Imran, Manal

412 Background: Previously we have reported comparative effectiveness data regarding survival of first line (1L) treatment options in mRCC. However, it is not known how the life-prolonging frontline combinations compare to patient-reported outcomes. Methods: Electronic databases including MEDLINE and EMBASE were searched from each database’s inception through July 1st 2023. Phase III randomized controlled trials (RCTs) assessing 1L immune-checkpoint inhibitor (ICI) combination therapies for mRCC and reporting HrQoL were included. Small sample size adjusted standardized mean differences (SMD; Hedges’ g) with 95% confidence intervals (CI) were computed for global, physical, functional, and emotional QoL. Positive SMD indicated an improvement. A network meta-analysis was conducted to assess the comparative HrQoL across different treatment options. P-scores were computed to assess relative treatment rankings. Results: Of 5770 citations identified, five trials (nine references) were included in this analysis. Patient-reported outcomes have not been reported in the JAVELIN Renal 101 or COSMIC-313 trials yet. Global QoL was significantly improved with cabozantinib-nivolumab (CaboNivo) as compared to Nivo-ipilimumab (SMD 2.74, 95% CI 2.54; 2.93), lenvatinib-pembrolizumab (LenPem; 2.79, 2.53; 3.06), sunitinib (2.87, 2.72; 3.03), Pem-axitinib (PemAxi; 3.09, 2.89; 3.30) and atezolizumab-bevacizumab (AteBev; 3.24, 3.04; 3.45). Global QoL improvement was also observed with NivoIpi compared to sunitinib (0.14, 0.02; 0.25), PemAxi (0.36, 0.18; 0.54) and AteBev (0.51, 0.33; 0.68). Physical QoL improvement were consistent with CaboNivo. Likewise, LenPem significantly improved QoL compared to sunitinib (0.26, 0.04; 0.47), PemAxi (0.38, 0.13; 0.64) and NivoIpi (0.51, 0.27; 0.76). Significant functional QoL benefits were only observed with CaboNivo (0.32, 0.17; 0.48) and NivoIpi (0.19, 0.08; 0.31) compared to sunitinib. No significant mixed treatment comparisons were observed for emotional QoL, however, currently available data suggests that LenPem (rank 1) may potentially improve QoL (Table). Conclusions: CaboNivo and NivoIpi as 1L therapy may offer an improved overall HrQoL compared to other contemporary treatment options in mRCC. [Table: see text]

230 Background: Elevated suicide risk is established in cancer patients compared with the general population. We aim to investigate the risk of SRD among individuals diagnosed with mGU cancers. Methods: Surveillance, Epidemiology, and End Results (SEER) database (2004-2020) was queried to obtain data on suicide death in adults (>20 years of age) diagnosed with mGU cancers including bladder cancer (BC), kidney cancer (KC), and prostate cancer (PC). Standardized mortality ratios (SMRs) with 95% confidence interval (CI) were computed overall and by latency period of <1, 1-5, and >5 years (y) after the initial diagnosis of mGU cancers. SMR >1 indicated increased while <1 indicated decreased SRD. Stratification was done by age (<50y, 50-70y, >70y), race (White, Black, Asian, Native American), ethnicity (Hispanic, non-Hispanic), chemotherapy, radiotherapy, surgery, and marital. Results: This analysis included 87,357 mGU patients. In overall population, the risk of suicide-related deaths was highest <1y after diagnosis (SMR: 3.29, 95% CI: 2.47-4.29) followed by 1-5y (2.61, 2.0-3.35) and >5y (1.27, 0.61-2.34) after diagnosis. With respect to race, SRD was significantly higher in Whites (3.31, 2.46-4.36) but not in Blacks (2.58, 0.31-9.33), and Asians (2.03 (0.05-11.3). In ethnic subgroups, non-Hispanics were observed to have increased SRD (3.71, 2.77-4.86) but not Hispanics (0.83, 0.1-3.0). Patients who received chemotherapy (3.74, 2.10-6.18) or those who did not receive radiotherapy (3.66, 2.68-4.89) were more likely to die from suicide. In terms of marital status, single patients had a higher SRD (4.39, 2.94-6.30) compared to those who were married (2.54, 1.65-3.76). Detailed results are outlined in the Table. Conclusions: Patients with GU malignancies are at increased risk of SRD. Targeted and timely interventions in highest risk subgroups such as Non-Hispanic patients with a recent cancer diagnosis with no partner support, may reduce the risk of SRD in patients diagnosed with mGU cancers. [Table: see text]

