Background FURVA, a randomised, double-blind Phase II trial, investigated whether the addition of vandetanib to fulvestrant improved progression-free survival (PFS) in patients with an aromatase inhibitor(AI)-resistant advanced breast cancer. Methods Postmenopausal women with oestrogen receptor-positive (ER+ve)/HER2-negative advanced breast cancer, who experienced disease progression on an AI, were randomised (1:1) to fulvestrant 500 mg (Q28) with vandetanib 300 mg od (f + v) or placebo (f + p) until disease progression or discontinuation. The primary endpoint was PFS; secondary endpoints included overall survival (OS) and the influence of REarranged during Transfection (RET) signalling on outcomes. Results In total, 165 participants were randomised to f + v ( n = 80) or f + p ( n = 85). Median PFS was 5.5 months (m) for f + v compared to 5.5 m for f + p (hazard ratio (HR) 0.88; 95% CI: 0.62–1.23; P = 0.22). Unexpectedly, high total RET expression was associated with a PFS advantage of 8.87 m vs 3.94 with low RET (HR 0.493: 95% CI 0.32–0.77; P = 0.002) independent of the treatment arm, supported by an OS advantage 21.95 m vs 18.04 (HR 0.584; 95% CI 0.34–1.00; P = 0.051) in the high-RET group. Conclusion The addition of vandetanib to fulvestrant does not improve PFS. However, high total RET expression was associated with improved PFS, suggesting RET may have a prognostic role in patients treated with fulvestrant. Clinical trial registration ClinicalTrials.gov, NCT02530411.

Background: Paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer (MBC) patients. However, with response rates of 21.5-53.7% and significant risk of peripheral neuropathy, there is need for better chemotherapy. Patients and methods: This open-label phase II/III trial randomised HER2-negative MBC patients 1:1 to either 6 cycles of three-weekly cabazitaxel (25 mg/m2), or, weekly paclitaxel (80 mg/m2) over 18 weeks. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL). Results: 158 patients were recruited. Comparing cabazitaxel to paclitaxel, median PFS was 6.7 vs 5.8 months (HR 0.87; 80%CI 0.70-1.08, P = 0.4). There was no difference in median OS (20.6 vs 18.2 months, HR 1.00; 95%CI 0.69-1.45, P = 0.99), ORR (41.8% vs 36.7%) or TTR (HR 1.09; 95%CI 0.68-1.75, P = 0.7). Grade & GE;3 adverse events occurred in 41.8% on cabazitaxel and 46.8% on paclitaxel; the most common being neutropenia (16.5%) and febrile neutropenia (12.7%) cabazitaxel and neutropenia (8.9%) and lung infection (7.6%) paclitaxel. Peripheral neuropathy of any grade occurred in 54.5% paclitaxel vs 16.5% cabazitaxel. Mean EQ-5D-5L single index utility score (+0.05; 95%CI 0.004-0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1-12.3, P = 0.001) were higher in cabazitaxel vs paclitaxel. Conclusions: Three-weekly cabazitaxel in HER2-negative MBC does not significantly improve PFS compared to weekly paclitaxel, although it has a lower risk of peripheral neuropathy with better patient reported QoL outcomes. It is well tolerated and requires fewer hospital visits.

