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New Phase III Trials Results on Targeted Therapy in Breast Cancer From the ASCO Annual Meeting

The American Society of Clinical Oncology (ASCO) Annual Meeting was held this past week in Chicago and below we have summarized some of the eagerly awaited results of phase III clinical trials in breast cancer.

Olaparib Superior to Chemotherapy in BRCA-Associated Metastatic Breast Cancer

According to results from the phase III OlympiAD trial presented by Mark Robson, MD (Memorial Sloan Kettering Cancer Center, New York, New York, United States) at the Plenary Session (abstract LBA4), treatment with the poly ADP-ribose polymerase (PARP) inhibitor olaparib improved progression-free survival (PFS) and quality of life compared to standard of care chemotherapy in pretreated patients with metastatic human epidermal growth factor receptor 2 (HER2)-negative, germline BRCA mutation-positive (gBRCAm) breast cancer. In this trial, olaparib monotherapy 300 mg twice daily compared to physician’s choice chemotherapy in 302 patients with metastatic HER2-negative gBRCAm breast cancer provided a statistically significant and clinically meaningful PFS improvement (7.0 months vs 4.2 months; HR 0.58, P = .0009). In addition, olaparib improved time to second progression or death (PFS2) (13.2 months vs 9.3 months; HR 0.57, P = .0033), and yielded higher objective response rate (ORR) (60% vs 29%), including a higher complete response rate (9% vs 2%). The olaparib benefit was most pronounced in patients with triple-negative disease. Adverse events (AEs) associated with olaparib were mild with fewer grade ≥3 AEs than chemotherapy. Dr Robson concluded that OlympiAD is the first phase III trial in metastatic breast cancer demonstrating benefit of PARP inhibitor over chemotherapy. The study was simultaneously published in The New England Journal of Medicine.

Allison Kurian, MD, MSc (Stanford University School of Medicine, Stanford, California, United States), who discussed this abstract, called these results practice changing. She also highlighted a number of questions raised by this trial, including whether olaparib will provide survival benefit when results are mature, what mechanisms of resistance we may expect, and what results we could expect if olaparib is compared to front-line taxane and/or anthracycline-based therapy or platinum-based therapy that is often correlated to sensitivity to PARP inhibitors.

Abemaciclib, A Third CDK4/6 Inhibitor Effective in Hormone Receptor (HR)-Positive/HER2-Negative Advanced Breast Cancer

According to results from the randomized phase III MONARCH 2 trial (abstract 100) that included 669 patients with HR-positive/HER2-negative advanced breast cancer who had progressed on endocrine therapy, the combination of the oral CDK4/6 inhibitor abemaciclib (150 mg twice daily) with the estrogen inhibitor fulvestrant (500 mg days 1 and 15 of the first cycle and every 28 days in subsequent cycles) improved PFS by 7.1 months compared with placebo plus fulvestrant (16.4 months vs 9.3 months; HR 0.553, P<.0000001). Results were consistent across all patient subgroups. Addition of abemaciclib also significantly improved ORR (35.2% vs 16.1%; P<.001), and a numerically greater percentage of patients achieved CR (3.1% vs 0.4%). Abemaciclib plus fulvestrant was associated with an increase in all grade AEs. Diarrhea (13.4%) and neutropenia (26.6%) were the most commonly occurring grade 3/4 AEs with this combination. Diarrhea typically occurred early; its intensity and frequency was related with the starting dose and it was manageable with dose adjustment and antidiarrheal medication.

The presenter, George Sledge, MD (Stanford University, Stanford, California, United States), concluded that abemaciclib plus fulvestrant is an effective treatment for women with HR-positive advanced disease who have progressed on prior endocrine therapy and that these results provide evidence for the use of this combination in advanced breast cancer. Based on these results, a trial of adjuvant abemaciclib plus endocrine therapy is planned. Results of the MONARCH2 trail were published as a rapid communication article in the Journal of Clinical Oncology.

Discussant Ingrid Mayer, MD (Vanderbilt University Medical Center, Nashville, Tennessee, United States), put these and other CDK4/6 data into perspective. She noted the differences in PFS in MONARCH2 and the previously reported PALOMA 3 trial, which compared palbociclib and fulvestrant with placebo and fulvestrant, explaining that the shorter PFS in the PALOMA-3 trial is likely due to different patient eligibility criteria, as patients included in MONARCH 2 were less pretreated. Dr Mayer suggested that sequencing of available agents in HR-positive breast cancer should rely on biology and needs to be individualized for each patient. However, she pointed out that CDK4/6 inhibitors in combination with endocrine therapy should be incorporated into treatment at some point based on the long duration of clinical benefit and overall good quality of life with these agents.

Is Adjuvant Pertuzumab/Trastuzumab and Chemotherapy a New Standard of Care for HER2-Positive Early Breast Cancer?

Results from the phase III APHINITY study (abstract LBA 500) demonstrated modest improvement in invasive disease-free survival (iDFS) for the addition of pertuzumab to trastuzumab plus chemotherapy in 4804 patients with HER2-positive early breast cancer. The addition of pertuzumab resulted in a 3-year iDFS of 94.1%, compared with 93.2% in patients who received trastuzumab/chemotherapy only (HR 0.81, P = .045). The benefit of pertuzumab was most pronounced in the node-positive and HR-negative subgroups. Three-year overall survival (OS) was 97.7% in both treatment arms (HR 0.89, P = .467). AEs were similar in both treatment arms, with the exception of an increase in grade ≥3 diarrhea in patients receiving pertuzumab (9.8% vs 3.7%). The presenter, Gunder von Minckwitz, MD, PhD (University of Heidelberg, Heidelberg, Germany), commented that continued follow-up for 10 years will be key for determining the actual benefit of pertuzumab, including any potential impact on OS. Results from this study were simultaneously published in The New England Journal of Medicine.

The discussant of this abstract, Carey Anders, MD (University of North Carolina, Chapel Hill, North Carolina, United States), emphasized that one year of adjuvant trastuzumab remains the standard of care for HER2-positive breast cancer patients. However, the addition of dual HER2 targeted therapy to chemotherapy can be considered for some patients with multi node-positive and HR-negative/HER2-positive breast cancer. Additionally, neratinib may be added post-trastuzumab for patients with high risk estrogen receptor positive disease based on results from the ExteNet trial.

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