Full report on the toremifene Phase III fracture prevention trial

Toremifene is a selective estrogen receptor modulator or SERM. Some time ago, its developer (GTx, Inc.) initiated a Phase III clinical trial to investigate whether toremifene at a dose of 80 mg/day lowered risk for new vertebral fractures in prostate cancer patients being treated with androgen deprivation therapy (ADT). The full report on this trial has now been published … but don’t expect this drug to be available in the US any time soon. We’ll explain why below.

Smith et al. carried out a large, 2-year-long, international, randomized, double-blind, placebo-controlled, multi-center, Phase III clinical study. All patients were 50 years of age or older. They had to have been diagnosed with prostate cancer, on continuous ADT, and at clearly elevated risk for vertebral fracture based on their age (> 70 years) or the presence of osteopenia at the femoral neck or at L1 to L4 in the lumbar spine. (Osteopenia is a reduced level of bone mineral density or BMD).

The patients were randomized to be treated either with toremifene (as an oral tablet) or with a placebo.

Here are the primary results of the trial:

  • 1,284 patients were enrolled into the study.
    • Half (646 patients) were randomized to toremifene.
    • Half (638 patients) were randomized to placebo.
  • The average (median) age of the patinets was 76 years.
  • The average (mean) time that patients had been on ADT treatment when they entered the trial was 3.8-4.0 years.
  • Nearly all of the patients (92 percent) had castrate levels of serum testosterone (i.e., a serum T level < 50 ng/dl).
  • At 2 years from initiation of treatment …
    • Patients in the toremifene group had a 2.5 percent incidence of vertebral fractures.
    • Patients in the placebo group had a 4.9 percent incidence of vertebral fractures.
    • Patients in the toremifene group had a 6.3 percent risk for all fractures.
    • Patients in the placebo group had a 10.1 percent risk for all fractures.
    • Compared to the patients on placebo, the patients on toremifene had significantly increased levels of BMD at the lumbar spine, hip and femoral neck.
    • Also compared to the patients on placebo, the patients on toremifene had a significant decrease in markers of bone turnover and a  significant improvment in lipid profiles.
  • 17 patients (2.6 percent) treated with toremifene had a venous thromboembolic event as compared to 7 patients (1.1 percent) on placebo.
  • All other adverse events are reported to have been similar between the two groups of patients.

It seems very clear that toremifene at 80 mg/day not only reduced the risk for vertebral fractures in this group of patients compared to a placebo. It also seems to have had beneficial effects on BMD, on markers of bone turnover, and on serum lipid levels. But … the problem lies with the venous thrombolic effects …

Venous thromboembolism (basically, blood clots) is a disorder that affects circulation of the blood, and it has a high risk for mortality. So what happened in assessing the results of this trial is that the significant benefit of reduction of risk for fractures in these patients has to be counterbalanced against the significant increase in risk for venous thromboembolism.

As we first reported nearly 2 years ago, GTx submitted these data to the US Food & Drug Administration (FDA), hoping to get toremifene 80 mg approved for the prevention of vertebral fractures. The FDA, however, said that they were worried by the significant increase in risk of venous thromboembolism. What the FDA told GTx was, basically, “We can’t approve toremifene on the basis of this trial alone. If you do another large Phase III trial, and you get the same benefit in terms of the reduced risk of fractures, and lesser risk for venous thromboebolic events, then we would be prepared to reconsider.”

As far as we know, GTx has decided that doing another large trial like this isn’t going to be worth the cost or the risk. They have decidced to focus their energies on other drugs in their pipeline. However, this study offers a particularly simple example of the risk-benefit equations that drug developers and the FDA (and other regulatory agencies around the world) must constantly try to solve. All drugs come with some degree of risk. The question is always whether the demonstrable benefit for patients suffiently outweighs the demonstrable risks. In this particular case, the answer — probably correctly — was no, not on the basis of the available data.

2 Responses

  1. Decreased bone density is a potential risk for many patients on hormonal blockade therapy, and that risk caught my attention back in early 2000 after starting Lupron in December 1999. Back then the risk was not fully appreciated, and my excellent urologist team was not comfortable in exploring or managing that side effect, so they referred me to a medical oncologist. Diagnosed with osteopenia, I was on a bisphosphonate for bone density from September 2000 until April of this year. I stopped Boniva after my bone density scan showed my hip and L1 to L4 vertabrae averaged a normal level. (I’m now in my third off-therapy period of an intermittent triple androgen deprivation therapy program, with finasteride as maintenance during the vacation each time.)

    I wish the toremifene trial had turned out more favorably, as it would have given us another option, especially one with a nice impact on lipid levels. However, it is reassuring that we already have a small arsenal of bisphosphonate drugs available in the US. In fact one of them, Fosamax, has been available so long that it is now available as generic alendronate.

    However, I’m curious whether any of these other established drugs also have any side effects potentially as serious as the thromboembolism risk found in the toremifine trial. We already know about the osteonecrosis issue with the more powerful bisphosphonates, particularly Zometa, and there is some evidence of an infrequent risk of fracture of the femur for other bisphosphonates.

  2. Another well-known drug in the same category, raloxifene, is approved in the U.S. for women, is prescribable off-label for men and has had some validation in the same setting. I have not delved into the subject enough to know how it compares. The usefulness of these drugs is based on the role of estrogen in bone metabolism in men, and the question of using low doses of estrogen in men has been raised. The subject is reviewed in
    an article by Khosla.


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