1008 Background: Paclitaxel is commonly used as first line chemotherapy for HER2 negative MBC. However, with response rates of 21.5-53.7% and a significant risk of peripheral neuropathy there is a need for more effective and better tolerated chemotherapy (CCT). Methods: This open label randomised (1:1) phase 2 trial compared 6 cycles of cabazitaxel (25 mg/m2) every 3 weeks, with weekly paclitaxel (80mg/m2) over 18 weeks as first line CCT. HER2 negative and performance status ≤1 patients were eligible. Patients on cabazitaxel received GCSF prophylaxis. Primary endpoint was Progression Free Survival (PFS) with 127 events required to detect a hazard ratio (HR) of 0.65 with 85% power. Secondary endpoints included objective response rate (ORR; RECIST 1.1), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL). Results: 158 patients were recruited from 14 UK hospitals (79 in each arm). Median age (range) was 56(34-81) in the cabazitaxel arm and 61(34-79) in the paclitaxel arm. 61% of patients were performance status 0. Median time on treatment was 15 weeks for both arms, but more patients on paclitaxel had a treatment delay (61% vs 39%) or dose reduction (37% vs 24%). Comparing cabazitaxel to paclitaxel after 146 PFS events, median PFS was 6.7 vs 5.8 months (HR 0.84; 95%CI 0.60–1.18, P = 0.3). There was no difference in OS, median 19.3 vs 20.0 months (HR 0.94; 95%CI 0.63-1.40, P = 0.7), ORR (42% vs 37%) or TTR (HR 1.09; 95%CI 0.68–1.74, P = 0.7). Grade ≥3 adverse events occurred in 42% of patients on cabazitaxel and 48% on paclitaxel. Diarrhoea, febrile neutropenia and nausea were the most common grade ≥3 events in the cabazitaxel arm with rates of 11%, 11% and 10% respectively compared to 1%, 1% and 0% in the paclitaxel arm. In the paclitaxel arm the top grade ≥3 events were lung infection and peripheral neuropathy, 6% and 5% respectively compared to 2.5% and 0% in the cabazitaxel arm. Peripheral neuropathy of any grade was reported by 55% of patients treated with paclitaxel vs 17% on cabazitaxel. Alopecia occurred in 41% of patients on paclitaxel compared to 27% on cabazitaxel. Adverse events leading to discontinuation were more frequent with paclitaxel (22%) than cabazitaxel (14%). Over the course of treatment, mean EQ5D single index utility score (+0.05; 95%CI 0.004-0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1-12.3, P = 0.001) were higher in the cabazitaxel arm compared to paclitaxel suggestive of better QoL on Cabazitaxel. Conclusions: 3 weekly cabazitaxel as first line chemotherapy in HER2 negative MBC does not significantly improve PFS compared to weekly paclitaxel, though it has a lower risk of peripheral neuropathy with better patient reported overall health outcomes. Cabazitaxel is safe and well tolerated for MBC and requires fewer hospital visits, an important consideration in the COVID pandemic and beyond. Clinical trial information: NCT03048942 .

PURPOSE:In patients with early breast cancer, adjuvant zoledronic acid (zoledronate) may reduce recurrence and improve survival. However, zoledronate is associated with the occasional development of osteonecrosis of the jaw (ONJ). We report on the frequency of ONJ and investigate oral health-related quality of life (Oral-QoL) in a large randomized trial (Adjuvant Zoledronic Acid to Reduce Recurrence [AZURE]). PATIENTS AND METHODS:Three thousand three hundred sixty women with stage II or III breast cancer were randomly assigned to receive standard adjuvant systemic therapy alone or with zoledronate administered at a dose of 4 mg for 19 doses over 5 years. All potential occurrences of ONJ were reported as serious adverse events and centrally reviewed. Additionally, we invited 486 study participants to complete the Oral Health Impact Profile-14 (OHIP-14) to assess Oral-QoL around the time the patients completed 5 years on study. Multivariable linear regression was used to calculate mean scores and 95% CIs in addition to identifying independent prognostic factors. RESULTS:With a median follow-up time of 73.9 months (interquartile range, 60.7 to 84.2 months), 33 possible cases of ONJ were reported, all in the zoledronate-treated patients. Twenty-six cases were confirmed as being consistent with a diagnosis of ONJ, representing a cumulative incidence of 2.1% (95% CI, 0.9% to 3.3%) in the zoledronate arm. Three hundred sixty-two patients (74%) returned the OHIP-14 questionnaire. Neither the prevalence nor severity of impacts on Oral-QoL differed significantly between zoledronate patients and control patients. CONCLUSION:Adjuvant zoledronate used in the intensive schedule studied in the AZURE trial is associated with a low incidence of ONJ but does not seem to adversely affect Oral-QoL.