Despite significant improvements in clinical outcomes within the field of breast cancer in the last 50 years, the triple-negative breast cancer (TNBC) subtype remains an area of huge unmet clinical need.

Triple-negative breast cancer denotes the lack of the three common receptors known to drive breast cancer: estrogen, progesterone and HER2. Since the tumour cells lack these receptors, the most commonly used targeted treatments are rendered ineffective.

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New era in the treatment of TNBC

However, recent developments mean that the treatment paradigm for this subset of patients is expected to undergo dramatic change. Specifically, the generation of poly ADP ribose polymerase (PARP) inhibitors and programmed cell death protein 1 (PD-1) inhibitors is expected to herald a new era in the treatment of TNBC.

Lynparza and Talzenna

Changes in the treatment paradigm began with US Food and Drug Administration (FDA) approval of two PARP inhibitors, AstraZeneca’s Lynparza (olaparib) on 12 January 2018 and Pfizer’s Talzenna (talazoparib) on 16 October 2018, both of which are approved to treat metastatic TNBC patients harboring (or suspected to harbor) a BRCA (breast cancer Type 1 susceptibility protein) mutation, which represent 10–20% of the patient population.

Approval for these two drugs was based on data derived from the OlympiAD and Embraca Phase III trials, both demonstrating similar and significant improvements in disease-free survival compared to standard single-agent chemotherapy of physician’s choice. Despite both drugs reaching their primary endpoint for a benefit in progression-free survival (PFS), neither provided a significant improvement in overall survival (OS).

Subsequent subgroup analysis of OlympiAD has since shown a trend towards an OS benefit in patients who had not received prior chemotherapy. It is likely the trial would have demonstrated a significant OS benefit for chemo naïve patients if it had been designed to evaluate Lynparza treatment versus chemotherapy in first-line patients.

Despite a lack of clarity in overall survival benefit, the exploitation of the DNA repair defects through PARP inhibition represents a new targeted weapon in the treatment of a therapeutically elusive subset of breast cancer.

Tecentriq, Keytruda and Bavencio

In comparison, the OS benefit with the use of PD-1 inhibitors appears to be clear and potentially practice-changing for a significant proportion of TNBC patients. There are currently several Phase III PD-1 inhibitors for the treatment of patients with metastatic TNBC: Roche’s Tecentriq (atezolizumab), Merck & Co’s Keytruda (pembrolizumab) and Merck KGaA and Pfizer’s Bavencio (avelumab).

Leading the way is Tecentriq, having been granted a priority review designation in November 2018. In the Phase III Impassion 130 trial comparing Tecentriq + nab-paclitaxel versus placebo + nab-paclitaxel, the Tecentriq-treated patients demonstrated a significant PFS improvement, both in the intention to treat (ITT) population and in patients with positive PD-L1 expression. In terms of OS, the benefit was significantly greater in the PD-L1 positive subgroup (41% of patients).

Tecentriq-treated patients showed a significant increase in OS (25.0 months versus 15.5 months), highlighting PD-L1 expression on tumour-infiltrating lymphocytes (TILs) as a predictive biomarker for efficacy of Tecentriq in this population.

GlobalData notes that an improvement of this duration is unprecedented in this historically difficult-to-treat subset of patients.

The FDA is expected to make its decision regarding Tecentriq on 12 March 2019, and it is likely to be the first-to-market immuno-oncology drug in breast cancer. Vying for space in this market will be Keytruda. Merck & Co is expected to publish its findings of the Phase III Keynote-355 trial comparing Keytruda + chemotherapy versus placebo + chemotherapy at the end of the year.

If Tecentriq is approved in March it will represent a win for Roche’s Tecentriq over the market-leading Keytruda and will allow Tecentriq to temporarily monopolize the market for treatment of TNBC patients with metastatic disease. Further developments involve testing the efficacy of PD-1 inhibitors in the neoadjuvant setting, representing a potential future market for this class in combination with chemotherapy in early TNBC.

GlobalData expects that the emergence of PARP and PD-1 inhibitors will potentiate positive changes in the treatment of triple negative breast cancer. Furthermore, the evolving stratification of TNBC by BRCA mutation status or PD-L1 TIL expression will serve to provide targets for a type of cancer once considered untargetable.