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FDA Approves Another Drug For Early Prostate Cancer Use

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    FDA Approves Another Drug For Early Prostate Cancer Use

    According to Dr. Bruce Roth, Professor of Medicine at Washington University School of Medicine, primary hormonal therapy, either by surgical removal of the testicles or the administration of an intramuscular injection with a class of drugs called LHRH agonists, reduces the testosterone level in the blood by about 90-95%, but levels inside tumor cells are reduced only by 40-60%.

    This means that their are other sources of testosterone in the body. One source is the adrenal glands, which produce a number of important hormones. Scientists have also discovered that prostate cancer cells themselves can make their own testosterone, and that process of synthesis of testosterone utilizes the same set of enzymes found in the adrenal gland.

    Zytiga (abiraterone) blocks one of those enzymes, effectively shutting down synthesis of testosterone, and thus deprives some of the remaining cancer cells of this compound that they need to survive and multiply.

    Johnson & Johnson (J&J) won USFDA approval for its prostate cancer pill Zytiga to be used earlier in the disease.

    Zytiga can be prescribed before chemotherapy in men whose prostate cancer has spread to other parts of the body and is resistant to testosterone-lowering treatments, the Food and Drug Administration said today in a statement.

    The drug extends survival when given before chemotherapy and prolongs the time before patients seek chemotherapy and pain treatments, according to Michael Meyers, J&J’s development team leader for Zytiga.

    The approval may expand use by as much as fourfold, Meyers said. About 20,000 men in the U.S. have used the drug since it was cleared in April 2011.

    “As we move into earlier stages of disease, what we’re doing is not only prolonging survival, what we are doing is prolonging the time that men with metastatic castration-resistant prostate cancer have good quality of life and are able to maintain their functioning,” Meyers told Bloomberg News.

    Prostate cancer is the second-leading cause of cancer death in American men behind lung cancer. About 241,700 new cases will be diagnosed this year and almost 28,200 men will die of the disease, according to the American Cancer Society.

    Zytiga decreases the production of testosterone, which stimulates prostate tumors to grow, the FDA said.

    Patients in a clinical study who took Zytiga for its new use along with a steroid lived a median of 35.3 months, or 5.2 months longer than those who took a sugar pill in combination with steroids, according to the FDA’s statement.

    Patients on Zytiga hadn’t experienced further tumor growth during the study while those on the sugar pill saw growth after a median of 8.3 months.

    Provenge was approved for a similar use and could be used with Zytiga and in sequence, Meyers said.

    Xtandi was cleared in August by the FDA for patients whose disease has advanced beyond the prostate even with previous treatments.

    J&J is studying Zytiga in men with prostate cancer who haven’t yet received hormonal therapy, Meyers said.

    Zytiga (abiraterone acetate) is also better absorbed with food, though the label says empty stomach. Some oncologists have been able to reverse Zytiga resistance by having patients take it with a fatty meal.

    Zytiga costs $44,000 a year. The drug extended life by an average of less than 5 months to 16 months, according to a company spokesperson.

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    Gregory D. Pawelski

    Abiraterone (Zytiga) in Metastatic Prostate Cancer Without Previous Chemotherapy

    Abiraterone in Metastatic Prostate Cancer Without Previous Chemotherapy

    N Engl J Med. 2012 Dec 10; CJ Ryan, MR Smith, JS de Bono, et al

    (OncologySTAT) - Abiraterone plus prednisone significantly improved progression-free survival and significantly delayed other clinical endpoints, compared with placebo plus prednisone, in patients with metastatic castration-resistant prostate cancer in this phase III, randomized, double-blind study.

    Hormonal therapies as second-line therapies for metastatic castration-resistant prostate cancer may produce responses but do not improve survival outcomes. Chemotherapy or immunotherapy may improve survival, but have had limited use. Cytochrome P-450c17 is an enzyme involved in androgen synthesis. The cytochrome P-450c17 inhibitor abiraterone acetate has been shown to improve survival in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel. In addition, previous studies have demonstrated durable responses to abiraterone in patients not previously treated with chemotherapy. This randomized, double-blind, placebo-controlled phase III study evaluated abiraterone in patients with progressive metastatic castration-resistant prostate cancer not previously treated with chemotherapy who had not yet shown clinically significant cancer-related symptoms.

