KEY TAKEAWAYS
- In Phase III of the PROfound study, patients with mCRPC were screened. Their plasma samples were retrospectively sequenced using circulating tumor DNA (ctDNA) Next-Generation Sequencing (NGS) to test for BRCA/ATM alterations.
- Patients that tested positive were grouped into two to compare the efficacy of Olaparib to Abiraterone or Enzalutamide.
- The efficacy of Olaparib was consistent irrespective of the method used to identify the BRCA/ATM alterations.
- The study demonstrated that ctDNA NGS might be used to identify mCRPC patients with BRAC/ATM alterations as an alternative to tissue-based NGS testing.
The Phase III PROfound study was conducted to demonstrate the clinical utility of identifying patients with metastatic Castration-Resistant Prostate Cancer (mCRPC) and BRCA1, BCRA2, and ATM (BRCA/ATM) alterations who may be eligible for Olaparib treatment, using the circulating tumor DNA (ctDNA) Next-Generation Sequencing (NGS) testing instead of tumor-based NGS testing. Additionally, the efficacy of Olaparib was evaluated as compared to Abiraterone or Enzalutamide (control) in treating patients with mCRPC with tumor Homologous Recombination Repair (HRR) gene alterations.
During the screening of the study, plasma samples were collected and later retrospectively sequenced to test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA with the help of the FoundationOne®Liquid CDx test. The patients who tested positive for BRCA/ATM alterations in the tissue testing were grouped in Cohort A (n=245), and only these patients were evaluated.
73.9% of the Cohort A patients (n=181) consented to plasma sample ctDNA testing. 76.8% of them (139 patients) yielded a result with 111 patients (79.9%) identified with BRCA/ATM alterations. These patients were then grouped into the ctDNA group (n=73) and received Olaparib. The remaining 38 patients received the control drug. Notably, the characteristics and baseline demographics of the patients, along with the prevalence of the HRR alterations, were at par with the Cohort A ITT (intention-to-treat) population.
Clinical outcomes of Cohort A and ctDNA subgroup were compared. The Radiological Progression Free Survival (rPFS) was the primary outcome measure and was longer in the Olaparib group at a median of 7.4 versus 3.5 months in the control group and hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P < 0.0001. The results of the Cohort A ITT population were consistent at HR, 0.34; 95% CI, 0.25–0.47.
The Phase III PROfound study was concluded with the observation that ctDNA NGS testing proved to be a reliable alternative to testing the BRAC/ATM alterations in mCRPC patients that are eligible for Olaparib treatments when Tumor Tissue Testing has failed or is not feasible. The testing method does not affect the efficacy of the Olaparib treatment.
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02987543
Citation: Matsubara, N., de Bono, J., Olmos, D., Procopio, G., Kawakami, S., Ürün, Y., van Alphen, R., Flechon, A., Carducci, M. A., Choi, Y. D., Hotte, S. J., Korbenfeld, E., Kramer, G., Agarwal, N., Chi, K. N., Dearden, S., Gresty, C., Kang, J., Poehlein, C., Harrington, E. A., … Hussain, M. (2023). Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA. Clinical cancer research : an official journal of the American Association for Cancer Research, 29(1), 92–99. https://doi.org/10.1158/1078-0432.CCR-21-3577
