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How Breast Cancer Drugs Are Developed: The Bazedoxifene Story

Many of you may have read a news story about bazedoxifene (BZA), a SERM (selective estrogen receptor modulator) approved in Europe to treat osteoporosis that has been shown to stop the growth of hormone-receptor-positive breast cancer cells, even in cancers that had become resistant to tamoxifen or the aromatase inhibitors.

Women in this situation are wondering if they can try BZA – either prescribed by their doctor or in a clinical trial. The short answer is: not just yet. As an author on the BZA study, the three questions that I am asked most are:

  • How does BZA work?
  • How does BZA compare to the treatments we already have?
  • When will BZA be available for breast cancer treatment?

I’d like to offer more information about the medicine and the way cancer drugs are developed and approved.

How does BZA work?

The hormone estrogen plays an important role in the body, not only in the breast and uterus, but also in bone and in the brain. SERMs are a class of drugs that bind to the estrogen receptor (and thereby prevent estrogen binding to the receptor) and then regulate estrogen-dependent effects differently in different target tissues. For example, tamoxifen blocks estrogen activity in the breast and in breast cancer, but mimics estrogen activity in the bone, which actually increases bone mineral density in patients.

Since the discovery of tamoxifen, SERMs have been useful in treating estrogen-receptor-positive breast cancers. But SERMs have also been developed to treat osteoporosis that occurs in postmenopausal women as a result of the loss of estrogen production. BZA was developed as an osteoporosis treatment without really considering a role for BZA in breast cancer treatment. BZA is a SERM just like tamoxifen and Evista (chemical name: raloxifene), but BZA is a next-generation SERM that doesn’t activate estrogen’s action in cells in the uterus. You can think of it as an improved version of Evista. It’s different from Evista in that it:

  • is more potent
  • doesn’t cause hot flashes
  • is more effective at blocking the action of estrogen in the breast cells

BZA is different from SERMs in another way. Not only does BZA bind to the estrogen receptor in breast cells and stop estrogen from fueling the growth of hormone-receptor-positive breast cancers, it actually destroys the receptor. Without a receptor, estrogen has no effect on the cells. In that way, BZA works similarly to Faslodex (chemical name: fulvestrant), an estrogen receptor downregulator, which also is called a selective estrogen receptor degrader (SERD). SERDs reduce the number of estrogen receptors and change the shape of breast cell estrogen receptors so they don’t work as well; this allows the drug to block the effects of estrogen in breast cells by two methods.

How does BZA compare to the treatments we already have?

With respect to its effect on breast cancer cells, BZA is most similar to Faslodex. But while Faslodex works quite well on breast cancer cells in a petri dish and reasonably well in mice, it’s effectiveness in people hasn’t been as strong. As researchers, we initially thought that the limited response to Faslodex was because after a cancer became resistant to tamoxifen or an aromatase inhibitor, targeting the estrogen receptor wasn’t useful anymore. It turns out that in most breast cancers that are resistant to tamoxifen or aromatase inhibitors, the estrogen receptor is still present and is required for tumor growth. But the cells have changed their response to the estrogen receptor to allow the receptor to be active even with tamoxifen bound to it or without estrogen at all. More research has shown that it’s actually the chemical properties of Faslodex that limit its usefulness. Faslodex was initially designed to be a research tool; in some cases it’s not well taken up by the body. Additionally, its form, a liquid that has to be injected into a muscle each month, isn’t as easy for patients as taking a pill. That being said, right now it is the only SERD that has been approved for breast cancer treatment.

Ten years ago, our lab identified and developed another SERD that was effective in cell lines and animal models and could be given as a pill. Dupont, the company that purchased the drug in order to develop it, started a small trial and found that the SERD worked well in breast cancer patients, even in patients with cancers that had stopped responding to tamoxifen and the aromatase inhibitors. The response indicates that a drug working this way could be beneficial in treating patients with cancer that grows while taking tamoxifen or an aromatase inhibitor. Unfortunately, when Bristol Myers-Squibb (BMS) bought Dupont in 2001, BMS closed the trial. Because the SERD worked so well, the patients lobbied BMS to continue on the trial. BMS responded by destroying 4 million tablets of the drug. Since then, pharmaceutical companies have not been actively developing SERDs for the treatment of breast cancer.

Fast forward a decade, and we have the success and approval of Xtandi, a next generation androgen receptor inhibitor used to treat advanced-stage prostate cancer. Xtandi proved that there is still clinical benefit in targeting steroid receptors even if the cancer had become resistant to other drugs that targeted the receptors. So drug companies are interested in making SERDs again. Aragon (now Seragon) has been developing one that is loosely based on the drug that we developed 10 years ago; phase I trials for that drug started in February.

Despite the progress, it’s going to be at least 1 to 2 years before there is good trial data on these drugs. It will probably take a bit longer for the U.S. Food and Drug Administration (FDA) to approve any of them. In our view, that means that these drugs will come into use about 50,000 patients per year too late. The study that inspired the news release started with a question: was there a SERM that had already been developed, had a clinical history, and could potentially offer benefits while the SERDs worked their way through the approval process?

We were pleasantly surprised to find that BZA had such a similar activity-profile to Faslodex in cell lines, much more so than any of the other clinically relevant SERMs. Since BZA is readily absorbed by the body and can be given as a pill, we took it forward into mouse studies of tamoxifen-resistant breast cancer, which showed that BZA was as good as Faslodex in this test as well.

When will BZA be available for breast cancer treatment?

