Results from an early-phase trial conducted in patients with triple-negative breast cancer (TNBC) show that the combination of olaparib and radiotherapy was well tolerated.
Olaparib, a PARP Inhibitor, has already shown efficacy in some types of breast cancer, but in this study, the drug was investigated as a radiosensitizer to increase the efficacy of radiotherapy.
At a median follow-up of 34 months, only one patient developed late treatment-related grade 2 adverse events, and there were no late treatment-related events of grade 3 or greater.
This late-toxicity profile was similar to that seen with standard radiotherapy protocols, say the authors, led by Pierre Loap, MD, from the Department of Radiation Oncology, Institut Curie, Paris, France.
They also note that their results contrast with those from a separate trial that used another PARP inhibitor, veliaparib. In that trial, concern about late safety effects was reported. The authors of the current study note that the two drugs differ pharmacokinetically and that there were differences in the patient populations in the trials.
Their own results “suggest that use of olaparib as a radiosensitizer during breast radiotherapy may not be associated with an increased risk of late complications,” Loap and colleagues comment.
This approach also showed efficacy: while these were not primary endpoints, at 3 years, the overall survival rate was 83%, and the event-free survival rate was 65%.
The study was published online October 27 in JAMA Oncology.
About 15% of breast cancers are classified as TNBC, which is associated with a generally poor prognosis, especially when residual active disease is present following neoadjuvant chemotherapy, the authors note. They theorize that increasing the biological effectiveness of radiotherapy with radiosensitizers such as the PARP inhibitors could lead to greater tumor control and could improve outcomes.
Hence, they conducted a phase 1 prospective dose-escalation trial that included 27 patients with TNBC (median age, 46 years). Of this group, 21 women (87.5%) had an incomplete pathologic response following neoadjuvant chemotherapy, and three patients (12.5%) had unresectable tumors despite having received neoadjuvant chemotherapy. Those three patients subsequently underwent radiotherapy followed by mastectomy, but none achieved a complete pathologic response. Regional lymph node irradiation was conducted for 17 patients (70.8%), and 11 patients (45.8%) received adjuvant capecitabine.
Genetic analyses were conducted for 22 patients (91.7%). Of this group, 14 (63.6%) had homologous recombination–deficient tumors, and seven (31.8%) had homologous recombination–proficient tumors.
The primary outcome measures were the safety and tolerability of PARP inhibition with radiotherapy; secondary outcomes included overall survival and event-free survival.
Patients received olaparib at increasing doses (50 mg, 100 mg, 150 mg, or 200 mg twice daily), which was begun 1 week before radiotherapy and was then continued concomitantly with radiotherapy. A maximum dose of 200 mg twice daily was selected in order to limit the risk of hematologic toxic effects while at the same time maintaining antitumor efficacy.
Following breast-conserving surgery, radiotherapy at a total dose of 50.4 Gy was delivered to the whole breast, with a 63-Gy simultaneously integrated boost given to the tumor bed of patients younger than 60 years. For patients who underwent a radical mastectomy or for those with unresectable tumors despite neoadjuvant chemotherapy, a total dose of 50.0 Gy was delivered to the chest wall or to the whole breast (for unresectable tumors). In cases of node-positive disease, regional lymph node stations could be treated with a total dose of 50.0 Gy to 50.4 Gy.
Dose-limiting toxicity (DLT) was not observed at any olaparib dose level, and the maximum tolerated dose was not reached. This allowed for a safe dose escalation of olaparib to the highest planned dose. No patient deaths were reported within 6 weeks following completion of treatment. Acute non-DLT grade 3 and 4 adverse advents occurred in several patients. One patient (4.2%) had grade 3 lymphocele; one (4.2%) had grade 3 breast pain; two (8.3%) had grade 3 radiodermatitis; eight (33.3%) had grade 3 lymphopenia; three (12.5%) had grade 4 lymphopenia; and 11 (45.8%) had grade 3 or 4 lymphopenia.
There were no late treatment-related adverse effects of grade 3 or greater, and none of the patients developed a second cancer.
“Our findings suggest that for future trials evaluating the antitumor efficacy of this combination treatment, an olaparib dose of 200 mg twice daily should be considered,” conclude the authors.
The study was supported by AstraZeneca, manufacturer of olaparib. Several of the authors report relationships with industry, including AstraZeneca.
JAMA Oncol. Published online October 27, 2022. Abstract
Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.
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