Yeonjung Jo

PURPOSE: The treatment landscape of metastatic castration-resistant prostate cancer (mCRPC) has evolved with the recent approvals of lutetium Lu 177 vipivotide tetraxetan and poly (ADP-ribose) polymerase inhibitors, adding new layers of complexity to treatment sequencing. Cabazitaxel is an approved option in patients with disease progression on docetaxel. Real-world data on the effectiveness of cabazitaxel by line of therapy remain limited. To address this gap, we evaluated survival outcomes based on line of therapy in patients with mCRPC receiving single-agent cabazitaxel in a large real-world database. METHODS: This retrospective study used the US-based Flatiron Health electronic health record–derived deidentified database. Patients who were diagnosed with mCRPC and received single-agent cabazitaxel for the first time were eligible and included. Real-world time to next treatment (rwTTNT) and real-world overall survival (rwOS) were calculated from the date patients initiated the first cycle of cabazitaxel. Survival rates were summarized using medians and 95% CI using the Kaplan-Meier method. RESULTS: Among 24,105 patients with metastatic prostate cancer in the data set, 1,315 patients with mCRPC were eligible and included. The median age was 73 years (IQR, 67-78). The majority were non-Hispanic White (62%), treated in community practice (84%), had commercial insurance (81%), and received treatment in fourth line or later (58%). For the overall cohort, the median rwTTNT was 4.7 months (95% CI, 4.4 to 5.0), and the median rwOS was 8.6 months (95% CI, 8.0 to 9.3). The median rwTTNT ranged from 4.2 months to 6.8 months, and rwOS ranged from 6.3 months to 14 months based on the line of therapy. CONCLUSION: In this large, real-world study of patients with mCRPC, cabazitaxel retained its effectiveness regardless of its line of therapy.

PURPOSE: A composite multigene risk score derived from tumor-biology alterations specific to metastatic castrate-resistant prostate cancer (mCRPC) state was evaluated as a classifier to design biomarker-based enrichment clinical trials. METHODS: A plasma cell-free DNA copy number alteration risk score based on alterations in 24 genes was simulated to develop a biomarker classifier–based clinical trial design enriched for high-risk patients to detect a survival advantage of a novel treatment (hazard ratio of 0.70 with 80% power). We determined the design trade-offs between the number of patients screened and enrolled when varying the type of patients to enrich and the extent of enrichment needed. RESULTS: For a 2-year overall survival end point in mCRPC state, fully enriching patients with mCRPC having a high-risk score of 3 or more (the 95th percentile of a range of risk scores in patients with mCRPC) was determined to require screening to a maximum of 4,149 patients to enroll 259 patients for the targeted effect size. A nonenriched trial was determined to require enrolling 689 patients to be equivalently powered. We identified a pragmatic alternative, which is to enrich patients with mCRPC with a risk score of 1 or more (the 67th percentile) and an enrichment fraction of 0.25. This would require screening 658 patients to enroll 584 patients, and it maximizes the ability to detect a difference in treatment effect by risk score. CONCLUSION: A plasma multi-CNA risk score classifier can feasibly be leveraged to design an enrichment trial in mCRPC. Enriching 25% of patients screened with a risk score >1 was observed to be optimal for obtaining an adequately powered, biomarker-based mCRPC-enriched clinical trial.

By Gliceida M Galarza Fortuna, Nishita Tripathi & 16 more. Abstract from 2023 Precision Oncology Conferences

Approximately 20% of men with metastatic castration-sensitive prostate cancer (mCSPC) progress within 1 year of treatment, and biomarkers to identify them up front are lacking. In a randomized phase III trial in men with mCSPC (SWOG S1216), higher baseline circulating tumor cells (CTCs) were prognostic of inferior outcomes. We aimed to validate these findings and interrogate corresponding tumor genomic profiles. Consecutively seen men with newly diagnosed mCSPC undergoing systemic therapy and baseline CTC enumeration by CellSearch assay were included. Gene alterations were determined by comprehensive genomic profiling of tumor tissue by Clinical Laboratory Improvement Amendments—certified lab. The relationship between categorized CTC counts and both progression-free survival (PFS) and overall survival (OS) was assessed in the context of Cox proportional hazards models, both unadjusted and adjusted for age, Gleason score, PSA at androgen-deprivation therapy initiation, disease volume, de novo status, treatment intensification, and number of altered genes. Overall, 103 patients were included in the analysis. On multivariate analysis high CTCs (≥ 5 vs. 0) were associated with poorer PFS [HR, 4.52; 95% confidence interval (CI), 1.84–11.11; P = 0.001) and OS (HR, 3.59; 95% CI, 0.95–13.57; P = 0.060). Patients with higher CTC counts had a greater number of altered genes and total number of alterations (all P < 0.02). In this article, for the first time, we externally validate the association of higher CTC counts with inferior survival outcomes in men with mCSPC and show a distinct associated tumor genomic landscape. These findings may improve prognostication, patient counseling, and treatment selection in men with mCSPC.

Approximately 20% of men with metastatic castration-sensitive prostate cancer (mCSPC) progress within 1 year of treatment, and biomarkers to identify them up front are lacking. In a randomized phase III trial in men with mCSPC (SWOG S1216), higher baseline circulating tumor cells (CTCs) were prognostic of inferior outcomes. We aimed to validate these findings and interrogate corresponding tumor genomic profiles. Consecutively seen men with newly diagnosed mCSPC undergoing systemic therapy and baseline CTC enumeration by CellSearch assay were included. Gene alterations were determined by comprehensive genomic profiling of tumor tissue by Clinical Laboratory Improvement Amendments—certified lab. The relationship between categorized CTC counts and both progression-free survival (PFS) and overall survival (OS) was assessed in the context of Cox proportional hazards models, both unadjusted and adjusted for age, Gleason score, PSA at androgen-deprivation therapy initiation, disease volume, de novo status, treatment intensification, and number of altered genes. Overall, 103 patients were included in the analysis. On multivariate analysis high CTCs (≥ 5 vs. 0) were associated with poorer PFS [HR, 4.52; 95% confidence interval (CI), 1.84–11.11; P = 0.001) and OS (HR, 3.59; 95% CI, 0.95–13.57; P = 0.060). Patients with higher CTC counts had a greater number of altered genes and total number of alterations (all P < 0.02). In this article, for the first time, we externally validate the association of higher CTC counts with inferior survival outcomes in men with mCSPC and show a distinct associated tumor genomic landscape. These findings may improve prognostication, patient counseling, and treatment selection in men with mCSPC.

Supplementary Figure from External Validation of Association of Baseline Circulating Tumor Cell Counts with Survival Outcomes in Men with Metastatic Castration-Sensitive Prostate Cancer

Supplementary Table from External Validation of Association of Baseline Circulating Tumor Cell Counts with Survival Outcomes in Men with Metastatic Castration-Sensitive Prostate Cancer

Supplementary Table from External Validation of Association of Baseline Circulating Tumor Cell Counts with Survival Outcomes in Men with Metastatic Castration-Sensitive Prostate Cancer

Supplementary Figure from External Validation of Association of Baseline Circulating Tumor Cell Counts with Survival Outcomes in Men with Metastatic Castration-Sensitive Prostate Cancer