During the course of the trial, denosumab has partially displaced zoledronic acid as the bone-targeted agent of choice…. Whether the frequency of administration of denosumab can also be reduced is not known.

— Robert Coleman, MD, FRCP

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Bisphosphonates were first synthesized more than a century ago, with their initial usage restricted to a range of industrial processes until their potential clinical relevance was appreciated in the late 1960s.¹ Then, following development for the treatment of osteoporosis and Paget’s disease of bone, the potential role of bisphosphonates in oncology was studied.

In addition to efficacy in the treatment of hypercalcemia of malignancy,² small trials with oral clodronate and oral pamidronate suggested useful effects on skeletal morbidity and bone pain.³ Subsequently, randomized clinical trials to evaluate the effects of intravenous pamidronate on a new endpoint, termed skeletal-related events to objectively reflect the skeletal morbidity associated with metastatic bone disease, were performed.^4,5

Skeletal-related events included radiotherapy to bone for pain relief or structural damage, pathologic fracture, spinal cord compression, orthopedic intervention for impending or actual fracture, and hypercalcemia. These studies, and similar trials in breast cancer with oral clodronate,⁶ showed significant benefits, with a 20% to 30% absolute reduction in skeletal-related events, reduced pain, and improved quality of life.

Subsequently, more convenient and effective aminobisphosphonates have emerged, including zoledronic acid and (in Europe) both intravenous and oral ibandronate. In a randomized, double-blind, multicenter trial comparing the efficacy of zoledronic acid and pamidronate,⁷ the proportion of patients with at least one skeletal-related event (the primary efficacy endpoint) was similar, and the preestablished criterion for noninferiority of zoledronic acid to pamidronate was met.⁷

A subsequent multiple-event analysis showed that zoledronic acid reduced the relative risk of developing a skeletal complication by an additional 20%.⁸ This slight efficacy advantage and the shorter infusion time as well as positive placebo-controlled trials in other disease settings associated with bone metastases^9,10 led to zoledronic acid becoming the standard bisphosphonate, not only in the United States but also in many countries around the world. Additionally, a placebo-controlled trial of zoledronic acid performed in Japanese women with breast cancer confirmed the efficacy of zoledronic acid with a 21.5% absolute reduction (30.7% vs 52.2%) in the proportion of patients experiencing at least 1 skeletal-related event.¹¹

Optimizing Duration and Schedule

In all of these studies, with both pamidronate and zoledronic acid, a 3- to 4-weekly regimen of treatment was tested—a schedule based largely on the duration of control of hypercalcemia and short-term effects on surrogate bone biomarkers rather than detailed dose-and-schedule–finding studies in normocalcemic patients with bone metastases. The registration trials for both pamidronate and zoledronic acid assessed the primary endpoint of skeletal-related event prevention at 12 months and, although there were exploratory extension studies that reported on efficacy out to 24 months^8,12 and clinical guidelines recommend continuation of treatment throughout the course of the disease,^13,14 high-quality data on both duration and schedule of treatment have always been lacking.

Furthermore, due to the prolonged retention of bisphosphonates in the skeleton, the pharmacologic effects on bone cell function are long, with residual biologic activity still detectable years rather than months after treatment.¹⁵ It is therefore not surprising that both clinicians and the regulatory agencies have had an interest in performing high-quality prospective clinical trials to assess both duration and schedule of bisphosphonate treatment.

OPTIMIZE-2

The OPTMIZE-2 study, reported by Hortobagyi and colleagues and reviewed in this issue of The ASCO Post, was designed to test the clinical prejudice for continuing treatment on a monthly schedule against either a reduced, every-12-week administration or stopping treatment altogether after an induction period of 9 to 12 months.¹⁶ Over a 7-year period, 402 patients were recruited from over 100 centers across the United States. Only 17 of them were randomized to stop treatment, and this arm was abandoned due to poor accrual and both patient and clinician reluctance to randomize to no further treatment.

Bone metastases from breast cancer are common, and bisphosphonate use during the recruitment period was routinely used; denosumab (Xgeva) as an alternative to a bisphosphonate did not become available until 2011. It is thus self-evident that the patients recruited to OPTIMIZE-2 are but a tiny fraction of the potentially eligible population treated at the participating centers, and it is not possible to determine how representative they are of the totality of patients seen in routine clinical practice.

OPTIMIZE-2 was designed to exclude a 10% absolute difference in the proportion of patients experiencing ≥ 1 skeletal-related event. This approximates to almost 50% of the benefit of zoledronic acid compared to placebo¹¹ and several times the absolute differences observed between zoledronic acid and pamidronate.^7,8 The -OPTIMIZE-2 study did meet its primary endpoint of noninferiority, with an absolute deficit of only –1.2% and a lower 95% confidence interval (CI) boundary of –9.8%.

So, we can conclude with reasonable statistical confidence—and within the constancy assumptions between the registration trial and OPTIMIZE-2 necessary to set noninferiority margins—that treatment every 12 weeks retains approximately 50% to 60% of the overall efficacy of treatment. It is for clinicians (and patients) to determine whether a potential loss of up to 40% to 50% of the overall efficacy of treatment is an acceptable trade-off for the convenience and cost savings associated with the every-12-week regimen. Zoledronic acid and bone-targeted agents in general are well tolerated, and it was not possible to identify any differences in adverse events of interest such as osteonecrosis of the jaw (2 vs 0 patients), atypical femoral fractures (0 vs 0), and increases in serum creatinine (6 vs 1) between the 4- and 12-week schedules, respectively.

