MUNICH – Lynparza's front-line effects in the treatment of ovarian cancer were the most eye-popping data on poly-(ADP-ribose) polymerase (PARP) inhibitors presented at the European Society of Medical Oncology (ESMO) 2018 Congress. (See story in this issue.)

But it was also the tip of the iceberg in terms of understanding how to use PARP inhibitors and information on BRCA mutation status.

And beyond PARP inhibition and BRCA mutations, there is a rich (or bewildering, depending on your perspective) variety of other mutations that affect the DNA damage response, and drugs that target them.

"We talk about mutational load as if it's one thing," Andrew Tutt told the audience at an educational session on "Clinical implication of PARP inhibitors." But BRCA1-mutated tumors have a high rate of chromosome instability, which does not increase neoantigen load and tumor visibility to the extent that microsatellite instability does.

Tutt is head of the division of breast cancer research and director of the Breast Cancer Now Toby Robins Research Centre at the Institute for Cancer Research and Guy's Hospital at King's College London.

At the ESMO Congress, data presented from the phase II TRITON-2 study on the use of Rubraca (rucaparib, Clovis Oncology Inc.) in metastatic castration-resistant prostate cancer (mCRPC) suggested that BRCA testing of prostate cancer patients could, and perhaps should, become standard practice.

An unplanned interim analysis of 85 patients, or about half of the planned TRITON-2 total, showed a 44 percent confirmed objective response rate (ORR) in 25 evaluable patients, and a 51 percent PSA response rate in 45 evaluable patients with a BRCA1/2 mutation who were treated with Rubraca.

The trial is testing for more than a dozen mutations in DNA damage response genes overall, not just BRCA mutations. So far, though, that's where most of the action seems to be – though it is noteworthy that because the focus is on BRCA, patients with both BRCA mutations and mutations in other DNA damage genes would be in the BRCA+ genes group, possibly obscuring the contributions of other mutations.

The data, which led to Rubraca's being given breakthrough status in BRCA-mutated mCRPC by the FDA on Oct. 2, were presented in a poster session on Sunday, and part of a poster discussion section on Sunday morning.

Discussant Joaquin Mateo, principal investigator of the Prostate Cancer Translational Research Group at the Valle d'Hebron Institute of Oncology, cautioned against reading too much into the results of an unplanned interim analysis.

Nevertheless, Mateo was willing to say that based on the strength of the data, "we may have PARP inhibitors coming soon into the clinic for patients with BRCA1 or BRCA2 mutations" with prostate cancer.

With that comes questions of how far, and how, to expand BRCA mutation testing.

'Still to be defined'

In August, Mateo and his colleagues published the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT), which aims to assist clinicians in clinical decision-making by prioritizing mutations. BRCA mutations are so far rated tier I, corresponding to "ready for implementation in routine clinical decisions," for breast and ovarian cancers, but not other tumor types.

In an educational session on "Germline BRCA mutation: Ripe for precision oncology?" Elena Castro Marcos, member of the Prostate Cancer Clinical Research Unit at the Spanish National Cancer Research Centre, opined that the best screening strategy for BRCA mutations in prostate cancers is "still to be defined."

BRCA2 mutations are associated with a two- to sixfold increase in the risk of developing prostate cancer, giving them a lifetime risk of 35 percent as opposed to roughly 12 percent in the general population. Both BRCA1 and BRCA2 mutations are also associated with more aggressive disease and shorter survival.

With the preliminary TRITON-2 data, as well as data presented at the American Society of Clinical Oncology earlier this year showing that Lynparza significantly extended the PFS of mCRPC patients when added to Zytiga (abiraterone acetate, Janssen oncology), there are treatment options coming down the pike. Lynparza also has breakthrough status in mCRPC.

Still, that does not make germline screening a foregone conclusion. BRCA mutation screening remains plagued by variants of unknown significance, and PSA screening is a stark example of the perils of overscreening that causes overtreatment.

Tumor screening is one method to avoid overscreening. And here, there are good arguments to be made for casting a wide net.

Because of BRCA's fame as "the breast cancer gene," it is easy to fall into the trap of assuming that if an individual has a BRCA mutation, family history will necessarily give clues to its existence, and cancer will necessarily strike at a younger age.

Neither is true.

Nearly half of all of BRCA mutation carriers who are identified after being diagnosed with breast or ovarian cancer do not present with family history.

And ovarian cancer patients who are diagnosed when they are over 70 have roughly an 8 percent BRCA mutation rate. Angela George, clinical lead for the Cancer Genetics Unit of the Royal Marsden National Health Service Foundation Trust, warned that capping BRCA testing at age 70, as is being discussed in some health systems, "will miss significant numbers of patients."

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