AUA report and update no. 2: Sunday, April 26, 2009

Two important papers presented this afternoon addressed data on the use of toremifene and denosumab on the bones of men receiving treatment with androgen deprivation therapy (ADT).

The toremifene trial was a double-blind, randomized, multi-center, placebo-controlled study designed to determine whether toremifene 80 mg once daily would prevent fractures compared to placebo. The trial enrolled 1,389 men with prostate cancer who were randomized to receive either toremifene 80 mg or placebo for up to 24 months. The primary clinical endpoint of the trial was the number of new vertebral fractures.

Data presented by Lin et al. based on this trial showed the following:

  • All patients had received ADT for ≥ 6 months, had a serum PSA level of ≤ 4 ng/ml, were > 70 years of age, and were at or below WHO bone mineral density (BMD) thresholds for spine or hip.
  • The modified intent to treat population evaluated was the set of all randomized subjects who received at least one dose of study medication and had at least one on-treatment radiograph.
  • There was a 50 percent reduction in the number of vertebral fractures identified in the patients treated with toremifene compared to those treated with placebo.
  • The rate of new vertebral fractures identified in the placebo group in this study was 4.93 percent at 24 months.

The question that is going to arise, based on these data, is whether, even though there is clear benefit from toremifene in reducing vertebral fractures compared to placebo, these data are comparable to or better than the effects demonstrated by older products such as the bisphosphonates in preventing fractures in this patient population.

Additional data presented in this study suggest that, in the placebo group:

  • The rate of new vertebral fractures together with worsening vertebral fractures and clinical fragility fractures was 10.1 percent.
  • The rate of treatment failures, defined as new or worsening vertebral fractures and/or clinical fragility fractures was 23.8 percent.

Kim et al. note that these fracture rates are significantly higher than those historically reported in the literature.

The denosumab data reported by Smith et al. are from a 3-year, randomized, double-blind, multi-center study in 1,468 men receiving ADT for prostate cancer. Eligible patients were stratified by duration of prior ADT (≤ 6 months vs. > 6 months) and age (< 70 years vs. ≥ 70 years). All patients received either denosumab (60 mg every 6 months) or placebo, and all patients were instructed to take daily supplements of calcium and vitamin D.

The results of this trial were very straightforward:

  • Denosumab consistently increased bone mineral density in all patient subgroups compared to placebo, but only by a relatively small amount, ranging between 3.9 and 8.5 percent.

As with the toremifene trial data above, while these data are statistically significant, the question is going to be how clinically significant these data are compared to historic experience with the bisphosphonates.

It seems to The “New” Prostate Cancer InfoLink that, as and when toremifene and denosumab get approved by the FDA, which they probably will, we are going to need additional direct comparative trials before we can determine what the best form of treatment is to prevent bone loss and fractures in men receiving ADT.

Clearly there may be a benefit to denosumab in that it can be administered as just two injections a year. Equally, the potential benefit of toremifine is that it is a once-daily oral tablet.

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