ASCO GU 2021: Olaparib Efficacy in Patients with Metastatic Castration-Resistant Prostate Cancer Carrying Circulating Tumor DNA Alterations in BRCA1, BRCA2 or ATM: Results from the PROfound Study

( In 2016, Pritchard and colleagues reported that mutations in DNA-damage repair genes, particularly homologous recombination repair genes, were relatively common among patients with advanced metastatic castration-resistant prostate cancer (mCRPC). This opened the potential for targeted therapy using poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors which lead to an accumulation of DNA single-stranded breaks which have particularly profound clinical consequences for patients who lack standard homologous recombination repair mechanisms as a result of mutations in important genes in this pathway, including BRCA1 and BRCA2.

Early data supporting the use of the PARP inhibitor olaparib from the TOPARP-A trial found improvements in progression-free and overall survival in men with heavily pre-treated mCRPC. Similar results were observed in the phase II TOPARP-B trial and subsequently confirmed in the phase III PROfound trial which demonstrated improved progression-free survival and overall survival for men with homologous recombination repair-deficient mCRPC following treatment with 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 who received olaparib, as compared to a switch in novel oral androgen-axis targeting agent. Inclusion in this trial required evidence of homologous recombination repair (HRR) gene alteration, which is typically determined by tumor tissue testing. However, ctDNA testing may also allow testing of HRR status. In the plenary abstract presentation in the Poster Highlights Session: Prostate Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Matsubara and colleagues performed a retrospective assessment of ctDNA to identify alterations in BRCA1, BRCA2, and ATM among men in the PROfound trial.

The methodology of PROfound has been previously reported and published but, to summarize, 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 were recruited. Patients with prior taxane exposure were allowed. 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).


In this analysis, the authors examined patients who consented and provided plasma samples from Cohort A (BRCA/ATM alteration positive by tissue testing). ctDNA samples were sequenced at FMI, using the FoundationOne Liquid CDx assay for alterations in BRCA1, BRCA2 (BRCA), and ATM, using plasma samples collected during screening in PROfound. In keeping with the primary endpoint of the study, radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) in patients positive for alterations in ctDNA was analysed via stratified log-rank test. Other secondary efficacy endpoints (Objective Response Rate [ORR], Overall Survival[OS]) were also assessed.

Among 245 patients in the cohort A, 181 (73.9%) consented and provided a plasma sample for ctDNA testing, of which 139/181 (76.8%) had a ctDNA result reported (either mutation-positive or mutation-negative) and 42 patient samples failed testing due to insufficient DNA yield or a technical failure of the test.

BRCA/ATM alterations were identified in 111/139 (79.9%) patients with the remaining 28 not reporting a BRCA/ATM mutation on ctDNA testing either due to lack of ctDNA shedding from the tumour or ctDNA levels below the sensitivity of the assay. Demographic, baseline characteristics, and proportions of BRCA1, BRCA2, and ATM mutations were similar between those with BRCA/ATM ctDNA alterations and those in the overall Cohort A.

Among patients with ctDNA BRCA/ATM alterations, rPFS was significantly longer among patients who received Olaparib, compared to investigator’s choice of anti-androgen switch.


The authors conclude that ctDNA testing in patients with mCRPC is both feasible and, for the most part, concordant with tissue-based assessment of HRR mutation status. Further, responses to Olaparib were similar between patients identified as having BRCA/ATM alterations on the basis of ctDNA and those in the overall cohort A.

Presented by: Nobuaki Matsubara, MD, National Cancer Center Hospital East, Chiba, Japan

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021

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