New Data Suggest that Olaparib-Related Adverse Events are Manageable in High-Risk Early Breast Cancer

Patricia A. Ganz, MD

Quality of life results from the phase 3 OlympiA trial suggest that adverse events (AEs) related to treatment with olaparib (Lynparza) may be adequately managed in patients with germline BRCA1/2 mutations in patients with high-risk, HER2-negative, early-stage breast cancer, according to a presented at the 2021 San Antonio Breast Cancer Symposium.1

“Olaparib was well tolerated as adjuvant therapy with no clinically meaningful increase in fatigue during treatment or significant impact on quality of life,” Patricia A. Ganz, MD, professor of medicine in the David Geffen School of Medicine at UCLA and director of the Center for Cancer Prevention and Control Research at the Jonsson Comprehensive Cancer Center said during the presentation. “While olaparib treatment led to slight increases in severity of nausea and vomiting, it did not persist after treatment ended. Scores on physical and emotional functioning as well as global health slowly improved during the 24 months after adjuvant chemotherapy, and one year of olaparib did not meaningfully affect this recovery.”

Assessing Quality-of-Life Post-Treatment

This sub-study included 1,751 patients, of whom 875 received neoadjuvant chemotherapy (440 patients assigned olaparib and 435 patients assigned placebo) and 876 received adjuvant chemotherapy (436 patients assigned olaparib and 440 assigned placebo). At baseline, patients assigned olaparib or placebo had similar quality-of-life and symptom scores.

Patients treated with olaparib had greater fatigue severity compared with those treated with placebo at 6 months (neoadjuvant chemotherapy: difference = –1.3; 95% CI, –2.4 to –0.2; P = .024; adjuvant chemotherapy: difference = –1.3; 95% CI, –2.3 to –0.2; P = .017). This was also seen at 12 months (neoadjuvant chemotherapy: difference = –1.5; 95% CI, –2.8 to –0.2; P = .024; adjuvant chemotherapy: difference = –1.3; 95% CI, –2.4 to –0.2; P = .027). Despite these differences in fatigue severity, they were not considered clinically meaningful based on criteria with the FACIT-Fatigue Scale. Differences in fatigue severity did not significantly differ between both groups at 18 months and 24 months.

Although the differences were small, patients treated with olaparib had worse nausea and vomiting symptom severity than those treated with placebo at 6 months (neoadjuvant chemotherapy: difference = –6; 95% CI, 4-8; P < .001; adjuvant chemotherapy: difference = 5.3; 95% CI, 3.4-7.2; P < .001) and 12 months (neoadjuvant chemotherapy: difference = 6.3; 95% CI, 4.4-8.2; P < .001; adjuvant chemotherapy: difference = 4.5; 95% CI, 2.8-6.2; P < .001). Differences were not observed at 18 months and 24 months.

Clinically meaningful differences between the olaparib and placebo groups were not seen with regards to other symptoms and quality-of-life subscales. In fact, there were improvements in functioning over time.

Ganz mentioned that a limitation of this sub-study is that this analysis was performed before quality-of-life data collection was completed.

“With complete data in the future, there may be a better estimate of quality-of-life recovery in the year after the end of olaparib treatment,” she added. “The final analyses of the [patient-reported outcomes] study will be able to examine the role of important treatment related covariates as they may interact with symptoms and quality of life in patients receiving olaparib.”

Potential Exacerbation of End-of-Treatment Symptoms

In this randomized-controlled trial, researchers assessed the impact of 1 year of adjuvant olaparib after completing chemotherapy (neoadjuvant or adjuvant) and local therapy on distant disease-free survival, invasive disease-free survival and overall survival. This patient-reported outcomes sub-study focused on quality-of-life factors.

“The central question for the OlympiA [patient-reported outcomes] study is to understand whether or not olaparib might exacerbate end-of-treatment symptoms such as fatigue and possibly delay improvement in quality of life after chemotherapy,” Ganz said.

Ganz added that previous studies have demonstrated the potential toxicities associated with chemotherapy.

“Research has demonstrated that chemotherapy has substantial acute toxicities, leaving patients with fatigue and decreased physical functioning at the end of treatment, requiring as much as one to two years to recover to pretreatment levels,” she explained. “In OlympiA, patient-reported outcomes were collected to inform discussions between physicians and their patients regarding risks and benefits of this additional adjuvant therapy.”

In particular, information on patient-reported outcomes were collected via validated questionnaires before randomization, during treatment (at 6 months and 12 months) and after treatment (at 18 months and 24 months).

“This schedule captured [patient-reported outcome] assessments during the year on treatment and the year after treatment ended,” she said.

The primary endpoint for this sub-study was fatigue measured with the FACIT-Fatigue Scale. A clinically meaningful difference was defined as 3 or more points. The primary protocol-specified hypothesis related to patient-reported outcomes was that patients may experience greater fatigue at 6 months and 12 months while treated with olaparib.

Secondary endpoints included gastrointestinal symptoms (diarrhea, nausea and vomiting) and several quality-of-life domains assessed with the EORTC QLQ-C-30 questionnaire.

“These questionnaires were selected due to their reliability and validity in multiple languages of patients enrolled in this international trial,” Ganz said during the presentation.

Clinically meaningful differences were considered small if they were between 5 to 10 points and moderate if they were between 10 and 20 points. Secondary hypotheses for patient-reported outcomes included that patients treated with olaparib may have greater GI symptom severity at 6 months and 12 months, with no difference by 24 months; fatigue severity after treatment would not differ at 18 months and 24 months; and quality of life would not differ throughout the duration of this sub-study between patients receiving olaparib or placebo.

Reference

1. Ganz PA, Bandos H, Spanic T, et al. Quality of life results from OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)-adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER-2 negative early breast cancer. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; Virtual. Abstract GS4-09