Ravi, Praful

220 Background: There is a critical need to identify biomarkers of response and resistance to 177Lu-PSMA-617. Post-hoc analyses of VISION have explored the prognostic and predictive value of select clinical parameters. However, we are still in the early stages of deciphering which molecular changes are associated with favorable or adverse treatment outcomes. Methods: We conducted a retrospective analysis of patients with metastatic castration-resistant prostate cancer (mCRPC), who received 177Lu-PSMA-617 at Mayo Clinic in Rochester, Minnesota, in the interval of March 2022 to March 2023. We included patients who provided research authorization, had a baseline PSA of at least 2 ng/mL, received at least 2 cycles of treatment, and had circulating tumor DNA (ctDNA) genomic profiling performed by Guardant (83 gene panel) within 60 days of treatment initiation. Clinical, laboratory, genomic, and radiomic parameters were abstracted by trained research personnel. Two independent analyses of “response” and “resistance” were performed. Response to treatment was defined as 50% or greater decrease in PSA from baseline (PSA50 response: dichotomized yes versus no), and resistance was defined as non-decreasing or rising PSA during treatment (PSA non-response: dichotomized yes versus no). Associations between gene alterations and response and resistance were evaluated via Fisher’s exact tests. Results: Between March 2022 and March 2023, 273 patients received cycle 1 of 177Lu-PSMA-617. A total of 108 patients met the inclusion criteria. The median number of cycles at data cutoff was 6 (IQR: 4,6) with 57 (53%) patients receiving all 6 planned cycles. The median PSA at baseline was 16.65 ng/ml (IQR: 5.20, 66.12). A total of 65 patients (60%) experienced a PSA50 response. No molecular alterations were associated with a higher rate of PSA50 response; however, alterations in ARID1A, AR, and CHEK2 were associated with lack of PSA50 response (Fisher’s exact p < 0.05). Of the 108 evaluable patients, 20 (19%) met criteria for PSA non-response. Alterations in AR, ARID1A, MYC, TP53, CHEK2, ATM, EGFR, and NOTCH1 were significantly associated with PSA non-response (Fisher’s exact p < 0.05); in each case, the presence of the alteration was positively associated with resistance (i.e., more instance of PSA non-response). No biomarkers were found to be inversely associated with PSA non-response. Conclusions: ctDNA assessed by commercially available, targeted sequencing panels prior to treatment may be useful in identifying the patients least likely to benefit from 177Lu-PSMA-617. Further work is ongoing to integrate ctDNA findings with clinical parameters in the hopes of understanding the factors mediating response and resistance to therapy.

175 Background: It is well-known that patients with liver metastases from metastatic castration resistant prostate cancer (mCRPC) have poorer or transient responses to many forms of systemic therapy. Data on outcomes following treatment with Lutetium-177–PSMA-617 is scarce. The VISION trial reports hazard ratios for overall survival in the subgroup of patients with liver metastases without disclosing the absolute duration of survival. Using real-world clinical data, we examine this important subgroup of patients, describing their PSA response rates and survival. Methods: A single institution database was assembled to include all patients receiving 177-Lu-PSMA-617 at Mayo Clinic Rochester, MN, and starting treatment in the interval of March 2022 to March 2023. Baseline clinicopathologic and imaging characteristics were abstracted. Patients were categorized based on the presence or absence of measurable liver metastases on their baseline PSMA PET scan. Best PSA response while on treatment was annotated and reported as percent decline from baseline. Survival was calculated from date of first cycle of 177-Lu-PSMA-617. PSA50 response and overall survival (OS) outcomes for the two groups (liver metastases versus no liver metastases) were compared using Chi square test and Kaplan-Meier method, respectively. Those with available pre-treatment circulating tumor DNA (ctDNA) genomic profiling, performed by Guardant (83 gene panel), were assessed for the presence of pathogenic and likely pathogenic alterations. Findings are summarized using descriptive statistics. Results: The overall cohort consisted of 212 patients, including 29 (14%) with liver metastases on pre-treatment PSMA PET/CT. The median number of cycles received was 4 (range, 1-6) for patients with liver metastases and 6 (range, 1-6) for those without hepatic involvement. The observed PSA50 response trended lower for those with liver metastases (34.5% [10/29] versus 51% [94/183], p= 0.091). At median (IQR) follow-up of 10 (8-12) months, there was a numerical but not statistically significant difference in median OS (11.28 months versus NR, p=0.066). In the exploratory analysis of baseline ctDNA, BRCA2 copy number loss was relatively enriched among patients with liver metastases (4 of 19, 21%) versus patients without liver disease (5.7%, 9/158). Conclusions: Our data suggest that the presence of liver metastases predict poorer outcomes in patients receiving Lutetium-177–PSMA-617 treatment, which is similar to data reported with other forms of systemic therapy for mCRPC. To maximize the anti-tumor activity of radioligand therapy in the liver, combination approaches should be explored.

