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]
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.
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]
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]
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