Future Prostate Cancer Treatments


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This may sound strange, but there’s never been a better time to have prostate cancer. By that we mean there is aggressive activity into the research and development of new prostate cancer treatments, and they hold a great deal of promise. So in response to the question, “What’s on the horizon when it comes to prostate cancer treatments?” we are glad to say, quite a bit.

The surge in new prostate cancer treatments can be attributed in part to a greater understanding of how the disease works and the role testosterone has in promoting prostate cancer. This broader appreciation of prostate cancer, which will be diagnosed in more than an estimated 241,000 men in the United States in 2012 and be the cause of death in about 28,000, will hopefully lead to a cure for the disease. For now, however, here’s what on the horizon and what has already dawned when it comes to prostate cancer treatments.

New prostate cancer treatments

Abiraterone

Abiraterone (Zytiga®) is an oral medication approved by the FDA on April 28, 2011, after the drug’s manufacturer, Johnson & Johnson, stopped the clinical trial it was conducting because the results were so good, they did not want to deprive the men in the placebo portion of the trial from the benefits.  Like cabazitaxel, abiraterone is for men who have metastatic hormone therapy resistant prostate cancer that has also resisted treatment with docetaxel. However, abiraterone works in a way that differs from that of cabazitaxel. Abiraterone reduces the production of a protein and hormone called cytochrome P450 17A1 (CYP17A1), which is critical in the production of testosterone. In turn, abiraterone can reduce production of testosterone at three sources: the testicles, adrenal glands, and the prostate tumor itself. Men with advanced prostate cancer often become extremely resistant to hormone therapy that attempts to reduce testosterone production, but abiraterone appears to have an impact on the hormone.

The effectiveness and safety of abiraterone were shown in a clinical study involving 1,195 men with late-stage hormone therapy resistant prostate cancer who had not responded to docetaxel. Men were given either abiraterone once daily along with prednisone twice daily, or placebo along with prednisone twice daily. Overall mean survival among men who took abiraterone was 14.8 months compared with 10.9 months among men who took placebo.

Use of abiraterone was associated with joint swelling, low potassium levels, fluid retention, muscle aches, hot flashes, diarrhea, urinary tract infections, cough, high blood pressure, heartbeat disorders, urinary frequency, upset stomach, and upper respiratory tract infections. Abiraterone treatment comes at a high cost: about $5,000 per month, with an average need for 8 months of treatment.

Cabazitaxel

Cabazitaxel (Jevtana®) is a drug that was approved by the Food and Drug Administration (FDA) on June 17, 2010, for use in men who have late-stage, metastatic  prostate cancer that has not responded to hormone therapy or to the chemotherapy drug docetaxel.  The drug is given via injection and used in combination with prednisone. It works by preventing the formation of microtubules, which are structures that pull the chromosomes apart in cancer cells.

Cabazitaxel was approved based mainly on the results of a randomized trial that involved 755 men with metastatic hormone-resistant prostate cancer who had failed to respond to docetaxel. The men were randomly assigned to take either 25 mg/m2 of cabazitaxel every three weeks along with 10 mg/day or prednisone, or 12 mg/m2 of mitoxantrone every three weeks along with 10 mg/day of prednisone.

Men in the cabazitaxel group survived a mean of 15.1 months compared with 12.7 months for men treated with mitoxantrone. Side effects associated with cabazitaxel included neutropenia and leucopenia (abnormally low white blood cell counts), anemia, diarrhea, fatigue, nausea and vomiting, abdominal pain, back pain, anorexia, hair loss, peripheral neuropathy, constipation, asthenia (loss of strength), thrombocytopenia (decline in platelets), and fever. The cost associated with extending survival is about $8,000 per treatment, with six months being the average treatment course.

Enzalutamide

Enzalutamide (Xtandi®) was approved for prostate cancer on August 31, 2012, by the FDA after it was shown to extend overall survival in men who had advanced disease that had spread or recurred after treatment with hormone therapy and chemotherapy (docetaxel). Researchers are continuing to test its effectiveness in men who have earlier stage prostate cancer, but Xtandi has not been approved by the FDA for this indication. Formerly known as MDV3100, enzalutamide works by interfering with testosterone and dihydrotestosterone (DHT) receptors that are on the surface of prostate cancer cells, and also by preventing these receptors from exchanging signals with prostate cancer cells, thus stopping cancer growth.