    Patients had metastatic adenocarcinoma of the prostate, prostate-specific antigen (PSA) progression, ongoing androgen deprivation, and mild or no symptoms and were previously treated with an antiandrogen. Patients were randomly assigned to receive oral prednisone (5 mg twice daily) with either oral abiraterone (1 g/day) or placebo. Interim analyses were to be conducted after observation of 116, 311, and 445 progression-free events, and a final analysis was planned for after observation of 773 events. In addition, an interim analysis of overall survival was planned after 333 deaths. The study was unblinded after the second interim analysis, based on the efficacy and safety data from that time point.

    A total of 1088 patients were randomly assigned to the abiraterone + prednisone (n = 546) or placebo + prednisone (n = 542) group. Median follow-up was 22.2 months. At the first interim analysis, risk of radiographic progression or death was reduced by 57% in the a abiraterone group compared with placebo (median not reached vs 8.3 months; HR, 0.43; 95% CI, 0.35–0.52; P < .001). At the second interim analysis, median time to radiographic progression-free survival was 16.5 and 8.3 months in the abiraterone and placebo groups, respectively (HR, 0.53; 95% CI, 0.45–0.62; P < .001). At the interim analysis for overall survival, more patients died in the placebo group compared with the abiraterone group (34% vs 27%). Median overall survival was greater in the abiraterone group compared with placebo (not reached vs 27.2 months), and there was a 25% reduction in risk of death in the abiraterone group compared with placebo (HR, 0.75; 95% CI, 0.61–0.93; P = .01), although this was not significant at the prespecified level of P ≤ .001. In addition, abiraterone + prednisone improved outcomes in several secondary endpoints compared with placebo + prednisone, including risk of decline in Eastern Cooperative Oncology Group (ECOG) performance status (12.3 vs 10.9 months; HR, 0.82; 95% CI, 0.71–0.94; P = .005), time to initiation of cytotoxic chemotherapy (25.2 months vs 16.8 months; HR, 0.58; 95% CI, 0.49–0.69; P < .001), time to opiate use for cancer-related pain (not reached vs 23.7 months; HR, 0.69; 95% CI, 0.57–0.83; P < .001), and median time to PSA progression (11.1 vs 5.6 months; HR, 0.49; 95% CI, 0.42–0.57; P < .001).

    A total of 48% and 42% of patients reported grade 3 or 4 adverse events (AEs) in the abiraterone and placebo groups, respectively. A total of 33% and 26% of patients reported serious AEs in the abiraterone and placebo groups, respectively; and 4% and 2% of patients in the abiraterone and placebo groups, respectively, had AEs resulting in deaths. AEs that were more common in the abiraterone group included fatigue, arthralgia, and peripheral edema. Grade 3 or 4 hepatotoxic AEs were reported in 8% and 3% of patients in the abiraterone and placebo groups, respectively. The treatment groups had similar rates of AEs leading to treatment discontinuation, and proportions of patients with grade 3 or 4 serious AEs. The abiraterone group had a higher rate of mineralocorticoid-related toxic effects.

    Abiraterone + prednisone significantly improved progression-free survival and significantly delayed other clinical endpoints, compared with placebo + prednisone, in patients with metastatic castration-resistant prostate cancer.
    Gregory D. Pawelski


