(UroToday.com) In the second Prostate Cancer session at this year’s Society of Urologic Oncology virtual annual meeting, Dr. Maha Hussain discussed the role of poly ADP ribose polymerase (PARP) inhibitors, particularly olaparib, in metastatic castration-resistant prostate cancer.
Dr. Hussain began by reviewing the rationale for targeting PARP-1 in advanced prostate cancer given its implicated role in many aspects of prostate cancer including its role in mediating DNA repair response to alkylating agents, in cellular survival in BRCA deficient cells, and in androgen-receptor mediated prostate cancer cellular proliferation. Further, the Stand Up To Cancer (SU2C) project analysis demonstrated that more than 20% of patients with mCRPC harbor DNA repair pathway aberrations including BRCA2, BRCA1, ATM and many others of which 8-10% are pathogenic germline findings.
Early, non-randomized data demonstrate that responses to the PARP inhibitor olaparib are much higher among patients with DNA defect repair mutations than those without. These data formed the rationale for the PROfound study, Study of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound Study), examining olaparib, compared to switched androgen-axis inhibition, in patients with metastatic castration-resistant prostate cancer (mCRPC). This trial has now resulted in two New England Journal of Medicine (NEJM) publications in 2020.
The methodology of the PROfound study has previously been presented and published but in short, it recruited men with metastatic castrate-resistant prostate cancer who had progressed on previous abiraterone acetate or enzalutamide administered at the time of non-metastatic castrate-resistant prostate cancer or at the time of metastatic castrate-sensitive prostate cancer, many of who had previously been treated with taxane chemotherapy. The investigators then used an investigational assay based on the FoundationOne CDx to identify alterations in one of 15 pre-specified genes involved in homologous recombination repair (BRCA 1/2, ATM, BRIP1, BARD1, CDK12, CHEK 1/2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L).
The authors used biomarker-driven stratification to derive two study cohorts: Cohort A had alterations in BRCA1, BRCA2, or ATM while Cohort B had alterations in any of the other 15 included genes. In both cohorts, patients were randomized 2:1 to olaparib vs. abiraterone or enzalutamide. Within each biomarker strata, randomization was stratified based on prior taxane use and measurable disease burden (according to RESIST 1.1 criteria).
The primary outcome was radiographic progression-free survival in Cohort A, while overall survival was a key secondary endpoint and formed the focus of the second manuscript.
Dr. Hussain presented baseline characteristics of this cohort, emphasizing that visceral disease was seen in 27% of patients randomized to Olaparib and 34% of those in the control arm. Further, pre-treatment was common with 45% of patients having previously received docetaxel alone and 20% having receiving docetaxel and cabazitaxel. She further emphasized that Olaparib treatment was relatively well tolerated.
Dr. Hussain then presented the primary outcome data examining imaging-based progression-free survival in Cohort A and in the combined cohort A+B. While there was a statistically significant benefit to Olaparib in each of these analyses, the effect was larger in Cohort A with a hazard ratio of 0.34 (95% confidence interval 0.25 to 0.47). Further, assessing time to pain progression, an important patient-related outcome, this was improved for patients receiving Olaparib in both cohort A and cohort A+B.
Dr. Hussain then emphasized the overall survival analyses, performed separately in both cohort A and cohort B. While there were statistically significant improvements in overall survival for patients receiving Olaparib in cohort A (which were even larger in crossover-adjusted analyses), no such benefit was observed in cohort B.
Gene-by-gene analysis, while exploratory, demonstrated that the benefit of olaparib differed significantly between patients depending on their underlying mutation. In particular, patients with BRCA2 mutations appeared to derive particular benefit from the use of Olaparib.
Dr. Hussain then highlighted data from the TRITION2 study, A Study of Rucaparib in Patients With Metastatic Castration-resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON2), a single arm analysis of rucaparib in patients with mCRPC and BRCA DNA damage repair gene alterations demonstrating a median radiographic progression-free survival of 9.0 months (95% confidence interval 8.3 to 13.5).
As a result of data from TRITON2 and PROfound, the United States Federal Drug Administration (FDA) approved both rucaparib and olaparib, with slightly different indications, for patients with mCRPC and DNA defect repair mutations.
Dr. Hussain closed by highlighting that olaparib is the first targeted therapy proven to improve radiographic progression-free survival and overall survival in a phase III trial of patients with metastatic castration-resistant prostate cancer and homologous recombination repair mutations with progressive disease following treatment with abiraterone acetate or enzalutamide. As a result of these data, Dr. Hussain suggested that we have now entered an era of precision medicine in prostate cancer. Moving forward, she identified ongoing needs to optimize the timing of therapy in relation to the other treatments with a proven overall survival benefit in mCRPC, to identify combination treatment approaches utilizing PARP inhibition, and to evaluate the role of PARP inhibitors earlier in the disease process.
Presented by: Maha H.A. Hussain, MD, FACP, FASCO, Genevieve Teuton Professor of Medicine, Division of Hematology-Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine
Written by: Christopher J.D. Wallis, MD, PhD, FRCSC, Contact: @WallisCJD on Twitter, during the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC
Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Can Be Preselected to Maximize Benefit of Olaparib - Maha Hussain