(UPDATE) Talazoparib in Breast Cancer

Commentary by Breast Cancer Site Editor for JNCCN 360 

William J. Gradishar, MD

Betsy Bramsen Professor of Breast Oncology, and Chief, Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago

The approval of poly (ADP-ribose) polymerase (PARP) inhibitors in breast cancer has expanded the potential number of treatment options available to patients with germline BRCA-mutated, estrogen receptor (ER)-positive or -negative, HER2-negative breast cancer. Registration trials demonstrated an advantage for talazoparib or olaparib compared with standard chemotherapy choices in patients with metastatic disease, both in terms of clinical endpoints (overall response rate and progression-free survival) and quality of life.

One of the clinical challenges facing practitioners is the need to tailor the many available options for treatment of metastatic disease to the individual patient. For example, a patient with a germline BRCA-mutated, ER-positive breast cancer has the option of endocrine therapy plus a cyclin-dependent kinase 4/6 inhibitor or PARP inhibitor. Similarly, a patient with germline BRCA-mutated triple-negative breast cancer could receive chemotherapy plus a checkpoint inhibitor or a PARP inhibitor. Combinations of these therapeutic strategies, as well as others, are being investigated.

DISCLOSURES

Dr. Gradishar has served on a scientific advisory board or as a consultant or expert witness for Genentech; has served on a promotional advisory board or speakers bureau for Genomic Health; and has received patent, equity, or royalty from Biotheranostics and MGI Pharma.

Since the 2018 approval of the PARP inhibitor talazoparib for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer, clinical trial data have matured, further demonstrating the benefits of the drug in this patient population.

The EMBRACA trial compared talazoparib with chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer.¹ Primary analysis revealed a statistically significant improvement in progression-free survival (in White and non-White patients, supporting its use regardless of race), as well as overall response rate.

Although talazoparib did not improve overall survival compared with chemotherapy, patient-reported outcomes, including self-reported quality-of-life measures, continue to favor the PARP inhibitor over chemotherapy. Additionally, no new safety signals have been identified (cytopenia and anemia are still most frequent). EMBRACA is the largest trial of PARP inhibitor monotherapy to date in patients with germline BRCA-mutated, HER2-negative breast cancer.

Further Clinical Trial Updates

An integrated analysis of five clinical trials—including EMBRACA, ABRAZO, and a few phase I trials—showed that patients treated with talazoparib monotherapy had lower hospitalization rates than those receiving chemotherapy. They also used less supportive care medication.²

Presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, the phase II NEOTALA trial looked at neoadjuvant talazoparib in patients with early germline BRCA1/2-mutated HER2-negative breast cancer.³ Talazoparib monotherapy was active and yielded pathologic complete response rates comparable with those observed with combination anthracycline and taxane-based chemotherapy regimens.

The response rate in NEOTALA was 45.8% in the evaluable population and 49.2% in the intent-to-treat population. Adverse events were consistent with previous reports, with the most common high-grade event being anemia. According to the study authors, talazoparib is the first targeted monotherapy to achieve pathologic complete responses in patients with early germline BRCA-positive HER2-negative breast cancer, including in those with triple-negative disease.

In a similar but slightly smaller patient population, another nonrandomized, single-arm, multicenter phase II study showed that neoadjuvant single-agent oral talazoparib given once daily for 6 months without chemotherapy produced substantial pathologic response rates, with manageable toxicity.⁴ This substantive pathologic response to single-agent talazoparib supports the larger, ongoing neoadjuvant trial, results of which were reported at the 2021 ASCO Annual Meeting.

New Talazoparib Combinations

Although talazoparib is already approved for germline BRCA-mutation–positive metastatic breast cancer, it is also of interest in germline BRCA wild-type tumors as a radiosensitizing agent. A phase II trial at Emory University will assess the efficacy and safety of talazoparib, high-dose radiation, and atezolizumab in patients with PD-L1–positive metastatic triple-negative breast cancer with known germline BRCA1/2 status (ClinicalTrials.gov identifier NCT04690855).

These researchers hypothesize that talazoparib and radiotherapy might boost the number of immune epitopes recognized by atezolizumab, which would further improve outcomes over atezolizumab alone, without excess toxicity.

Updates to the NCCN Guidelines

According to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines for Breast Cancer,⁵ two PARP inhibitors—olaparib and talazoparib—now have category 1 recommendations for patients with germline BRCA1/2 mutations and metastatic breast cancer. Category 1 status indicates uniform NCCN consensus that the intervention is appropriate, based on high-level evidence.

References

1. Litton JK, Hurvitz SA, Mina LA, Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Ann Oncol 2020;31:1526–1535.
2. Mina L, Quek RGW, Ettl J, et al, Hospitalization and supportive care medication utilization among patients treated with talazoparib monotherapy: an integrated analysis of five clinical trials (phase 1–3) in advanced cancers. Abstract CLO20-052. From the NCCN 2020 Annual Conference.
3. Litton JK, Beck JT, Jones JM, Neoadjuvant talazoparib in patients with germline BRCA1/2 mutation-positive HER2-negative breast cancer: results of a phase 2 study. 2021 ASCO Annual Meeting. Abstract 505. Presented June 6, 2021.
4. Litton JK, Scoggins ME, Hess KR, Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant. J Clin Oncol 2020;38:388–394.
5. Gradishar WJ, Moran MS, Abraham J, et al. NCCN Clinical Practice Guidelines in Breast Cancer V.2.2022. Accessed March 23, 2022. To view the most recent version, visit org.