Testosterone (androgen)-depleting therapies are usually the first line of defense for men with newly-diagnosed or recurrent prostate cancer. But resistance to these therapies develop over time which leaves the patient and physicians with a number of choices as to the next sequence of therapies to be administered. Recently, guidelines, issued jointly by the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) in Canada, highlight recent advances in treating this more advanced form of prostate cancer. Six new treatments have been approved in the last two years for the treatment of prostate cancer and its symptoms. However, opinions differ as to the sequence of using these therapies and their cost, their relationships to a man’s quality of life, the disease stage of the cancer, and prior therapies received by the patient. Combination studies are certainly needed and underway. The new guidelines for hormone therapy – resistant tumors that have metastasized are based on a review of 56 randomized clinical trials published since 1979 and include the following recommendations.
a) Continue hormone-deprivation therapy indefinitely. b) In addition to hormone deprivation, offer patients one of three treatment options including Zytiga® (abiraterone acetate and prednisone), Xtandi® (enzalutamide), or alpha-radin (radium-223 chloride if the cancer has spread to the bones). All three treatments are associated with improved survival, quality of life and a favorable balance of benefit and harms. c) When considering chemotherapy, taxotere (docetaxel®) with prednisone should be an option but side effects must be discussed. See also the September 20th, 2014 blog. d) Offer cabazitaxel to men whose disease worsens even if taxotere has been tried, but again discuss the side effects. e) Offer Provenge® (sipuleucel-T) to men with no or minimal cancer symptoms. Some physicians maintain that it can be most effective to initially stimulate the immune system with agents like Provenge® before other agents are utilized. f) Offer mitoxantrone but include a discussion of the drug’s limited clinical benefit and side effect risk. Mitoxantrone is also used to treat leukemias and multiple sclerosis. g) Offer ketoconazole or the anti-androgen therapies bicalutamide, flutamide or nilutamide but discuss the limited clinical benefits of these three medications. h) Do not offer other anti-cancer drugs such as bevacizumab (Avastin®), estramustine or sunitinib. i) Begin discussions of palliative care early on while discussing treatment options.
The experts on the panel formulating these guidelines said the optimum sequence in which various treatments should be given remains unclear, but “ongoing clinical trials are exploring this question, as well as potential benefits of combining various treatments.”
Exelixis, the biotechnology firm developing the metastatic medullary thyroid cancer drug, cabozantinib, in the treatment of a variety of cancers, recently announced disappointing Phase III clinical trial results for the use of cabozantinib in the treatment of metastatic, hormone-resistant (refractory) prostate cancer. The drug continues to be clinically evaluated in metastatic renal cell and advanced hepatocellular carcinomas.
Taxotere (docetaxel®) and taxol are plant alkaloids derived from the European yew tree, Taxus Baccata. Taxotere is synthetically obtained by chemically converting a precursor extracted from the needles of the yew plant. Administered intravenously, both are used to treat several malignancies including breast, stomach, lung, ovarian and prostate cancers. Clinical trials completed in 2004 demonstrated that taxotere increased survival in hormone-resistant (refractory) prostate cancer patients. An excellent, updated review of taxotere in prostate cancer was recently published in the August, 2014 issue of the Prostate Cancer Research Institute (PCRI) Insights. The review article discussed taxotere’s mechanism of action, dosages and protocols of administration and significant side effects. Importantly however, it cited a recent study of 800 men with hormone-sensitive prostate cancer. The study concluded that taxotere’s beneficial effects may be even further enhanced by administering it at an earlier stage in men with newly-diagnosed, high-risk disease or men with hormone-sensitive, metastatic disease. Significant side effects include peripheral neuropathy, anemia, fatigue, hair loss, lowered white blood cell (neutorpenia) and platelet counts. Therefore the maximum benefit of using taxotere may be achieved by using it at the right time and in the right combination. Since there are several alternative therapies now approved and available for men with metastatic, hormone-resistant or -sensitive prostate cancers, consultation with an expert prostate cancer physician is absolutely critical. For additional information, see a 2007 article from Dr. Richard Lam, published in the PCRI Insights.
The following is an important blog in three sections. It describes another approved therapeutic agent for men with metastatic, hormone-refractory prostate cancer. Also included are important discussions regarding the need for future clinical studies to maximize cancer remissions and overall survival.
In 2012, the Food and Drug Administration approved Xtandi® (enzalutamide) for men with metastatic, hormone-refractory prostate cancer who previously had undergone chemotherapy with taxotere (docetaxel®). This month, however, the FDA approved Xtandi® for use in the same patients before they had been treated with chemotherapy, thus creating one more option for men. Xtandi® is a second line hormonal therapy administered orally once daily which can suppress testosterone at three different sources giving many men an additional cancer response after initially failing hormone therapy. The November 2012 issue of the Prostate Cancer Research Institute (PCRI) Insights contains a very informative article by Dr. Neal Shore summarizing the use and mechanism of action of Xtandi®. The reader is advised to see the 2012 link at this point.
The second article by Dr. Mark Scholz is a blog from the February 2014 meeting of genitourinary section of American Society of Clinical Oncology (ASCO). Dr. Scholz mentions that Xtandi® (also formerly known as MDV3100 during its developmental stage) has been shown to extend life in both cohorts of prostate cancer patients discussed above. For specific details of the PREVAIL study, see the linked blog. Xtandi® now joins Zytiga® (abiraterone acetate) and Provenge® as therapeutic options for men before administering chemotherapy with taxotere. The question is now raised as to the optimal way to sequence administration of these agents. Dr. Scholz makes an argument that Provenge® which works by stimulating the immune system, should be administered first. After Provenge®, it is specially noted that the anticancer effects of Xtandi® is reduced when administered after Zytiga® and vice versa. This progressively increasing cancer resistance is not surprising. No data is currently available on the effect of sequencing these therapies on overall survival. Comparative studies and studies involving combination therapies are in order.
The third portion of this post are two very informative videos from Dr. Charles “Snuffy” Myers wherein he discusses the PREVAIL study results and prostate cancer remissions in general. In the first video, Dr. Myers notes the significant delay in radiological progression (e.g. bone, lymph node metastases) demonstrated by Xtandi® (11.2 months vs. 2.8 months for placebo). This will enable Xtandi® to be recognized as a first choice option for therapy. However, in the PREVAIL study, the overall survival result was less dramatic; only 2.2 additional months for Xtandi®. Dr. Myers poses the question of how a therapeutic agent can delay metastases yet minimally affect survival time. He notes it may take a long time to observe the effects of a drug if one is basing the effects on following PSA changes alone. The PSA can increase while the whole cancer is responding. Hence, one should not overly depend on PSA. Instead he proposes using alkaline phosphatase and the circulating tumor assay (CTC) as better markers. Insurance coverage is also discussed. One needs to have a complete remission in order to see significant survival effects. It is rare to observe remissions from a single agent. Studies involving combination therapies are needed. Dr. Myers suggests that studies involving sequential single agents may not be the best, but combination studies are needed to witness overall survival benefits. The second video mainly discusses the mechanism of action of Xtandi®, its safety profile and potential side effects. Dr. Myers notes that under 20% of patients receiving Xtandi® in the PREVAIL study went into complete remission. It is more safe and effective than casodex (liver damage). The major side effect is fatigue. Four-six weeks are needed to reach a therapeutic drug level and 2-3 months are required to see a clinical benefit. The unique mechanism of action of Xtandi® may also require changes in other drugs being taken by a patient.
