Talazoparib Plus Carboplatin Induces Synergistic Activity in Multiple TNBC Cell Lines

Alexia Cotte, MD

The combination of the PARP inhibitor talazoparib (Talzenna) and carboplatin demonstrated synergistic activity in 7 cell lines of triple-negative breast cancer (TNBC), with greater DNA damage and cell death observed in PARP inhibitor–resistant cell lines and at lower concentrations of talazoparib when combined with carboplatin, according to preclinical data that were presented in a poster during Week 1 of the virtual AACR Annual Meeting 2021.¹

Additionally, the findings demonstrated that sequential treatment with talazoparib followed by carboplatin led to a 70.4% inhibition (P < .0001) in cell migration compared with the control and a 51.5% inhibition in primary tumor volume (P = .008) with the concomitant strategy vs the control.

Moreover, an in vivo sequential strategy of talazoparib followed by carboplatin demonstrated a 66.7% inhibition in primary tumor volume (P < .0001). This strategy induced a 76.3% inhibition in liver metastasis (P = .02) and a 56.4% inhibition in lung metastasis (P < .0001). With the concomitant approach, lung metastasis was inhibited by 19.6% (P < .05).

“We need to evaluate the impact of the combination of talazoparib and carboplatin to better understand which TNBC [subtype] will benefit from this combination. [Also, we need to evaluate] how different sequencing strategies can impact primary tumor growth and distant metastasis development,” said Alexia Cotte, PhD, a postdoctoral fellow at the Centre de recherche du CHUM in Montreal, Quebec, in a presentation of the data.

TNBC accounts for approximately 15% to 20% of all breast cancers and is the most aggressive subtype. Historically, available therapeutic options have been limited in TNBC, with the majority of patients receiving chemotherapy but still experiencing rapid disease progression.

PARP inhibitors induce synthetic lethality by targeting PARP1/2 and BRCA1/2 mutations, in turn preventing the release of PARP1 from DNA and stalling or accelerating the replication fork. PARP inhibitors also trap PARP1/2 enzymes on damaged DNA, which allows the PARP-DNA complexes to induce cytotoxicity in cancer cells.

To date, the PARP inhibitors olaparib (Lynparza) and talazoparib have demonstrated improved progression-free survival in patients with locally advanced or metastatic germline BRCA1/2-mutant HER2-negative breast cancer.^2,3 The agents were subsequently approved in 2018 for the treatment of these patient populations.^4,5

Talazoparib has also shown preclinical efficacy in TNBC cell lines with BRCA-mutant or BRCA wild-type phenotypes.1

Combining talazoparib with carboplatin could improve efficacy; however, investigational combinations have evaluated low-potency PARP inhibitors, focused on patients with BRCA-mutant disease, or were tested only in patients with metastatic disease.

A 10-day chemosensitivity assay was performed using 7 BRCA-mutant and BRCA wild-type TNBC cell lines. Talazoparib and carboplatin were evaluated at 9 concentrations each. Automated high-content imaging with Operetta was used after treatment.

Each treatment group consisted of 8 to 14 NOD scid gamma mice that were treated with 35 mg/kg of intraperitoneal carboplatin plus 0.03 mg/kg of oral gavage talazoparib in sequential or concomitant dosing strategies. The concomitant strategy began with talazoparib followed by carboplatin 3 days later. Each strategy was compared with a vehicle control.

The results of the study showed that the combination of talazoparib and carboplatin induced synergistic effects in all 7 cell lines analyzed (CI < 1). The greatest synergy (CI < 0.65) was identified in HCC1143, MDAMB231, and Hs578T, which were cell lines resistant to PARP inhibitors. Moreover, in these cell lines, the mean 53BP1 product score was increased between 7- and 16-fold with the combination of talazoparib and carboplatin vs talazoparib alone.

The apoptotic index, defined as the percentage of cells positive for cleaved-PARP, also increased by 4- to 26-fold.

Both sequential and concomitant treatment approaches induced genomic instability by increasing replication fork speed over a tolerance threshold.

References

1. Cotte A, Beniey M, Haque T, et al. Pre-clinical combination of a PARP inhibitor, talazoparib, and carboplatin in triple-negative breast cancer. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract 1066.
2. Robson M, Im SA, Senkus E, el al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533. doi:10.1056/NEJMoa1706450
3. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-763. doi:10.1056/NEJMoa1802905
4. FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. News release. FDA. Published January 12, 2018. Accessed April 12, 2021. https://bit.ly/3wOZOIq.
5. FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. News release. FDA. Published October 16, 2018. Accessed April 12, 2021. https://bit.ly/3tcE1Ip.