173 Background: The data for combining PARPi and ARPi in mCRPC have shown conflicting results. Here, we report a quantitative summary of benefits by clinically meaningful subgroups (HRR mutation status, BRCA mutation status) to guide the use of PARPi and ARPi combination in mCRPC setting. Methods: MEDLINE, EMBASE, and CENTRAL were systematically searched from each database’s inception through September 7, 2023. Phase III studies comparing PARPi + ARPi with ARPi + placebo in mCRPC were included. Radiographic progression-free survival (rPFS) and overall survival (OS) in patient subgroups based on HRR and BRCA mutation status were assessed. Hazard ratios for rPFS and OS with 95% CI were collected at the level of each trial, and a random-effects meta-analysis was conducted using an inverse variance approach. Subgroup differences were assessed and p-value of interaction <0.1 was considered statistically significant. Results: The literature search identified 4976 studies from which 3 trials (11 references) – TALAPRO2, PROpel and MAGNITUDE met the inclusion criteria. A total of 2254 participants were eligible for analysis. PARPi + ARPi prolonged rPFS in patients with HRR mutations (HR: 0.55, 95%CI: 0.38-0.78) as well as in patients without HRR mutations (HR: 0.74, 95%CI: 0.63-0.88). There is no evidence of treatment interaction by HRR mutation status (p = 0.14). In patients harboring HRR mutations, improved rPFS was observed in those with BRCA mutations (HR: 0.28, 95%CI: 0.13-0.62) as well as those without BRCA mutations (HR: 0.72, 95%CI: 0.59-0.87). However, there is evidence that patients with BRCA mutations derived greater rPFS benefit as compared to patients without BRCA mutations (p =0.02). PARPi + ARPi showed no significant improvement in overall survival either in patients with HRR mutations (HR: 0.79, 95%CI: 0.59-1.05) or in patients without HRR mutations (HR: 0.92, 95%CI: 0.74-1.14). Conclusions: Genomic testing for HRR genes is mandatory to guide clinical decision making in mCRPC patients. Patients harboring BRCA mutations are most likely to derive clinically meaningful benefit from combination PARPi + ARPi treatment. [Table: see text]

5088 Background: Previous evidence suggests that there may be no additional benefit of triplet therapy in low volume disease based on limited data. Therefore, we investigated the efficacy of triplet therapy as compared to docetaxel (D) and androgen pathway inhibitor (API) doublets by volume of disease using the most up to date results from the ARASENS trial. Methods: Phase III randomized controlled trials (RCTs) assessing treatment intensification with API, and/or D in patients with mCSPC were included. Precomputed hazard ratios (HR) with 95% confidence intervals (CI) for OS were pooled using an inverse-variance approach. A DerSimonian-Laird random-effects meta-analysis was conducted to assess the efficacy of triplet therapy compared to D doublet therapy. P-value of interaction was computed to assess difference between high (HV) and low volume (LV) disease subgroups (Pint <0.1 - statistical significance). Additionally mixed treatment comparisons were computed using network meta-analysis (NMA) to assess the comparative effectiveness of triplet therapy compared to API doublets by volume of disease. Results: Pairwise meta-analysis included a total of 3 RCTs (ARASENS, PEACE-1, ENZAMET) with 2518 patients (HV: 1820; LV: 698) as shown. In patients with HV disease, 385 (43%) and 484 (53%) deaths were observed with triplet therapy, and D doublet, respectively. Triplet therapy significantly improved OS as compared to D doublet in HV (HR: 0.73; 95% CI: 0.64-0.84). In patients with LV disease, 73 (20%) and 94 (28%) deaths were observed with triplet therapy, and D doublet, respectively. Triplet therapy significantly improved OS as compared to D doublet in LV (HR: 0.71; 95% CI: 0.52-0.97). There was no statistically significant interaction by volume of disease for triplet therapy vs. D doublet (Pint: 0.86). NMA including 10 clinical trials and over 11500 patients updated as of 13th Feb 2023 showed that in HV mCSPC, triplet therapy was ranked as potentially the most efficacious treatment option and may improve OS compared to API doublet therapy (HR: 0.83; 95% CI: 0.66-1.03). In LV mCSPC, API doublet therapy was ranked as potentially the most efficacious treatment followed by triplet therapy. There was no significant difference between triplet therapy and API doublet therapy (HR: 1.12; 95% CI: 0.74-1.12). Conclusions: These results underscore that triplet therapy may be preferred in mCSPC patients with HV disease whereas API doublet therapy may be preferred in LV disease. [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]