      Abiraterone (Zytiga) in Metastatic Prostate Cancer Without Previous Chemotherapy

      Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy

      Charles J. Ryan, M.D., Matthew R. Smith, M.D., Ph.D., Johann S. de Bono, M.B., Ch.B., Ph.D., Arturo Molina, M.D., Christopher J. Logothetis, M.D., Paul de Souza, M.B., Ph.D., Karim Fizazi, M.D., Ph.D., Paul Mainwaring, M.D., Josep M. Piulats, M.D., Ph.D., Siobhan Ng, M.D., Joan Carles, M.D., Peter F.A. Mulders, M.D., Ph.D., Ethan Basch, M.D., Eric J. Small, M.D., Fred Saad, M.D., Dirk Schrijvers, M.D., Ph.D., Hendrik Van Poppel, M.D., Ph.D., Som D. Mukherjee, M.D., Henrik Suttmann, M.D., Winald R. Gerritsen, M.D., Ph.D., Thomas W. Flaig, M.D., Daniel J. George, M.D., Evan Y. Yu, M.D., Eleni Efstathiou, M.D., Ph.D., Allan Pantuck, M.D., Eric Winquist, M.D., Celestia S. Higano, M.D., Mary-Ellen Taplin, M.D., Youn Park, Ph.D., Thian Kheoh, Ph.D., Thomas Griffin, M.D., Howard I. Scher, M.D., and Dana E. Rathkopf, M.D. for the COU-AA-302 Investigators

      N Engl J Med 2013; 368:138-148January 10, 2013DOI:10.1056/NEJMoa1209096


      Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy.

      In this double-blind study, we randomly assigned 1088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The coprimary end points were radiographic progression-free survival and overall survival.


      The study was unblinded after a planned interim analysis that was performed after 43% of the expected deaths had occurred. The median radiographic progression-free survival was 16.5 months with abiraterone–prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone–prednisone vs. prednisone alone, 0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone–prednisone (median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the efficacy boundary. Abiraterone–prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more common with abiraterone–prednisone.


      Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer. (Funded by Janssen Research and Development, formerly Cougar Biotechnology; number, NCT00887198.)

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      Gregory D. Pawelski


        A “Clinical Trial” Too Far?

        Robert A. Nagourney, M.D.

        An interesting paper was published in the January 10 NEJM (Abiraterone in Metastatic Prostate Cancer with Previous Chemotherapy, Ryan et al). The study randomized 1,088 hormone-refractory prostate cancer patients to receive abiraterone plus prednisone, or placebo plus prednisone.

        Abiraterone (Zytiga) works by blocking the syntheses of testosterone (the critical survival factor for prostate cancer cells), both in the adrenal glands and within the tumor cells themselves. The drug had previously been approved for patients who had failed hormone therapy, but was only approved for those who had also failed Taxotere chemotherapy.

        The results were so strongly positive in favor of the treatment arm, revealing a significant progression-free survival 16.5 versus 8.3 months (p < .001) and overall survival hazard ratio 0.75 (p = .01) that the monitoring committee invoked early stoppage rules. Virtually all of the other markers of disease also strongly favored the treatment arm. All of this speaks for an effective therapy in hormone-refractory prostate cancer and we applaud their success.

        The question remains: Did we really need to conduct this study?

        On a biochemical level, abiraterone represents an effective mechanism for androgen ablation. The drug has been established to work well in patients who have failed prior hormone and Taxotere chemotherapy. In that prior exposure to Taxotere would not be expected to substantively influence abiraterone efficacy, the wisdom of committing 1,088 hormone-refractory patients to a “placebo controlled” randomized trial to prove its efficacy in the Taxotere naive population seems questionable.

        Prostate cancer generally afflicts older men. While most patients respond to hormonal ablation, hormone-refractory disease develops in virtually all patients over time. A comparatively mild oral therapy like abiraterone represents a demonstrably superior alternative to a comparatively toxic alternative intravenous cytotoxic drug like taxotere. Did we need to marshal a multi-million dollar trial to prove that abiraterone worked in people who had not received Taxotere, when there was absolutely no reason to believe that it wouldn’t?

        The reason that this trial was conducted was to meet an increasingly onerous regulatory environment that demands that every use of every drug in every situation be proven with a large and enormously expensive clinical trial.

