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Neoadjuvant PARP inhibitor yields ‘profound results’ in BRCA-positive breast cancer
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More than half of a small cohort of women with early-stage, BRCA-positive breast cancer who received talazoparib once daily before surgery exhibited no evidence of disease at time of surgery, according to results of a phase 2 study.
Talazoparib (BMN-673; Pfizer) — an oral poly(ADP-ribose) polymerase (PARP) inhibitor — is not yet approved for any indication.
“To my knowledge, this study is the first to show that a single-agent targeted therapy has a pathologic complete response in women with BRCA mutations, including those with triple-negative breast cancer,” Jennifer K. Litton, MD, associate professor of breast medical oncology at The University of Texas MD Anderson Cancer Center, said in a press release. “Our median tumor volume decrease by ultrasound was 88% after just 2 months of patients receiving a single dose of talazoparib once daily.”
HemOnc Today spoke with Litton about the study, the implications of the findings, and what must be confirmed in subsequent research.
Question: Can you explain the rationale for this study?
Answer: Women with metastatic breast cancer who also have a BRCA mutation have had profound results with single-agent PARP inhibitors. We conducted a pilot study in which we gave 2 months of a PARP inhibitor and a biopsy at baseline, and then again at 2 months followed by standard-of-care chemotherapy, so we could really understand the mechanism on the molecular level. We also wanted to know if women would even want to participate in a study in which they would delay chemotherapy for 2 months. So, our first study looked at whether we could accrue at least 20 patients in 2 years. We accrued quickly. We had about 13 patients on trial within 8 months. Even more profound was that, with only 2 months of the PARP inhibitor, we observed an 88% tumor reduction. At that point, we moved on to a full neoadjuvant study with pathologic response as the endpoint, which is what we presented at ASCO.
Q: How did you conduct the study?
A: We gave 6 months of a daily oral PARP inhibitor and proceeded to surgery. As simple as this sounds, this had never been done before.
Q: What did you find?
A: We were able to show pathologic complete response among women with a BRCA mutation who had triple-negative breast cancer and other types of breast cancer. We now have evidence that we can get a pathologic complete response if we choose the right target. Although not every patient achieved a pathologic complete response, the response was quite good at 53%. When adding in the minimal residual disease, the response rate was 63%. Moreover, the toxicity profile was different from what we have seen with chemotherapy. For those who responded to the PARP inhibitor, this was very exciting. For those who did not respond, or initially responded and then the tumor grew, we are going to use the tissue collected during this trial to try to identify any clues on the genomic and protein level to figure out exactly what happened. This will help us to understand the drugs and how to better combine them in the future.
Q: How likely is it that an oral agent could eliminate the need for neoadjuvant chemotherapy?
A: If validated in a larger confirmatory trial, the oral medication may replace chemotherapy for these women. We have shown in multiple studies that a pathologic complete response to neoadjuvant therapy is associated with long-term outcome.
Q: What must be confirmed in subsequent research?
A: Our next study will be a larger, multicenter confirmatory study to see if we observe the same pathologic response rate. If we do, this could potentially be a therapeutic change for women that could allow them to avoid chemotherapy. However, if people do not respond to the neoadjuvant PARP inhibitor, it does not preclude them from receiving adjuvant chemotherapy or other therapies. – by Jennifer Southall
Reference:
Litton JK. Abstract 508. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
For more information:
Jennifer K. Litton, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: jlitton@mdanderson.org.
Disclosure: Litton reports research funding from AstraZeneca, EMD Serono, Genentech and Pfizer, as well as advisory board roles with AstraZeneca and Pfizer.