“OlympiA is clearly a practice-changing trial, and olaparib should be offered to patients meeting the entry criteria for the study,” said Mark E. Robson, MD, Chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center, New York. Dr. Robson was invited to discuss the findings of OlympiA at the European Society for Medical Oncology (ESMO) Virtual Plenary.1
As background, Dr. Robson noted that the launch of inhibitors of poly (ADP ribose) polymerase (PARP), going from bench to bedside, was “rapid,” despite the challenges in developing trials for small molecularly defined subsets (ie, BRCA1/2 mutation carriers), “but everyone persisted.” This first resulted in the OlympiAD trial with olaparib2 and the EMBRACA trial with talazoparib3 in metastatic breast cancer. Both drugs significantly improved progression-free survival, though not overall survival. Nonetheless, the results were sufficient to garner regulatory approval for PARP inhibitors in the protocol-defined subsets, he said.
Now, olaparib has been approved in the adjuvant setting based on the results presented at the ESMO Virtual Plenary by Tutt et al.1 The central finding was the highly significant 3.8% absolute improvement in overall survival at 36 months (hazard ratio = 0.68; P = .009). The 3-year and 4-year invasive disease–free survival and distant disease–free survival rates reflect hazard ratios that were consistent with the prior analysis, with narrowing confidence intervals and no statistical evidence of heterogeneity, he noted.
Mark E. Robson, MD
“These findings are critically important, and I think will clearly define practice for this subset of patients,” Dr. Robson said. “However, they leave us with a few important clinical questions.”
What About Triple-Negative Disease?
Should patients with triple-negative disease who did not achieve a pathologic complete response to pembrolizumab receive olaparib or capecitabine, which significantly improved disease-free and overall survival in CREATE-X.4 The same benefit as a postneoadjuvant treatment has not been consistent, however, in all studies, and some studies suggest its benefit is limited to nonbasal disease. In OlympiAD and EMBRACA, capecitabine was the most common physician’s choice of chemotherapy, but in terms of response rates, it was notably “outperformed” by olaparib, Dr. Robson pointed out.
“In patients who do not achieve a pathologic complete response, I would favor olaparib over capecitabine (except possibly for patients insensitive to platinum). And I would not delay olaparib until after capecitabine—many events occur in the first 6 months in patients with triple-negative disease,” Dr. Robson commented.
Furthermore, in the neoadjuvant and adjuvant settings, should patients with triple-negative disease receive olaparib or pembrolizumab? In KEYNOTE-522,5 patients treated with pembrolizumab both preoperatively and postoperatively had an improvement in pathologic complete response and event-free survival, though not overall survival. This “challenging question” is being addressed in SWOG 1418; meanwhile, more than 40 studies have shown that these two drugs can be safely combined, he said. Dr. Robson added that he would opt to combine pembrolizumab and olaparib (though this is not approved by the U.S. Food and Drug Administration), and “if forced to choose,” he would favor olaparib because of its demonstrated survival advantage.
Estrogen Receptor–Positive Disease
In patients with estrogen receptor–positive breast cancer, should postoperative treatment be with olaparib or a cyclin-dependent kinase (CDK) 4/6 inhibitor (ie, abemaciclib)? In the MonarchE trial, abemaciclib was associated with a 31% reduction in the risk of distant relapse–free survival.6 Although only a minority of cancers in OlympiA were estrogen receptor–positive, these patients clearly derived a benefit from olaparib. The safety of PARP inhibitors in combination with CDK4/6 inhibitors is unknown, and overlapping myelosuppression is a potential concern.
“In patients with estrogen receptor–positive disease, I would favor the sequential use of olaparib (for 1 year) and abemaciclib (for 2 years), particularly for high-risk patients, and if forced to choose, I’d favor olaparib,” he said.
Test All Newly Diagnosed Women for BRCA1/2?
Do the findings mean that all newly diagnosed patients with early-stage breast cancer should be tested for BRCA1/2 alterations? National Comprehensive Cancer Network (NCCN) criteria allow for testing any patient with triple-negative disease and any patient aged 46 and younger with estrogen receptor–positive tumors; for other patients, there are caveats.
By NCCN criteria, approximately 13% of BRCA1/2 carriers are missed, but testing all patients is probably not the answer, said Dr. Robson. The conclusion of a study by Yadav et al was that universal testing will identify mutations in just 0.3% of women older than age 60 and 0.4% of those older than age 50 who do not meet NCCN criteria.7
“Genetic testing should be liberalized for women who meet OlympiA entry criteria, but the detection rate in women between the ages of 50 and 60 who do not meet NCCN criteria is very low,” Dr. Robson noted. He reminded clinicians to test appropriate patients with estrogen receptor–positive disease, who are often overlooked. n
DISCLOSURE: Dr. Robson disclosed relationships and financial interests in Artios Pharma, AstraZeneca, Change Healthcare, Clinical Education Alliance, Genome Quebec, MJH Associates, Pfizer, Physicians’ Education Resource, and myMedEd.
REFERENCES
1. Tutt ANJ, Garber J, Gelber RD, et al: Prespecified event-driven analysis of overall survival in the OlympiA phase III trial of adjuvant olaparib in germline BRCA1/2 mutation associated breast cancer. ESMO Virtual Plenary. Abstract VP1-2022. Presented March 16, 2022.
2. Robson M, Im SA, Senkus E, et al: Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523-533, 2017.
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 379:753-763, 2018.
4. Masuda N, Lee SJ, Ohtani S, et al: Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376:2147-2159, 2017.
5. Schmid P, Cortes J, Dent R, et al: Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 386:556-567, 2022.
6. O’Shaughnessy J, Rastogi P, Harbeck N, et al: Adjuvant abemaciclib combined with endocrine therapy: Updated results from MonarchE. ESMO Virtual Plenary Session. Abstract VP8-2021. Presented October 14, 2021.
7. Yadav S, Hu C, Hart SN, et al: Evaluation of germline genetic testing criteria in a hospital-based series of women with breast cancer. J Clin Oncol 38:1409-1418, 2020.
