“Promising antitumor activity” was detected in patients whose breast cancers expressed mutated BRCA1 and BRCA2 germline breast cancer susceptibility genes and were treated with the PARP inhibitor talazoparib after previous therapy with platinum or multiple cytotoxic chemotherapy regimens.
Findings from the phase II ABRAZO study were reported in a session on metastatic breast cancer at the 2017 ASCO Annual Meeting by first author Nicholas C. Turner, MD, PhD, Academic Consultant Medical Oncologist at the Royal Marsden Hospital and Institute of Cancer Research in London (Abstract 1007).
Turner explained that patients with breast cancer associated with BRCA1 and BRCA2 germline mutations were good candidates for PARP inhibitor therapy. “These cancers are potentially very sensitive to PARP inhibitors and, in this study, we looked at the most potent PARP inhibitor in clinical development, talazoparib, and we showed this drug has an encouraging efficacy with response rates of 21 percent in patients with prior platinum and 37 percent in patients who were heavily pre-treated.”
All 84 patients in the study had locally advanced or metastatic breast cancer that tested positive for either BRCA1 or BRCA2 mutation and were treated with talazoparib. A cohort of 49 of them had been treated previously with platinum-based chemotherapy, and the remaining cohort of 35 patients had prior treatment with at least three platinum-free cytotoxic regimens.
Turner said they had been looking for efficacy in terms of objective response rate (ORR) and the degree of tumor shrinkage. “And we saw pretty encouraging evidence of response with talazoparib in this specific, very important patient population. We saw a couple of complete responses—but most of the responses were partial.”
ORR was 24 percent for patients with BRCA1 mutation and 34 percent for those with BRCA2. But it did not vary much according to HER2 status. For triple negative breast cancer, ORR was 26 percent, compared with 29 percent for patients positive for HER2.
On treatment, a third of the patients developed anemia that was at least grade 3. Nineteen percent had grade 3 or higher thrombocytopenia and 15 percent had at least grade 3 neutropenia. Around half the patients became fatigued, a similar number had nausea, and a third of them had diarrhea of any grade. But talazoparib had to be discontinued in only three patients. Adverse events led to death in four patients but were assessed as not related to talazoparib.
At the same ASCO Annual Meeting phase III data—from the OlympiAD trial comparing PARP inhibition with olaparib to chemotherapy in patients with HER2-negative metastatic breast cancer and a germline BRCA mutation— reported that patients had “clinically meaningful” improvement in progression-free survival compared to standard treatment (which was “physicians' choice”).
Turner stated the positive phase II results with talazoparib provided an evidence base for the phase III EMBRACA trial of the drug in the same clinical setting, and he noted he was eagerly awaiting the results of it. He was reluctant to draw clinical conclusions from the phase II study data available so far, but he mentioned the positive findings from the similar OlympiAD trial and said we should not need to wait long for the outcome of EMBRACA. “All we can say at this point is [that there is] encouraging efficacy. And the phase III study with talazoparib has now been recruited, so we'll hope to see those results quite soon.”
There were potential benefits from using PARP inhibition, Turner noted. “The other options would have been chemotherapy. The potential attractiveness of PARP inhibitors is they are an oral therapy and they tend to be well-tolerated. So when we see an encouraging efficacy with a drug that's relatively well-tolerated that sounds like a very positive thing we can bring to our patients potentially.”
Clue From Ovarian Cancer
When Turner was asked why his study distinguished between the two patient cohorts according to their past therapy—with or without platinum—he explained they had wanted to mirror the well-known association in ovarian cancer between good response to platinum and the effectiveness of PARP inhibition. “So we were particularly keen to recruit these as separate cohorts to begin to work out how we might best use PARP inhibitors when patients have also previously been treated with platinum.”
He noted there were good reasons for using talazoparib in patients who tested positive for one of the BRCA mutations. “We know a lot about the science of what BRCA1 and 2 do, and [that] they are involved in a particular type of DNA repair that PARP inhibitors target. So we are really learning here from the science and bringing forward a targeted therapy that specifically targets those cancers.”
Additional PARP Targets
But Turner said it was possible that PARP inhibition could be clinically useful more widely in breast cancer. “I think the most exciting thing is [that] PARP inhibitors might work outside the BRCA1 and BRCA2 germline cancer—potentially [in] those with sporadic mutations in these genes—potentially other cancers as well. So I think the real next stage is to work out how we might be able to use PARP inhibitors in more breast cancers—other than those with just germline BRCA mutations.”
In positive light of the phase III findings from the partner study using olaparib, Turner was optimistic. “I think we will soon be able to use PARP inhibitors for our patients—within the indications of the study of course. And then, I guess, the challenge is: How can we incorporate them earlier—potentially in the adjuvant setting even?
In the discussion of the ABRAZO findings at the ASCO session on metastatic breast cancer, Leisha A. Emens, MD, PhD, Associate Professor of Oncology at Johns Hopkins University in Baltimore, said she regarded the data on talazoparib as “interesting.”
“It's a highly potent PARP inhibitor— one of the most potent that is available—and the data were promising enough that the sponsor has stopped the study and went on to a phase III trial. So I think: Stay tuned. I think we'll hear more about talazoparib.”
But Emens' main concern was to acquire more data. “I think the take-home message is that we need to continue to talk to our patients about this and encourage participation in clinical trials so we can develop more effective and less toxic therapies to treat triple negative breast cancer—particularly in the metastatic setting.”
Peter M. Goodwin is a contributing writer.