Related Studies

Several other trials, including ZOOM¹⁷ and BISMARK,¹⁸ have investigated whether the interval between bisphosphonate infusions can be increased to take advantage of the prolonged pharmacologic effect in bone. These studies suggested that reducing the frequency of administration did not significantly diminish the efficacy of zoledronic acid. However, these trials were underpowered to show noninferiority of the less-intensive schedules and have not influenced treatment recommendations.

More recently, the noninferiority of less frequent zoledronic acid administration was tested in the Cancer and Leukemia Group B (CALGB) 70604 trial.¹⁹ In the study, 1,822 patients with bone metastases, including 833 with breast cancer, were randomized from the initiation of treatment to zoledronic acid monthly or every 3 months for 2 years. The noninferiority margin for the primary endpoint of the proportion of patients developing ≥ 1 skeletal-related event was set at a 7% absolute difference.

In a preliminary report, there were no statistically significant differences in efficacy between the two treatment schedules. In all, 29% of patients in both treatment groups experienced ≥ 1 skeletal-related event (absolute difference = 0%; 95% CI= –3.3% to 5.1%). There were also no differences in time to first skeletal-related event or pain scores. Renal adverse events and osteonecrosis of the jaw were too infrequent for meaningful comparison.

Closing Thoughts

The investigators are to be congratulated for completing the OPTIMIZE-2 study and providing reassuring data on the potential to deescalate bisphosphonate treatment. Clinician prejudice clearly made recruitment a challenge. Their OPTIMIZE-2 results, coupled with those from CALGB 70604 and the other exploratory studies, argue strongly for the use of the 3-monthly schedule, potentially from the outset as tested by CALGB and certainly after loading of the skeleton with a few months of treatment with zoledronic acid or pamidronate.

During the course of the trial, denosumab has partially displaced zoledronic acid as the bone-targeted agent of choice, following the comparison with zoledronic acid that showed denosumab to be superior in delaying the first skeletal-related event.²⁰ Whether the frequency of administration of denosumab can also be reduced is not known and, because the mechanism of action is completely different, with no accumulation of the antibody in the skeleton, the results from OPTIMIZE-2 and CALGB 70604 should not be extrapolated to the use of denosumab. ■

Disclosure: Dr. Coleman has received institutional research funding from Amgen and Bayer and is a part-time employee of prIME Oncology.

References

1. Francis MD, Russell RG, Fleisch H: Disphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo. Science 165:1264-1266, 1969.

2. Sleeboom HP, Bijvoet OL, van Oosterom AT, et al: Comparison of intravenous (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate and volume repletion in tumour-induced hypercalcaemia. Lancet 2:239-243, 1983.

3. Wong R, Wiffen PJ: Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database Syst Rev 2:CD002068, 2002.

4. Hortobagyi GN, Theriault RL, Lipton A, et al: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate: Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16:2038-2044, 1998.

5. Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 17:846-854, 1999.

6. Paterson AH, Powles TJ, Kanis JA, et al: Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 11:59-65, 1993.

7. Rosen LS, Gordon D, Kaminski M, et al: Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: A phase III, double-blind, comparative trial. Cancer J 7:377-387, 2001.

8. Rosen LS, Gordon D, Kaminski M, et al: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in treatment of skeletal complications in patients with advanced multiple myeloma or breast cancer: A randomized, double-blind, multicenter, comparative trial. Cancer 98:1735-1744, 2003.

9. Saad F, Gleason DM, Murray R, et al: Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with advanced prostate cancer and bone metastasis. J Natl Cancer Inst 96:879-882, 2004.

10. Rosen LS, Gordon D, Tchekmedyian S, et al: Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with non small cell lung carcinoma and other solid tumors: A randomized, phase III, double-blind, placebo-controlled trial. Cancer 100:2613-2621, 2004.

11. Kohno N, Aoqi K, Minami H, et al: Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: A randomized, placebo-controlled trial. J Clin Oncol 20:3299-3301, 2005.

12. Lipton A, Theriault RL, Hortobagyi GN, et al: Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: Long term follow-up of two randomized, placebo-controlled trials. Cancer 88:1082-1090, 2000.

13. Coleman R, Body JJ, Aapro M, et al: Bone health in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 25(suppl 3):iii124-iii137, 2014.

14. Van Poznak CH, Temin S, Yee GC, et al: American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 29:1221-1227, 2011.

15. Brown JE, Ellis SP, Lester JE, et al: Prolonged efficacy of a single dose of the bisphosphonate zoledronic acid. Clin Cancer Res 13:5406-5410, 2007.

16. Hortobagyi GN, Van Poznak C, Harker WG, et al: Continued treatment effect of zoledronic acid dosing every 12 vs 4 weeks in women with breast cancer metastatic to bone: The OPTIMIZE-2 randomized clinical trial. JAMA Oncol. January 26, 2017 (early release online).

17. Amadori D, Aglietta M, Alessi B, et al: Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): A phase 3, open-label, randomised, non-inferiority trial. Lancet Oncol 14:663-670, 2013.

18. Coleman RE, Wright J, Houston S, et al, BISMARK Investigators: Randomized trial of marker-directed versus standard schedule zoledronic acid for bone metastases from breast cancer. 2012 ASCO Annual Meeting. Abstract 511. Presented June 1, 2012.

19. Himelstein AL, Qin R, Novotny PJ, et al: CALGB 70604 (Alliance): A randomized phase III study of standard dosing vs. longer interval dosing of zoledronic acid in metastatic cancer. 2015 ASCO Annual Meeting. Abstract 9501. Presented May 29, 2015.

20. Stopeck AT, Lipton A, Body JJ, et al: Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: A randomized, double-blind study. J Clin Oncol 28:5132-5139, 2010.