Will denosumab gain approval for prevention of onset of metastasis to bone?

The U.S. Food and Drug Administration (FDA) has questioned the value of denosumab (Xgeva®) as an agent capable of delaying the onset of metastatic disease to bone in men with progressive, castration-resistant prostate cancer.

An FDA Advisory Committee will meet on Wednesday this week to discuss the application by Amgen for approval of denosumab as an agent that can be used to prevent the onset of boney metastasis. Earlier today, the FDA issued a detailed “briefing document” that asks tough questions about the value of denosumab in the proposed indication.

The executive summary of the briefing document makes the following key points:

  • The application seeks approval of denosumab for the treatment of men with castrate-resistant prostate cancer at high risk of developing bone metastases, based on the results of a single, large, double-blind, randomized, placebo-controlled clinical trial.
  • Patients enrolled into this trial were not required to have no evidence of disease (NED); patients with locally progressive disease were eligible, as were patients with metastases to any lymph node, and 55 percent of the patients enrolled in the trial had received no prior local treatment for prostate cancer.
  • The FDA has previously advised Amgen that — although the overall design of this study was acceptable — “overall survival, patterns of metastases, and the development of symptomatic metastases” would be important review issues.
  • To be eligible for entry into this trial (i.e., to be defined as being at high risk for development of bone metastasis), patients had to meet one or both of two criteria:  a PSA level ≥ 8 ng/ml and/or a PSA doubling time ≤ 10 months.
  • Final analysis of the study data showed that
    • The median time to bone metastasis-free survival (BMFS) was 29.5 months for men in the denosumab arm and 25.2 months for men in the the placebo arm (hazard ratio [HR] =  0.85).
    • The median time to first bone metastasis was 33.2 months for men in the denosumab arm and 29.5 months for men in the placebo arm (HR = 0.84).
    • Median overall survival was 43.9 months for men in the denosumab arm and 44.8 months for men in the placebo arm (HR = 1.01).
    • Treatment with denosumab did not result in an improvement in either overall survival or progression-free survival.
    • Most patients in the trial were not followed until they experienced their first symptomatic metastasis.
  • The overall incidence of osteonecrosis of the jaw (ONJ) in the denosumab-treated men was about 5 percent per patient, which is higher than the incidence of ONJ observed in trials supporting the approved indication of denosumab (for prevention of skeletal-related events in patients with solid tumors metastatic to bone).

There are clearly serious questions about whether denosumab should or should not be approved for this proposed indication. It is for exactly this reason that the FDA holds advisory committee meetings — to allow the independent advisory board members to hear directly from both the sponsor of the proposed drug use (Amgen in this case) and the FDA’s own reviewers of the data.  The independent advisory committees sometimes agree with the company and recommend approval, and sometimes they agree with the FDA’s in-house reviewers and recommend non-approval. The final FDA decision most commonly does, in fact, follow the recommendations of its advisory committees under such circumstances (although there have been well known exceptions to this).

The “New” Prostate Cancer InfoLink suspects that in this case, the advisory committee is not going to recommend approval of denosumab for this indication. If the time to BMFS had been more like 36 months in the denosumab arm of the trial (a really clinically significant difference), or there had been fewer occurrences of ONJ, or there had been any strong suggestion that early use of denosumab really did lead to an overall survival benefit, the outcome would be much more likely to have led to an approval of denosumab for this indication … but one never knows what might happen at these meetings. A single member of the advisory group can sometimes sway the panel, or the panel may feel that the FDA is over-emphasizing the risks associated with the use of this product.  We’ll just have to wait and see what happens on Wednesday.

7 Responses

  1. Mike: I thought there was a study showing denomusab to be superior to Zometa, though I vaguely recall it may have been sponsored by Amgen!

  2. Denosumab is often named Prolia, and was developed as a medicine to slowly increase bone mineral density (BMD), to at least partially reverse the reduction of BMD that accompanies osteoporosis, e.g. when induced by adjuvant androgen deprivation therapy for prostate cancer. Amgen got FDA approval with some difficulty, I think less than 3 years ago. Its known side effects are non-trivial, the most dangerous but rarely occurring being osteonecrosis of the jaw (ONJ).

