Denosumab Safe, Effective in Increasing Bone Density in Nonmetastatic Prostate Cancer

Scott Tagawa, MD

Contrary to previous data, denosumab (Xgeva) was shown to decrease the risk of fracture without a higher incidence of cataracts in patients with nonmetastatic prostate cancer, according to results from a phase III trial presented at the 2018 ESMO Congress.

Men with nonmetastatic prostate cancer who are treated with androgen deprivation therapy (ADT) experience bone loss that may be associated with higher fracture risk and reduced survival. In a previous study, low-dose denosumab significantly increased bone mass and reduced vertebral fracture risk in these patients. However, unlike other randomized trials that evaluated denosumab, this study showed that this drug resulted in an increased development of cataracts in those who received it compared with those who were given placebo, said Scott T. Tagawa, MD, MS.

“We wanted to prove if these [earlier] results were real and not just a fluke, so we undertook this newer study,” Tagawa said.

In the randomized phase III trial (NCT00925600), men with nonmetastatic prostate cancer with bilateral orchiectomy or initiated ADT were randomized 1:1 to receive 60 mg of denosumab every 6 months or placebo. Patients were stratified by Lens Opacities Classification System III (LOCS III) score (<3.0 at all sites, ≥3.0 at any site) or by prior cataract history. The primary endpoint was lens opacifications (LO) development or progression by month 12 based on a change of&thinsp;≥1.0 in posterior subcapsular cataract, ≥1.0 in cortical cataract, or&thinsp;≥0.7 in nuclear opalescence per LOCS III score. Noninferiority was demonstrated if the upper bound of the 95% 2-sided confidence interval was <10%.

Development or progression of LO by month 12 was similar in the denosumab and placebo arms, 33.5% vs 33.2%, respectively. The absolute risk difference was 0.4% (95% CI, —6.3% to 7.2%; P&thinsp;=&thinsp;.0026), indicating that denosumab was noninferior to placebo for the primary endpoint. Rates of adverse events (AEs), AEs leading to treatment discontinuation, and death were similar in the 2 arms.

OncLive: What was the rationale for conducting this trial?

In an interview with OncLive during the 2018 ESMO Congress, Tagawa, assistant professor of Medicine and medical director of the Genitourinary Oncology Research Program at Weill Cornell Medical College, and assistant attending physician at NewYork-Presbyterian Hospital, discussed the clinical significance of these data in patients with nonmetastatic prostate cancer.Tagawa: We know that ADT in different forms remains the mainstay of therapy. This is true in a localized way with radiation therapy and, certainly, for patients with advanced prostate cancer. We also know there is an acceleration of bone loss that occurs naturally with age; this also increases the risk of fractures. There are several drugs available for the treatment of osteoporosis, but the majority of randomized trials have been conducted in women.

However, several relatively small studies—consisting of between 50 and 200 patients&mdash;have been done in the prostate cancer space, and looked at ADT alone or ADT in combination with another drug. In these studies, researchers have shown an improvement in bone density. The first study to show this, plus a decrease in fracture rate, was a study that evaluated low-dose denosumab; this trial was much larger. There have been 2 other studies [evaluating denosumab as well], with one looking at a higher dose. It definitely seems to be an effective drug; it is not without toxicity, although it definitely is not significant toxicity in terms of patients with cancer.

With that being said, amongst many different randomized studies performed in the cancer and noncancer space, the 1 study that happened to evaluate denosumab versus placebo in patients with nonmetastatic prostate cancer, showed increased bone density and decreased fracture rate and also happened to show a higher rate of cataracts. It was about 1% to 5%, and this was not observed in the other studies.

Therefore, we undertook this new study where men received either denosumab or placebo. It was a similar patient population, [those who were] nonmetastatic and at risk of fractures. We wanted to see if there was an increased rate of cataracts, so we designed this as a noninferiority study. Our results showed no increase in cataracts. We would say denosumab, at 1 year, is noninferior in terms of incidence in cataracts.

What would be your take-home message regarding this trial?

We know these men are at risk of cataracts regardless—about 33% of men on placebo or denosumab had cataracts or developed worsened cataracts&mdash;but there was no difference in the treatment arms. It is nice to have an effective drug that prevents an important adverse effect (AE), and now we know there is an additional safety signal.The only drug that we have out there, that has been proven to decrease fracture rate for men treated with ADT, is denosumab. [Our study showed] no increase in AE rate and, importantly, no increase in cataracts [in this patient population].

Tagawa, ST, Dai, T, Jandial, D. Phase 3 double-blind study evaluating lens opacifications (LO) in patients with nonmetastatic prostate cancer (PCa) receiving denosumab for bone loss due to androgen deprivation therapy (ADT). Ann Oncol. 2018;29 (suppl): 8. doi: 10.1093/annonc/mdy284.