Dosing and Duration of BMAs in an Older Patient With Prostate Cancer

Presentation

A 72-year-old white male patient with prostate cancer presents in early 2020 with a biochemical recurrence showing that his prostate-specific antigen (PSA) has increased with a projected doubling time (PSA-DT) of 6 months. He was first diagnosed with prostate cancer in 2015 and underwent a retropubic radical prostatectomy to remove the entire prostate and tissue around it. In 2017, he experienced a biochemical recurrence and received adjuvant radiotherapy (RT) and a short course (6 months) of androgen-deprivation therapy (ADT), which led to a stable PSA. He also has hypertension and a glomerular filtration rate (GFR) of 50, indicating a reduction in kidney function.

Workup

The patient resumes treatment with ADT. However, the risk of bone fracture begins at 4 months with ADT.¹ A dual-energy x-ray absorptiometry (DEXA) scan measuring bone mineral density shows osteopenia with T scores of -1.4 in the lumbar spine and -1.7 in the hip.

Treatment

The National Osteoporosis Foundation recommends preventive treatment with a bone-modifying agent (BMA) for patients with osteoporosis or osteopenia and risk factors. In factoring in the duration of treatment, the type of BMA, and the increased risk of osteonecrosis of the jaw (ONJ)², the patient is given an oral bisphosphonate.

Follow-up and Management

In December 2021, the patient develops castration-resistant prostate cancer (CRPC), and his PSA-DT has accelerated to 3 months. His PSA level is a 6.8 and test <20 on ADT. Imaging now shows limited axial bone metastases, but he has no pain in the sites of bony metastases on the lumbar spine.

Ultimately, the patient was given enzalutamide, a nonsteroidal antiandrogen. Since it has an association with increased fracture risk, zoledronic acid should be administered at least monthly or quarterly or denosumab should be given monthly for the prevention of skeletal-related events.

Zoledronic acid is indicated for persons with bone metastases from solid tumors in conjunction with standard cancer therapy. In persons with prostate cancer, the cancer should have progressed after treatment with one hormonal therapy. The dose of zoledronic acid is 4 mg intravenously over 15 minutes every 3-4 weeks. There are dose-reduction recommendations for those with impaired renal function. There are studies that indicate a longer dosing interval of 12 weeks does not increase the risk of skeletal events.^{3, 4} This dosing schedule may benefit those patients with a higher risk of renal failure or hypocalcemia. 

Denosumab is indicated in patients with bone metastases from solid tumors. The dose is 120 mg every 4 weeks as a subcutaneous injection in the upper arm, upper thigh, or abdomen. There are varied results when comparing extended dose intervals of denosumab to the indicated 4-week dosing schedule.^{5, 6, 7} Further data are needed prior to recommending increased dosing intervals of denosumab.

Discussion

Making decisions around duration and dosing of BMAs in metastatic breast cancer and castration-resistant prostate cancer is difficult but critical because patients are living longer. People living with either are projected to live significantly longer than 2 years thanks to novel treatments, making duration of BMAs a crucial discussion point.

Results from the open-label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer regarding safety of long-term denosumab confirmed the known safety profile of denosumab with long-term administration for a median 19.1 months (up to 5 years) in metastatic breast cancer and a median 12.0 months (up to 5.6 years) in metastatic prostate cancer.²

In 2020, the first systematic review summarizing the available data on the efficacy and toxicity of BMAs after 2 or more years of exposure was published. The review, which included three prospective studies and nine retrospective studies, found that the incidence of ONJ was 1–2% in the first 2 years, but rose after the first 2 years, ranging from 5.3% to 21%. Rates of hypocalcemia were as high as 14.4% but clinically significant hypocalcemia was uncommon, ranging from 1 to 2%. The incidence of severe decline in renal function was 3% or less.⁸

There are a number of factors to weigh in managing the treatment of the patient’s prostate cancer at this point, including renal function, efficacy, convenience, response to therapy, and the number and sites of metastasis. In addition, the outcome of tests for urine N-telopeptide and the bone turnover marker alkaline phosphatase will also impact clinical decision-making.⁹

References

1. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005 Jan 13;352(2):154-64. DOI: 10.1056/NEJMoa041943.
2. Stopeck AT, Fizazi K, Body JJ, et al. Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer. 2016 Jan;24(1):447-455. DOI: 10.1007/s00520-015-2904-5. Epub 2015 Sep 3.
3. Himelstein AL, Foster JC, Khatcheressian JL, et al. Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: A randomized clinical trial. JAMA. 2017 Jan 3;317(1):48-58.
4. Santini D, Galvano A, Pantano F, et al. How do skeletal morbidity rate and special toxicities affect 12-week versus 4-week schedule zoledronic acid efficacy? A systematic review and a meta-analysis of randomized trials. Crit Rev Oncol Hematol. 2019 Oct;142:68-75. doi: 10.1016/j.critrevonc.2019.07.013. Epub 2019 Jul 25.
5. Abousaud AI, Barbee MS, Davis CC, et al. Safety and efficacy of extended dosing intervals of denosumab in patients with solid cancers and bone metastases: a retrospective study. Ther Adv Med Oncol. 2020 Dec 23;12:1758835920982859. doi: 10.1177/1758835920982859.
6. Yerram P, Moore R, Wolf S, et al. Incidence of skeletal related events in patients with bone metastasis receiving denosumab every four weeks compared to intervals greater than every four weeks. J Oncol Pharm Pract. 2019 Apr;25(3):529-534. doi: 10.1177/1078155217743074. Epub 2017 Dec 5.
7. Kettle JK, Patel PB. Feasibility of extended dosing intervals of denosumab. J Oncol Pharm Pract. 2018 Jul;24(5):343-347. doi: 10.1177/1078155217703791. Epub 2017 Apr 9.
8. Ng TL, Tu MM, Ibrahim MFK, et al. Efficacy and toxicity of extending bone modifying agents beyond two years for bone metastases in breast of castrate-resistant prostate cancer patients: a systematic review. J Clin Oncol. 2020;38:15_suppl, e24083-e24083. DOI: 10.1200/JCO.2020.38.15_suppl.e24083
9. Lipton A, Smith MR, Fizazi K, et al. Changes in bone turnover marker levels and clinical outcomes in patients with advanced cancer and bone metastases treated with bone antiresorptive agents. Clin Cancer Res. 2016 Dec 1;22(23):5713-5721. DOI: 10.1158/1078-0432.CCR-15-3086. Epub 2016 May 2. PMID: 27140926.