    Now I shall stick my neck out. I am glad that the FDA will meet tomorrow to discuss this. For I don’t see how a medicine designed to reverse BMD reduction (which partially causes the osteoporotic “skeletal-related events” mentioned above, say, fractures and spinal compression) can delay the onset of metastatic disease. My quick look at the briefing document suggests that this is a problem that the FDA noted. Also, why the rebranding: from denosumab, to Prolia, to Xgeva?

    Finally, a chemist in the Netherlands advised a friend of mine who has osteoporosis not to use Prolia, since (he claimed) the potential side effects are severe and it is too new to know anything about possible future problems. If this is true, how can one now justify its use as Xgeva? (An Amgen publication about Prolia’s currently approved uses can be found if you click here.</a.)

  3. Rick:

    Denosumab (Xgeva) is already approved for the prevention of skeletal-related events in men with metastatic prostate cancer. In one of those trials, denosumab was indeed more effective than zoledronic acid (Zometa). However, in this trial patients were not on drug for nearly 4 years, and the incidence of serious side effects was lower. See section 14 of the prescribing information for Xgeva. And yes, you are correct, that trial was indeed also sponsored by Amgen.

  4. Dear George:

    It is very important indeed to distinguish with care between Xgeva and Prolia, which are two different branded formulations of the drug denosumab, intended for different conditions and target audiences (which is, indeed, potentially very confusing).

    Xgeva is a formulation of the agent denosumab that is given at a dose of 120 mg every 4 weeks as a subcutaneous injection. It is approved in the US and in Europe to prevent skeletal-related events (e.g., fractures) in men who already have metastatic prostate cancer.

    By contrast, Prolia is a formulation of denosumab that is given at a dose of just 60 mg every 6 months as a subcutaneous injection. It is approved in the US for three indications: (a) treatment of postmenopausal women with osteoporosis at high risk for fracture; (b) treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for non-metastatic prostate cancer; and (c) treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. (I believe it has the same three approved uses in Europe, but I am less certain of this.)

    You will note that the indication that Amgen is seeking for the Xgeva formulation of denosumab is for the prevention of onset of bone metastasis in men with non-metastatic, castration-resistant prostate cancer (at a dose of 120 mg given every 4 weeks). This higher dose of the drug given for a median period of near to 4 years probably accounts for the relatively high risk for ONJ seen in the Phase III trial.

  5. I see. The difference in the dose accounts for the rebranding. That is a good reason indeed. I missed that.

  6. First … Thanks for the clarification, Mike … In my eagerness to read the post (!), I missed the nuance of “prevention of onset” vs. “prevention of SREs where bone metastasis is already evident.”

    The discussion is of personal interest, since I needed a bisphosphonate to accompany my own hormone therapy. I received an annual shot of Zometa because I was marginally osteoporitic and receiving 27 months of Lupron. The Zometa was clearly prescribed as a prophylactic and was very effective; combined with appropriate exercise, my BMD improved 30% over 3 years.

    Looking online at men with comparable disease demographics, it seems there is a loose protocol to prescribe the standard dose of Zometa every 90 days for prevention, although I could not convince Kaiser to prescribe that frequently. I question if the FDA ruling is academic since Xgeva can still be prescribed off-label. I recognize it may have an impact on insurance reimbursement.

    To answer George, I also want to relay my lay understanding of how and why these drugs work; this was provided to me by Dr. Steve Harris, a nationally recognized endocronolgist at UCSF who I know personally.

    These drugs do a couple of things. Firstly, they make the surface of the bone slicker so it is harder for the cancer cells to gain a grip and enter the bone structure. I also understand they promote bone growth and make it denser — the bone can be likened to Swiss cheese, and the drug works to fill in the smaller holes. This may explain why a drug prescribed to increase BMD can also prevent bone metastasis.

  7. Rick D:

    Thanks for that. Your response shows how one drug can delay onset while at least partially reversing BMD reduction

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