171 Background: Treatment effects vary by volume of disease and timing of metastatic presentation in patients with mCSPC. Therefore, we updated the existing body of evidence to assess the comparative efficacy of systemic therapy in mCSPC by prognostic subgroups to inform clinical practice guidelines. Methods: This living systematic review was conducted using the living interactive evidence (LIvE) synthesis framework. Phase III clinical trials assessing contemporary systemic therapy in mCSPC and reporting overall survival (OS) by four prognostic subgroups were included. Prognostic subgroups included synchronous high volume (SHV), synchronous low volume (SLV), metachronous high volume (MHV), and metachronous low volume (MLV) disease. Mixed treatment comparisons were made using a network-meta-analytic approach in each subgroup. P-scores were used to assess relative treatment rankings in congruency with pairwise estimates. Higher scores indicated better efficacy. Results: This study included a total of nine trials with eight unique treatment options. In patients with SHV disease, darolutamide+docetaxel+ADT (DARO+D+ADT) significantly improved OS when compared to D+ADT (HR: 0.69; 0.57-0.85), enzalutamide (E)+ADT (HR: 0.67; 95% CI: 0.46-0.99), and apalutamide (APA)+ADT (HR: 0.65; 95% CI: 0.43-0.96). In patients with SLV disease, E+ADT (HR: 0.62; 95% CI: 0.42-0.91) and AAP+ADT (HR: 0.66; 95% CI: 0.49-0.89) significantly improved OS when compared to ADT. Although E+D+ADT trended toward improvement compared to other treatments, the results were not statistically significant. In patients withMHV disease, no statistically significant differences were observed among mixed treatment comparisons. However, OS with DARO+D+ADT trended toward improvement when compared to D+ADT (HR: 0.69; 95% CI: 0.39-1.23), APA+ADT (HR: 0.72; 95% CI: 0.23-2.33), E+ADT (HR: 0.67; 95% CI: 0.24-1.86), and E+D+ADT (HR: 0.59; 95% CI: 0.26-1.34). In patients with MLV disease, E+ADT significantly improved OS compared to ADT (HR: 0.51; 95% CI: 0.32-0.79), and D+ADT (HR: 0.48; 95% CI: 0.27-0.85). APA+ADT significant improved OS compared to ADT (HR: 0.22; 95% CI: 0.09-0.54), and D+ADT (HR: 0.21; 95% CI: 0.08-0.55). No other statistically significant differences were observed among mixed treatment comparisons. Conclusions: Current evidence suggests that triplet systemic therapy may be preferred in SHV, E systemic triplet and E hormonal doublet in SLV, DARO systemic triplet and APA hormonal doublet in MHV, and APA or E hormonal doublets in MLV mCSPC. [Table: see text]

111 Background: Comparative evidence of quality of life (QoL) outcomes regarding life-prolonging treatments for the management of first-line treatment of metastatic castration sensitive prostate cancer (mCSPC) is not known. Methods: This systematic review uses the living interactive evidence synthesis framework (PMID: 36862387). Phase III randomized controlled trials assessing contemporary systemic treatments in mCSPC were included. Small sample size adjusted standardized mean differences (SMD; Hedges’ g) with 95% confidence intervals (CI) were computed for global QoL at 3, 6, 12, and 24 mo. Positive SMD indicated better health-related QoL, with zero indicating a null effect. Mixed treatment comparisons were made using a network meta-analysis. P-scores were computed; a higher score indicated better QoL. Results: Of 10 clinical trials initially included, eight trials (15 references) reported QoL. At 3mo global QoL was improved with abiraterone (AAP)+ADT compared to D+ADT (SMD: 0.26; 95% CI: 0.13-0.39), enzalutamide (E)+ADT (0.18; 0.03-0.33), and ADT (0.14; 0.02-0.27). At 6mo, AAP+ADT significantly improved global QoL compared to D+ADT (0.74; 0.62-0.87), E+ADT (1.74; 1.56-1.92), and ADT (1.79; 1.65-1.93). D+ADT also improved global QoL at 6mo compared to ADT (1.05; 0.93-1.16) but not when compared to E+ADT. At 12mo, AAP+ADT improved global QoL compared to E+ADT (0.20; 0.05-0.34) and ADT (0.19; 0.07-0.31) but not compared to D+ADT (0.05; -0.07-0.17). D+ADT also improved global QoL at 12mo compared to ADT (0.14; 0.03-0.24) (Table). Global QoL has not been reported for ARASENS trial at this time. These results are available on the Living interactive website. Conclusions: The totality of evidence suggests improved global QoL with androgen-pathway inhibitors (API) doublet therapy. D+ADT may offer better QoL at longer 6 and 12 months of follow-up. QoL data for triplet therapy is still emerging and will be incorporated in the living review as soon as it becomes available. [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]

