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But more work is needed to determine how the pharmaceuticals can optimally extend survival

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  2. But more work is needed to determine how the pharmaceuticals can optimally extend survival
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This past August, the United States Food and Drug Administration (FDA) approved a new agent for the treatment of late-stage prostate cancer, adding to a growing arsenal of drugs that have been shown to extend life in men faced with the disease.

The approval was precipitated by data from the AFFIRM trial showing that patients who received the drug, enzalutamide (developed by Medivation in partnership with Astellas Oncology), lived a median of 18.4 months from the drug initiation, compared with 13.6 months for those who received a placebo. At the same time, 43% of men receiving the drug reported an improved quality of life, versus 18% of men treated with the placebo.1

Androgen deprivation therapy is generally the first treatment for patients with metastatic prostate cancer. However, despite initial response rates of 80% to 90%, nearly all men eventually develop progressive disease after androgen deprivation therapy, known as castrate-resistant prostate cancer. Enzalutamide is currently approved for the treatment of metastatic, castrate-resistant prostate cancer.

Influx of New Drugs

The pharmaceutical joins 3 other drugs that have been shown over the past 2 years to extend life in patients with advanced prostate cancer, and physicians and scientists are hopeful that these efforts are just the beginning of new therapies for the disease. At the same time, the drugs are well tolerated, with fewer side effects reported than with previous treatments.

“Not only do these drugs help men live longer and have a better quality of life, but they have taught us a lot about the way cancer invades the body and opened a number of new avenues that we can pursue,” says Johann de Bono, MD, PhD, who leads the prostate cancer team at the Institute of Cancer Research in London, United Kingdom, which has been active in trials evaluating these drugs. “We now understand better than ever before what makes these cancers survive despite the treatments we've used in the past.”

Enzalutamide is 1 of 4 drugs that have shown a survival benefit in patients with metastatic advanced prostate cancer since the approval of docetaxel by the FDA in 2004. The other new drugs include:

  • Cabazitaxel injection;

  • Abiraterone; and

  • Sipuleucel-T.

Although docetaxel and cabazitaxel are true cytotoxic drugs that are intended to kill dividing cells, sipuleucel-T is an immunotherapy vaccine. Enzalutamide and abiraterone are hormonal agents that are taken in pill form. The former is an antiandrogen whereas the latter lowers testosterone.

Another promising drug on the horizon that has not yet been approved by the FDA is radium-223 chloride, which also has been shown in clinical trials to increase survival in patients with bone metastases from advanced prostate cancer. Still more drugs that are being evaluated for the disease include cabozantinib, ipilimumab, and tasquinimod.

Why this sudden explosion of new drugs for the treatment of prostate cancer? “We learned a lot from failed studies earlier in the decade, so we're taking longer to evaluate a drug's benefits,” says Michael Carducci, MD, co-leader of the prostate cancer/genitourinary oncology program at the Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University in Baltimore, Maryland. “We've also been working with manufacturers to make sure we're not throwing away drugs or changing our endpoints too early.”

Scientists do not yet know exactly how long these drugs will help extend life in patients with advanced prostate cancer; however, if all the life-prolonging effects of each drug are added together, they could conceivably give patients an additional 18 to 19 months of life, Dr. Carducci says.

“We're going to see a big boost in life expectancy of metastatic prostate cancer patients in the next 5 years,” says Nicholas Vogelzang, MD, a medical oncologist with the Comprehensive Cancer Centers of Nevada in Las Vegas and chair and medical director of the developmental therapeutics committee and co-chair of the genitourinary committee for US Oncology Research. “Each of these drugs individually may not be groundbreaking, but we now know that they all extend life.”

Next Steps

The next question will be to determine whether the drugs can work in sequence or together to optimally extend survival. Previous studies have evaluated the drugs in patients who have already undergone chemotherapy, but new trials are evaluating their use prior to chemotherapy.

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Illustration 2. These drugs have taught us about the way cancer invades the body and opened a number of new avenues that we can pursue. -Johann de Bono, MD, PhD

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A new phase 2 study at The University of Texas MD Anderson Cancer Center in Houston, for example, is evaluating the safety and tolerability of enzalutamide in combination with abiraterone acetate plus prednisone. The former drug does not require steroids to be taken along with it to minimize side effects, whereas the latter does.

“Patients still get frustrated that we're not curing them, that they have to be on long-term therapy,” Dr. Carducci says. “There are a lot of nuances and personalizing in terms of how it's discussed with patients—what it means for them with their specific age and condition.”

Another pressing issue is cost. Enzalutamide will cost $7500 per month, and the average patient receives the drug for approximately 13 months. Furthermore, The New York Times estimates that all of these new drugs could add billions of dollars to the nation's medical bills.2

Sipuleucel-T, which extends survival by approximately 4 months, made headlines in 2011 when Medicare officials decided to cover its $93,000 price tag. Additionally, although enzalutamide and abiraterone are generally covered by insurance, out-of-pocket costs can be substantial, Dr. Carducci says.

“One of the key issues we have to think about as a community is how these drugs should be priced,” says Dr. de Bono. “Many of us believe they should be priced according to the amount of benefit the patient derives from the treatment, but at present it's difficult to see that happening entirely.”

Earlier-Stage Research

Scientists are beginning to research these drugs in patients with earlier-stage disease because they may have greater impact among individuals with a lower tumor burden. “The first trials were in men very close to death, and we're now pursuing trials in earlier-stage disease, which will require longer follow-up,” Dr. de Bono says. “We're hoping these studies will substantially improve and possibly cure more men, like Herceptin did for breast cancer patients.”

One example of such a study is the Abiraterone COUAA- 302 trial, which is evaluating the drug's effectiveness in advanced disease in an earlier stage among men who have not yet received chemotherapy. Still other trials are ongoing for men who have advanced stage disease at the time of diagnosis, are at high risk of developing advanced prostate cancer, or who have cancer that has not metastasized.

Scientists are working hard to develop intermediate endpoint biomarkers that can be used to demonstrate survival benefit in an effort to gain drug approval more rapidly, says Dr. de Bono.

Reference

  1. Top of page
  2. But more work is needed to determine how the pharmaceuticals can optimally extend survival
  3. Reference
  • 1
    Scher HI, Fizazi K, Saad F, et al. AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med.. 2012; 367: 1187-1197.
  • 2
    Pollack A. New drugs fight prostate cancer but at a high cost. New York Times. www.nytimes.com/2011/06/28/health/28prostate.html. Updated June 27, 2011. Accessed November 30, 2012.