While it appears that BZA would be beneficial for breast cancer treatment, it isn’t yet readily available, and getting it approved for breast cancer treatment is not as simple as patients, doctors, or perhaps even Pfizer (the maker of bazedoxifene) might like. Getting a drug approved requires a clinical trial that shows that the drug will be useful for a target population (in this case breast cancer). When a clinical trial is designed, a patient population is selected, so that the data are clear when the trial is over. We call this “powering” the trial. The clinical trials for BZA were designed to evaluate the ability of BZA to prevent bone loss in postmenopausal women. While fewer cases of breast cancer were observed, the trial wasn’t powered to evaluate the breast cancer angle. So Pfizer can’t say as yet that there was a clear benefit. In order for BZA to be approved for breast cancer treatment, the drug would have to be evaluated in patients who have breast cancer or are at higher risk for breast cancer. The cost of clinical trials spiral into the millions of dollars all too quickly, and so that’s not a step that will (or should) be taken lightly.

BZA is currently approved for the treatment of postmenopausal osteoporosis in Europe, but has not been registered for the same use in the United States. “Why?” is a question I have been asked several times. Part of that may be traced back to patents. One of the challenges in drug development is that a new and better drug that treats the same condition as an older drug often is at a disadvantage. Evista is approved to treat postmenopausal osteoporosis, as well as to reduce the risk of breast cancer in high-risk women who haven’t been diagnosed. Evista’s patent expires in March 2014; the only use for BZA that Pfizer has accrued sufficient trial data for is treating osteoporosis. As I said, BZA may also reduce breast cancer risk, but Pfizer doesn’t have enough clinical data to ask the FDA to approve that use. In this case, it is unlikely to matter to insurance companies that BZA causes fewer side effects – they will only see the cost per pill.

Some of those same reasons have to be considered when deciding whether to pursue BZA as a breast cancer treatment. From the company’s perspective, to get a drug approved to treat breast cancer, the company has to show that the drug is superior to, or that it works at least as well as, current drugs on the market. This has to be shown in a large, randomized clinical trial, which is very expensive to do. Then the company has to work very hard to market the drug so it’s recognized and used. It would be hard to get another SERM approved as a first treatment for breast cancer. While it has its limitations, tamoxifen works well for most women. To get another drug – say BZA – approved, Pfizer would have to show that BZA works just as well as tamoxifen and then compete in the market with tamoxifen. Since tamoxifen is a generic and would probably cost much less than BZA, it would be a losing battle.

Similarly, BZA would have to be compared head-to-head with Faslodex or another hormonal therapy medicine used to treat advanced-stage breast cancer, like Aromasin, to get approval as a second-line therapy for breast cancer. Faslodex is approved to treat advanced-stage, hormone-receptor-positive breast cancer and it’s also a generic. BZA is a pill, which gives it an advantage over Faslodex, but Arimidex and the other aromatase inhibitors are also pills. The company has to evaluate whether their drug, no matter how good it may be, can compete in the market.

In the meantime, it might be possible to get BZA through “compassionate use.” In certain situations, the FDA allows companies to provide their experimental drugs to people outside of clinical trials. This is called compassionate use.

If you’re interested in trying bazedoxifene, talk to your doctor about your options. For you to receive an experimental drug through the compassionate use program, your doctor must contact the drug company and then submit an application to the FDA. For the FDA to consider your request, you must meet certain criteria:

  • Your disease is serious or immediately life-threatening.
  • No treatment is available or you haven’t been helped by approved treatments for your disease.
  • You aren’t eligible for clinical trials of the experimental drug.
  • Your doctor agrees that you have no other options and may benefit from the experimental treatment.
  • The company that makes the drug agrees to provide it to you.

(Thank you, Dr. Timothy J. Moynihan, for the perfect wording.)

To find out more about the rules regarding compassionate use, visit the FDA website and search for “access to investigational drugs.” Talk to your doctor to see if BZA might benefit your unique situation. The more awareness there is about BZA, the more likely it is that Pfizer might consider registering it in the United States.

I only wish that I had more than just information to offer. I admire the courage of everyone diagnosed with breast cancer. Your strength inspires me. My colleagues and I are continuing to encourage Pfizer to consider registering BZA. Pfizer has been receiving many emails, phone calls, and letters about BZA, thanks to the awareness campaign being carried out by your own fellow patients on this website. If you have a vested interest in seeing that bazedoxifene is evaluated for use in breast cancer, I encourage you to join in, using the contact information below. Your contacts are being heard.

Pfizer Customer Service and Product Inquiries: 1-800-TRY-FIRST (1-800-879-3477) (answered Monday through Friday 8 a.m. to 8 p.m. EST)

Corporate Office: 1-212-733-2323; 235 East 42nd Street, New York, NY 10017

Suzanne Wardell, Ph.D., is a research scientist at Duke University. She is the lead author of a paper that was presented June 15, 2013 at the Endocrine Society Annual Meeting, which described the ability of bazedoxifene to inhibit the growth of breast cancer.

For more information on the research, read a media release from Duke University. The original research is published in the May 2013 issue of Clinical Cancer Research. This blog is based on conversations Dr. Wardell had with members of the Stage IV and Metastatic Breast Cancer ONLY forum in the Breastcancer.org Discussion Boards.

Suzanne Wardell, Ph.D. is a research scientist at Duke University in North Carolina. Her research interests lie in understanding the processes by which breast cancers develop resistance to tamoxifen and aromatase inhibitors and in developing drugs that will target estrogen receptor activity in these resistant tumors. When not in the laboratory, she enjoys experimenting in the kitchen and singing off-key in the car with her daughters.

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