A Closer Look at Targeted Therapies for Advanced Breast Cancer

Individualized treatment for breast cancer has improved clinical and economic outcomes. During a presentation at NAMCP 2020 Virtual Spring Managed Care Forum, Hatem Soliman, MD, associate member of the breast and immunology departments and medical director of the Clinical Trials Office at the Moffitt Cancer Center, discussed targeted therapeutic options, including poly-ADP ribose polymerase (PARP) inhibitors and PI3K inhibitors, for the treatment of advanced breast cancer.

Dr. Soliman outlined two clinical trials of PARP inhibitors. The 2017 randomized, open-label, phase III OlympiAD study published in The New England Journal of Medicine included 302 patients with BRCA-mutated human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer who were randomized 2:1 to receive olaparib 300 mg (n=205) or standard of care (capecitabine, eribulin, or vinorelbine; n=97).

Median progression-free survival (PFS) was significantly longer in the olaparib group than the standard-of-care group (7.0 months vs. 4.2 months; P<0.001). The response rate was 59.9% in the olaparib group and 28.8% in the standard therapy group. The rate of grade 3 or higher adverse events (AEs) was 36.6% in the olaparib group and 50.5% in the standard therapy group, and the rate of treatment discontinuation due to AEs was 4.9% and 7.7%, respectively.

The 2018 randomized, open-label, phase III EMBRACA trial published in The New England Journal of Medicine included 431 patients with advanced breast cancer and a germline BRCA1/2 mutation who were randomized 2:1 to receive talazoparib 1 mg (n=287) or standard single-agent therapy (capecitabine, eribulin, gemcitabine, or vinorelbine; n=144).

Median PFS was significantly longer in the talazoparib group than in the standard therapy group (8.6 months vs. 5.6 months; P<0.001), and the objective response rate was greater in the talazoparib group compared with the standard therapy group (62.6% vs. 27.2%; P<0.001). Hematologic grade 3/4 AEs occurred in 55% of the patients who received talazoparib and 38% of the patients who received standard therapy. Patient-reported outcomes favored talazoparib, according to the study.

Dr. Soliman noted that olaparib costs about $13,000 to $14,000 without coverage, while talazoparib costs about $15,000 without coverage. These drugs have significant associated toxicity, but not much more than the standard of care chemotherapy. Dr. Soliman said that “for now, only

in germline BRCA1/2 mutant breast cancer as a line of therapy similar to chemotherapy.” Additional research is needed to identify biomarkers that are particularly impacted by PARP inhibitor therapy to improve the cost/benefit ratio.

Next, he discussed the PI3K inhibitor alpelisib, the first U.S. Food and Drug Administration-approved alpha specific inhibitor among many drugs investigated. A 2019 randomized, phase III trial published in The New England Journal of Medicine included 572 patients with hormone receptor-positive, HER2–advanced breast cancer who had received endocrine therapy, 341 of whom had confirmed PIK3CA mutations. Patients received alpelisib 300 mg plus fulvestrant 500 mg or placebo plus fulvestrant. Among PIK3CA-mutated patients, PFS at a median follow-up of 20 months was 11 months in those receiving the alpelisib combination versus 5.7 months in the placebo-treated group (P<0.001).

Finally, he discussed tucatinib, an oral tyrosine kinase inhibitor that was investigated in the randomized HER2CLIMB trial published in 2020 in The New England Journal of Medicine. Patients with HER2+ metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine received tucatinib or placebo in combination with trastuzumab and capecitabine. 

One-year PFS was 33.1% in the tucatinib group and 12.3% in the placebo group (P<0.001), and median PFS duration was 7.8 months and 5.6 months, respectively. Two-year overall survival (OS) was 44.9% and 26.6%, respectively (P=0.005), and median OS was 21.9 months and 17.4 months, respectively. He described tucatinib as “another tool in HER2+ disease, likely in later line after treatment with pertuzumab and antibody drug conjugates.”

Presentation: Implementing New Data and Evolving Standards in Advanced Breast Cancer: Individualizing Treatment for Improved Clinical and Economic Outcomes. NAMCP 2020 Virtual Spring Managed Care Forum, April 16-17.