FDA Approves CDx Tests for Olaparib in HRR-Mutant mCRPC


Two companion diagnostic assays were granted FDA approval to identify male patients with metastatic castration-resistant prostate cancer who are eligible for treatment with olaparib.

The FDA granted approval to 2 companion diagnostic assays to identify male patients with metastatic castration-resistant prostate cancer (mCRPC) who are eligible for treatment with olaparib (Lynparza), an FDA-approved drug for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated mCRPC who progressed after prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga). One test is the BRCAAnalysis CDx, a product of Myraid Genetics, Inc, and the other is Foundation Medicine, Inc’s FoundationOneCDx.1,2

BRACAnalysis CDx was the assay used in the phase III PROfound trial of olaparib versus enzalutamide or abiraterone, the study that served as the basis for the FDA approval of olaparib as treatment of HRR-mutant mCRPC. In PROfound, olaparib demonstrated a 66% reduction in the risk of disease progression or death compared with enzalutamide or abiraterone in patients with BRCA1/2 or ATM mutations. The trial also met its primary end point, showing a median radiographic progression-free survival (rPFS) of 7.39 months in the olaparib arm compared with 3.55 with either enzalutamide or abiraterone (HR, 0.34; 95% CI, 0.25-0.47; P <.0001). These findings contributed to the BRACAnalysis CDx becoming the only FDA-approved germline test with the ability to identity BRCA1/2 mutations.3

“This approval is our seventh regulatory approval for BRACAnalysis CDx in support of Lynparza and further demonstrates our commitment to improving the lives of patients with cancer,” said Nicole Lambert, president Myriad Oncology and Women’s Health, in a statement. “The BRACAnalysis CDx test provides clinicians with the vital information needed to quickly match patients with an appropriate treatment option.”

The ongoing PROfound trial is an open-label, randomized study investigating the safety and efficacy of olaparib compared with enzalutamide or abiraterone in patients with mCRPC who progressed on earlier hormone therapy and have a mutation in the HRR gene. In the study, next-generation sequencing with BRACAnalysis CDx guides treatment with olaparib.

The in vitro assay gives approximate detection and sorting of variants found in the protein-coding regions and intron/exon boundaries of the BRCA1/2 genes. This is achieved with genomic DNA from whole blood specimens collected in ethylenediaminetetraacetic acid. In addition, the test identifies single nucleotide variants and small insertions and deletions through polymerase chain reaction testing and Sanger sequencing, and identifies large duplications and deletions in the genes through multiplex polymerase chain reaction testing.1,4

Accuracy of this assay was tested was evaluated in a blinded study of 110 patient blood–derived DNA samples. BRCA1/2 variants and mutations were identified, which included deletions, insertions, and single nucleotide variants. In another blinded study of 103 patient–derived blood samples, the BRACAnalysis CDx was compared to a similar companion diagnostic, BART CDx. With BRACAnalysis CDx, 29 samples were positive for BRCA1/2 and 74 samples were negative. With the comparator, 98 samples had valid results and 5 samples did not.4

In terms of specificity, research shows that BRACAnalysis CDx is not significantly affected by DNA input levels from 1 ng to 100 ng, and those from 2 ng to 12 ng produced callable results for all samples tested, and the results were in line with those for the BART CDx. An in-silico analysis also showed that no predictions were made on non-specific products for any primer pair combinations. Overall, based on an assessment of 3016 combinations, predictions of non-specific products were not made for any cross-reactive primer pairs with the BRACAnalysis CDx.

The BRACAnalysis CDx also has an FDA indication to detect patients with ovarian cancer to identify patients who are eligible for maintenance treatment with niraparib (Zejula). Knowledge of deleterious or suspected germline BRCA1/2 mutations may improve PFS in patients with ovarian cancer.

As the PROfound study continues in patients with mCRPC, Myriad predicts that BRACAnalysis CDx will eventually bring more treatment options into the landscape.

“Studies have demonstrated that PARP inhibitors are highly effective in men with BRCA1/2 mutations, in addition to other mutations in HRR pathways. Once we identify who these men are, they will have more options for treatment,” Todd Cohen, MD, board-certified urologist and vice president of Medical Affairs for Myriad Urology, said in a statement. “NCCN guidelines recommend that men with metastatic castration-resistant prostate cancer undergo genetic testing alongside an assessment of HRR gene mutations in the tumor.”

FoundationOne CDx is approved by the FDA as a broad companion diagnostic for over 20 targeted therapies. The comprehensive profiling assay is an in vitro diagnostic device using next-generation sequencing for the detection of substitutions, indels, and copy number alterations in 324 genes and select gene rearrangements.

The accuracy of this assay was evaluated and showed no false-positive BRCA mutation detections, in terms of sensitivity. Specificity with the FoundationOne CDx test, as assessed in an in-silico analysis, showed that all areas that may harbor alterations that the assay claims to detect have consistent high quality (MQS ≥ 30), deep coverage ≥ 250X. In a precision study that evaluated the assay’s ability to repeat and reproduce the same results, the assay had a failure rate of only 1.5% and a no call rate of 0.18%.2,5

Based on these results and other studies, FoundationOne CDx is considered a valid test for detection alteration in more than 324 genes and select gene rearrangements.2

“This therapy and companion diagnostic approval underscores the value of comprehensive genomic profiling in [patients with] advanced cancer as it validates our ability to identify alterations in the 14 HRR pathway genes within FoundationOne CDx’s 324 gene panel that indicate a patient may be eligible for treatment with Lynparza, a process not possible through single gene or hot spot testing,” said Brian Alexander, MD, MPH, chief medical officer at Foundation Medicine, in a statement. “This is an important advancement for patients with HRR-mutated metastatic castration-resistant prostate cancer, as there have previously been limited treatment options available for this specific condition.”


1. Myriad receives FDA approval of BRACAAnalysis CDx as a companion diagnostic for Lynparza in HRR-mutated metastatic castration-resistant prostate cancer [news release]. Salt Lake City, Utah: Myriad Genetics, Inc.; May 20, 2020. https://bit.ly/2z5Lu5C. Accessed May 20, 2020.

2. Foundation Medicine receives FDA approval for FoundationOne CDx as the companion diagnostic for Lynparza to identify patients with HRR-mutated metastatic castration-resistant prostate cancer [news release]. Cambridge, Massachusetts;May 20, 2020. https://bwnews.pr/2ZtfCSS. Accessed May 20, 2020.

3. Sandhu SK, Hussain M, Mateo J, et al. PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Ann Oncol. 2019;30(suppl. 9):IX188-IX189. doi: 10.1093/annonc/mdz446.007.

4. BRACAnalysis CDx® Technical Information. Myriad Genetics website. https://go.aws/2ymIBNi. Accessed May 20, 2020.

5. FoundationOne CDx™ Technical Information. FDA website. https://bit.ly/36h0slb. Accessed May 20, 2020.

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