        Registration trials cost between $10,000 and $20,000 per accrued patient. Using these figures, we can guess that this clinical trial cost between $10,000,000 and $20,000,000 to conduct. Those costs must now be recouped from patients and insurers. Thus, the very agency whose purpose is to protect patients and limit the inappropriate use of drugs has created an environment that adds to those expenses and it can be argued, prevents the appropriate use of drugs.

        To put this into perspective, let’s examine the female counterpart – breast cancer. Once aromatase inhibitors showed activity in postmenopausal women, they were rapidly incorporated into clinical therapeutics. Dovetailing nicely with the established antiestrogen tamoxifen, these drugs became second line hormonal therapies. While these drugs naturally assumed their roles in hormonal management of breast cancer, no one would ever demand that a breast cancer patient with ER positive cancer first receive chemotherapy before being allowed to use the well-established aromatase inhibitors. Had the FDA demanded that no one could receive anastrozole, letrozole or Aromasin until they had had Adriamycin, there would have been a march on Washington to reverse the policy. It was obvious to all those engaged in the field that these drugs worked and that they would work at different points in hormonal management of the disease.

        The physiology of and clinical experience in breast cancer management allowed smart scientists with the approval of the regulatory agencies to “crosswalk” the application of these important agents. It is time for the American public to demand that clinical trials be conducted (and resources allocated) when the questions they address can only be answered through the expenditure of these vast financial and human resources.
        Gregory D. Pawelski


          Small steps in treating prostate cancer

          Herman Kattlove, M.D.

          New drugs are beginning to make a dent in the invincibility of metastatic prostate cancer. The basis for these advances began with a professor at my medical school, Charles Huggins. Huggins was awarded the Nobel Prize in 1966 for his work dating from the 1930’s that linked the male hormone, testosterone, to the growth of prostate cancer.

          Most of his work was in mice and rats, but my professors loved to regale us with the story of his first patient treated with his newfound knowledge. The patient was in his 60s and had prostate cancer that has spread throughout his bones, and was causing severe pain.

          Huggins proposed a startling new treatment for his cancer – castration – removal of this testosterone-producing organ. Not something that men were prone to accept, but in this case, it beat the alternative. The patient underwent this simple procedure and enjoyed several years of good health afterwards.

          News of the success of this treatment spread quickly and widely through the urology community. Soon castration became the standard treatment for widespread prostate cancer. Unfortunately, some surgeons in my community would use it even of the cancer hadn’t spread. Why not? “Old” men in their 60’s and 70’s didn’t need their testicles – did they?

          In spite of this overuse, castration is still an effective therapy for metastatic prostate cancer. But it has been displaced by drugs such as Lupron (leuprolide) that also reduce a man’s testosterone. And it is more acceptable to most men.

          Other drugs have been developed that do the same thing as well as drugs that can block the effect of testosterone on the prostate cancer. But eventually, the drugs (or castration) stop working.

          The theory is that there is still a little testosterone or other male hormones produced by a man that cause the cancer to grow. The theory is the cancer cells have developed an increased sensitivity to these hormones – they will grow even in the presence of tiny amounts. And the blockers just don’t block enough.

          Unfortunately once the cancer starts growing after all these hormonal treatments there is little to stop it. Chemotherapy buys a little time, but not much, and of course has its side effects. But there are new drugs.

          A few years ago, a drug called abiraterone acetate (Zytiga) was discovered that effectively blocks all male hormone production. It works even when castration or the other blocking drugs fail.

          And now a second drug, called enzalutamide (Xtandi), is available. It destroys the molecule in the cancer cell, called the androgen receptor. It is this androgen receptor that causes the cancer to grow when it is exposed to any male hormone or male hormone-like substance in the body. Enzautamide (Xtandi) also works when abiterone (Zytiga) stops working. Each of these drugs buys another 5 months, on average, of life and freedom from cancer growth.

          These are small steps and eventually these drugs stop working. Prostate cancer is a serious disease that is hard to prevent and screening has not yet paid off in saving lives. The only consolation for most of us men is that if we do get the disease, we will be old enough to have lived out most of our lives. A very small consolation.
          Gregory D. Pawelski