531 Background: Neoadjuvant cisplatin-based chemotherapy (NAC) is established in the management of MIBC. Pathologic complete response (pCR, ypT0N0) and downstaging (<ypT2N0) are associated with long term survival in patients with MIBC. Several trials have evaluated neoadjuvant immunotherapy (NAI) and chemoimmunotherapy (NACI) for MIBC. We aimed to conduct a meta-analysis of available trials to compare the incidence of pathological response with NAC, NAI and NACI in MIBC patients undergoing radical cystectomy. Methods: Phase II/III clinical trials assessing neoadjuvant systemic therapies (NAC, NAI, or NACI) in patients with MIBC undergoing radical cystectomy were identified through a systematic search of MEDLINE and EMBASE. Outcomes of interest included pCR and pathological downstaging. A DerSimonian and Laird random-effect meta-analysis was conducted to estimate pooled incidence of events using the Freeman-Tukey transformation. Clopper-Pearson method was used to estimate the associated 95% confidence intervals (CI). Results: Of the 5357 records initially identified, 28 trials with a total of 2138 patients were considered eligible for inclusion. Neoadjuvant chemotherapy was assessed in 15 trials (1535 patients), NAI in 5 (288 patients), and NACI in 8 (315 patients). The pooled incidence of patients experiencing a pCR was 30.91% (95% CI: 26.54%-35.45%) with NAC, 30.92% (23.22%-39.14%) with NAI, and 42.25% (36.6%-48.0%) with NACI. The difference in pCR among these therapies was statistically significant (p <0.05). Similarly, the pooled incidence of achieving pathological downstaging was 40.91% (34.26%-47.72%) with NAC, 38.84% (26.73%-51.64%) with NAI, and 62.88% (57.22%-68.39%) with NACI. Consistently, there was statistically significant effect modification by the choice of neoadjuvant systemic therapy (p <0.01). The results were consistent across different clinically important subgroups (Table). Conclusions: NACI may achieve better pCR and pathological downstaging than NAC and NAI alone in MIBC patients which may potentially be associated with long-term survival. Definitive data from phase III trials are pending. [Table: see text]

