Women with metastatic breast cancer to the bone may receive bisphosphonates less often after the first year of monthly administration. With that change in practice, patients with breast cancer and bone metastasis may also reduce their risk of serious side effects, according to a study led by researchers at The University of Texas MD Anderson Cancer Center. The research was presented at the American Society of Clinical Oncology (ASCO) 2014 Annual Meeting (30 May-3 June, Chicago, USA) by Prof. Gabriel Hortobagyi.
Prof. Hortobagyi presented the study data in an oral presentation session. The overwhelming majority of metastatic breast cancer patients will develop a bone metastasis at some point during their care. The study found that receiving zoledronic acid every 12 weeks after one year of monthly administration was as efficacious as continuing to receive it monthly.
OPTIMIZE-2: Less may be better than more
Findings from the OPTIMIZE-2 study could have an impact not just in the setting of metastatic breast cancer, but other solid tumours, as well as multiple myeloma, where monthly intravenous bisphosphonates are used to prevent skeletal related events and the loss of bone mass.
MD Anderson has a long history of research discoveries with bisphosphonates. In the 1990s, Prof. Hortobagyi and Richard Theriault, DO, authored the practice-changing publications in metastatic breast cancer showing pamidronate's association with fewer skeletal-related events (SRE) - including bone fractures and bone pain, and spinal cord compression – leading to the incorporation of the drug class into the metastatic disease management.
"With those findings, it became standard of care to continue bisphosphonates for the life of the metastatic breast cancer patient. Yet there were no definitive studies or guidelines confirming this clinical practice or looking at long-term side effects," said Prof. Hortobagyi, the study's principal investigator.
"The OPTIMIZE-2 trial is the largest study designed to date looking at the frequency of bisphosphonate delivery. The study determined that giving the therapy less often after a year of earlier treatment was non-inferior than receiving the therapy monthly, and we found that less frequency is likely associated with a reduced toxicity," he continued.
The phase III prospective, randomised, double-blind study enrolled 403 metastatic breast cancer patients. All had previously received nine or more doses of bisphosphonates in their first 10-15 months of therapy. Patients were randomised (1:1) to receive an additional year of 4 mg i.v. of zoledronic acid, either every month (q4 we) or every three months (q12 we) for an additional year. Median age was 59 years old, and baseline disease characteristics were similar in both arms.
The study's primary endpoint was the proportion of participants with ≥ 1 SRE on study. Primary analysis was non-inferiority, with a pre-defined margin of 10% for the difference in SRE rates. Secondary endpoints included time to first SRE, skeletal morbidity rate, bone pain score, change in bone turnover markers, and safety.
The researchers found that the SRE rate was comparable in both groups of patients, 22% in the monthly arm, and 23.2% in the every three month arm, indicating less treatment was non-inferior. The researchers also found similar changes from baseline in bone turnover markers, and the incidence of treatment-emergent adverse events in the 2 arms. However, more renal-related adverse events were reported in the monthly arm (9.6%, compared to 7.9% in the every three week arm). Two patients in the monthly arm developed osteonecrosis of the jaw.
The research lets both patients and physicians know that in this case, less may be better than more – a lesson that may extend beyond these findings, according to Prof. Hortobagyi.
"In general in breast cancer, we're getting to the point where our patients are doing well enough that we can begin to start reducing the treatments they receive, as we're likely over-treating the majority of our patients – and this study is an example of that," says Prof. Hortobagyi.
However, Prof. Hortobagyi noted that the study is not without limitations and should be interpreted with cautious. The placebo arm was dropped because of low accrual. The trial was of relatively modest size and there are statistical concerns related to the determination of the non-inferiority margin.
The study focused on patients for one year post-initial bisphosphonates treatment, whereas many patients receive bisphosphonates for the length of their treatment for metastatic disease, even if they develop an SRE.
Novartis supported the trial with funding. Prof. Hortobagyi served as member and chair of the OPTIMIZE-2 Steering Committee and was compensated for that activity.
Hortobagyi GN, Lipton A, Chew HK, et al. Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: Results of the OPTIMIZE-2 trial. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA9500^).