Activity in Relapsed Progressive TNBC With Niraparib Plus Pembrolizumab

Shaveta Vinayak, MD

According to a preliminary prospective study presented at the 2018 ASCO Annual Meeting, half of patients with metastatic triple-negative breast cancer (TNBC) achieved disease control with a treatment combination of a poly (ADP-ribose) polymerase (PARP) inhibitor and an anti—PD-1 agent.

Objective responses to treatment with niraparib (Zejula) and pembrolizumab (Keytruda) were seen in 13 of 46 evaluable patients. Additionally, 10 patients had stable disease. Clinical activity was observed in patients beyond those with germlineBRCAmutations

Niraparib-associated thrombocytopenia was minimized by using a lower starting dose, and the incidence of immune-mediated adverse events (AEs) did not increase or worsen with the addition of a PD-1 inhibitor, according to the report.

“The combination resulted in promising, durable antitumor activity in patients with advanced triple-negative breast cancer,” said Shaveta Vinayak, MD, an oncologist at University Hospitals Case Medical Center in Cleveland, Ohio. “Clinical activity was observed in patients withBRCAwild-type andBRCA-mutated cancers. The median duration has not been reached, and 5 patients have ongoing long-term clinical benefit in excess of 1 year.”

Several studies of single-agent PARP inhibitor therapy have shown clinical activity in TNBC associated with germlineBRCAmutations but not other TNBC subgroups. PD-1 inhibitor monotherapy has demonstrated modest clinical activity in previously treated PD-L1 positive TNBC.

Preclinical studies have suggested potential synergistic interaction between a PARP inhibitor and anti-PD-1 agent, regardless ofBRCAor PD-L1 expression status, said Vinayak. One potential mechanistic explanation involves activation of the stimulator of interferon genes (STING) pathway by the presence of abnormal DNA in the cytoplasm, a remnant of niraparib-induced unrepaired DNA damage. STING activation, in turn, leads to increased expression and release of type 1 interferons, induction of gamma-interferon, and intratumorally filtration of effector T-cells.

The rationale for PARP inhibitor/anti-PD-1 combination therapy in TNBC was evaluated prospectively in the phase II TOPACIO trial involving patients with recurrent or progressive TNBC. Eligible patients had received no more than 2 prior lines of cytotoxic therapy for advanced disease. Patients with a history of anti-PD-1, anti-PD-L1, anti-PD-L2, or PARP inhibitor therapy were excluded.

Treatment consisted of niraparib 200 mg given orally daily plus pembrolizumab 200 mg given intravenously every 21 days. The primary endpoint was the objective response rate (ORR).

Investigators enrolled a total of 55 patients who had a median age of 54. Almost 80% of the patients had received neoadjuvant or adjuvant cytotoxic therapy, 38% had prior exposure to platinum therapy, and 35% had no prior treatment for advanced TNBC.

The combination therapy led to 3 complete responses and 10 partial responses for an ORR of 28%. The addition of the 10 patients with stable disease resulted in a disease control rate of 50% (23 of 46 evaluable patients). Nine patients remained on treatment: 2 patients who attained complete response, 6 who had partial responses, and 1 patient who had stable disease.

Among patients evaluable for biomarker status, 15 had tumorBRCA(tBRCA) mutations, 5 had homologous recombination repair (HRR) mutations (excluding BRCA mutations), 20 had tBRCA and HRR wild type tumors, 25 were PD-L1 positive, and 13 were PD-L1 negative.

Nine of the 15 patients withtBRCAmutations had objective responses and 3 others had stable disease for a disease control rate of 80%. The 20 patients with HRR or tBRCA mutations had a response rate of 55% and disease control rate of 80%. Nine of the 25 patients with PD-L1 positive tumors had objective responses, and 13 (52%) attained disease control. The median duration of response had yet to be reached.

The patients withtBRCAmutations had a median progression-free survival (PFS) of 8.3 months. The 20 patients with HRR or tBRCA mutations had a median PFS of 6.4 months.

Reference:

Vinayak S, Tolaney SM, Schwartzberg LS, et al. TOPACIO/Keynote-162: niraparib + pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial. J Clin Oncol. 2018;36(suppl; abstr 1011). abstracts.asco.org/214/AbstView_214_213387.html.

The most frequent AEs (all grades, all 55 patients) were nausea (55%), fatigue (42%), anemia (31%), thrombocytopenia (24%), and constipation (20%). Grade ≥3 AEs consisted of anemia (15%), thrombocytopenia (13%), and fatigue (7%).