193 Background: We maintain a network meta-analysis for the treatment of mCSPC using a living interactive evidence (LIvE) synthesis framework. Recently, the STAMPEDE trial presented evidence regarding a new triplet regimen (enzalutamide-abiraterone-androgen deprivation therapy [E+AAP+ADT]). Hence, in this report we provide the most-up-to-date evidence to inform the choice of optimal therapy in mCSPC patients. Methods: Phase III randomized controlled trials (RCTs) assessing treatment intensification with androgen pathway inhibitors (API), docetaxel (D), or both in patients with mCSPC were included. Mixed treatment comparisons for overall-survival (OS) and progression-free survival (PFS) were made across randomized comparisons using a frequentist network-meta-analysis. Additionally, subgroup data from three trials (ENZAMET, TITAN, ARCHES) by the receipt of docetaxel were abstracted to evaluate the comparative effectiveness of different triplet regimens. Treatment effects were expressed as hazard ratio (HR) and 95% confidence intervals (CI). Relative treatment rankings were evaluated using P-scores and assessed in congruency with the pairwise estimates. Results: This report includes 10 clinical trials (30 references) and over 11500 patients updated as of 1st October 2022. Using randomized data in overall patient population, AAP+D+ADT (rank 1; HR: 0.50; 95% CI: 0.35-0.72) and E+AAP+ADT (rank 4; HR: 0.76; 0.62-0.93) significantly improved PFS compared to D+ADT (rank 7) but not when compared to E+ADT (rank 2) and APA+ADT (rank 3). Similarly, darolutamide (DARO)+D+ADT (rank 1; HR: 0.68; 0.57-0.81), AAP+D+ADT (rank 2; HR: 0.75; 0.59-0.95) significantly improved OS when compared to D+ADT (rank 7). Efficacy by volume of disease and timing of metastatic presentation was consistent with prior update. Using subgroup data by the receipt of docetaxel, a total of five triplet regimens (DARO+D+ADT, AAP+D+ADT, E+D+ADT, apalutamide (APA)+D+ADT, and E+AAP+ADT) were evaluable for comparisons. E+D+ADT (rank 3) improved PFS compared to D+ADT (rank 9; HR: 0.52; 0.41-0.66) and E+AAP+ADT (rank 6; HR: 0.70; 0.52-0.94). Compared to AAP+ADT (rank 7), E+D+ADT (HR: 0.64; 0.49-0.84) and AAP+D+ADT (rank 2; 0.62; 0.42-0.91) significant improved PFS. However, no significant differences were observed among E+D+ADT, AAP+D+ADT, and APA+D+ADT. Similarly, DARO+D+ADT (rank 1) improved OS compared to APA+D+ADT (HR: 0.47; 0.24-0.93). Conclusions: Current evidence favors the use of emerging triplet regimens over docetaxel doublet but not API doublets in overall population. Among different triplets, E+AAP+ADT may not delay progression compared to docetaxel triplets. Hence, access to treatment, toxicity, disease volume and timing of metastases should be carefully considered in mCSPC patients.

Importance The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown. Objective To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups. Data Sources For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database’s inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a “living” auto search was created with weekly updates to identify new evidence as it became available. Study Selection Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC. Data Extraction and Synthesis Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022. Main Outcomes and Measures Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life. Results This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT. Conclusions and Relevance The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

ImportanceProstate cancer (PCa) is marked by disparities in clinical outcomes by race, ethnicity, and age. Equitable enrollment in clinical trials is fundamental to promoting health equity.ObjectiveTo evaluate disparities in the inclusion of racial and ethnic minority groups and older adults across PCa clinical trials.Data SourcesMEDLINE, Embase, and ClinicalTrials.gov were searched to identify primary trial reports from each database's inception through February 2021. Global incidence in age subgroups and US population-based incidence in racial and ethnic subgroups were acquired from the Global Burden of Disease and Surveillance, Epidemiology, and End Results 21 incidence databases respectively.Study SelectionAll phase 2/3 randomized PCa clinical trials were eligible for age disparity analyses. Trials recruiting exclusively from the US were eligible for primary racial and ethnic disparity analyses.Data Extraction and SynthesisThis study was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Data were pooled using a random-effects model.Main Outcomes and MeasuresEnrollment incidence ratios (EIRs), trial proportions (TPs) of participants 65 years or older or members of a racial and ethnic subgroup divided by global incidence in the corresponding age group, or US population–based incidence in the corresponding racial and ethnic subgroup, were calculated. Meta-regression was used to explore associations between trial characteristics and EIRs and trends in EIRs during the past 3 decades.ResultsOf 9552 participants among trials reporting race, 954 (10.8%) were African American/Black, 80 (1.5%) were Asian/Pacific Islander, and 8518 (78.5) were White. Of 65 US trials, 45 (69.2%) reported race and only 9 (13.8%) reported data on all 5 US racial categories. Of 286 global trials, 75 (26.2%) reported the enrollment proportion of older adults. Outcomes by race and age were reported in 2 (3.1%) and 41 (15.0%) trials, respectively. Black (EIR, 0.70; 95% CI, 0.59-0.83) and Hispanic (EIR, 0.70; 95% CI, 0.59-0.83) patients were significantly underrepresented in US trials. There was no disparity in older adult representation (TP, 21 143 [71.1%]; EIR, 1.00; 95% CI, 0.95-1.05). The representation of Black patients was lower in larger trials (meta-regression coefficient, −0.06; 95% CI, −0.10 to −0.02; P = .002).Conclusions and RelevanceThe results of this meta-analysis suggest that Black and Hispanic men are underrepresented in trials compared with their share of PCa incidence. The representation of Black patients has consistently remained low during the past 2 decades.