( MULTIPLE COMAPRISONS ) and evidence maps ( MAP ). Conclusions: LISRs can potentially reduce redundancy, increase transparency, reproducibility, enable shared-decision making (at a guideline level, or in a patient-clinician dyad) and support living guidelines.