During clinical trials, men who took Xtandi lived for an average of 18.4 months compared with 13.6 months among men who took a placebo. Side effects associated with the use of Xtandi include anxiety, back pain, blood in the urine, diarrhea, dizziness, headache, high blood pressure, hot flush, upper or lower respiratory infections, muscle weakness, sleep problems, spinal cord compression, and tingling in the extremities.

Radium-223

Radium-223 (Xofigo) works in a way totally different from other drugs for advanced prostate cancer. Radium-223’s target is bone, because spread of cancer (metastasis) to the bone is a common and serious occurrence among men who have hormone therapy resistant prostate cancer. Radium-223 is not for use in patients whose cancer has spread to other organs as well.

Radium-223 is an injectable drug given every four weeks for six weeks. It uses radiation decay to kill cancer cells. Radium is chemically similar to calcium, so radium-223 naturally seeks cancer cells in bone, which are rich in calcium. Because radium-223 involves alpha radiation rather than beta or gamma radiation (which have a longer range than alpha radiation), the drug causes less damage to adjacent healthy tissue, including bone marrow. The common side effects include nausea, vomiting, diarrhea, and swelling of the leg, foot, or ankle.

Radium-223 demonstrated some impressive results in a Phase 3 clinical trial, enough so that the drug’s maker, Algeta, stopped the study so the control group could take the drug. In the trial, the investigators found that radium-223 extended overall survival by 44%: men treated with radium-223 lived a mean of 14 months compared with 11.2 months in the placebo group. The drug was was put on the fast track and was approved by the FDA on May 15, 2013. It is marketed by Bayer in the US.

Sipuleucel-T

Sipuleucel-T, better known as Provenge, was approved by the FDA on April 29, 2010, for treatment of asymptomatic or minimally symptomatic metastatic hormone resistant prostate cancer. Unlike other drugs on the market or in the pipeline for advanced prostate cancer, sipuleucel-T is referred to as a vaccine, although it does not prevent disease, as traditional vaccines are designed to do.

Rather, sipuleucel-T warrants the vaccine label because it is a type of immunotherapy. The vaccine is made by using a patient’s own immune system cells, specifically mononuclear blood cells, which are harvested and then cultured with a recombinant human protein (PAP-GM-CSF, which stands for prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor). The end result is a “vaccine” that helps make prostate cancer cells susceptible to attack by the immune system.

Approval of sipuleucel-T was based on results from a randomized, double-blind, placebo-controlled study that involved 512 men (age range, 40-89) with metastatic prostate cancer who had failed hormone therapy. Eighteen percent had also failed chemotherapy. The participants received either sipuleucel-T (341 men) or placebo (171) during three sessions. Average survival time for men who received sipuleucel-T was 25.8 months compared with 21.7 months for men in the control group. A subsequent, smaller trial supported the findings of the bigger trial: 25.9 months vs 21.45 months, respectively.

Common side effects associated with sipuleucel-T include chills, fatigue, fever, back pain, nausea, joint pain, and headache. Serious adverse reactions reported more often in patients who took sipuleucel-T compared with placebo included stroke and acute infusion reactions. Because doses of sipuleucel-T are unique and individually  prepared for each patient, the cost of each treatment course is enormous—about $100,000.

Prostate cancer drugs in development

Cabozantinib

Cabozantinib, formerly known as XL 184, has been demonstrating an ability to kill tumor cells, inhibit the formation of new blood vessels that nourish tumors (angiogenesis), and reduce the spread of cancer. Thus far, clinical trials have tested cabozantinib against thyroid cancer, hormone-resistant metastatic prostate cancer, lung cancer, and ovarian cancer, as well as observed its activity against metastatic bone lesions in five types of tumor, including prostate.

Cabozantinib works by attacking two proteins—MET and VEGFR2—that have a key role in the development and progression of various types of cancer. A Phase 2 trial evaluated the use of cabozantinib in the treatment of 171 men with hormone therapy resistant metastatic prostate cancer, more of 75% of whom had bone metastases. All of the men were treated with cabozantinib for 12 weeks. Here’s what the investigators found after 12 weeks:

  • Among the men whose cancer had spread to the bone, a bone scan showed that 76% of them had partial or complete disappearance of the bone metastases
  • Of the men with cancer that had spread to the bone and who had been taking narcotics to control bone pain, 67% experienced a reduction in pain and 56% stopped or reduced their use of narcotics
  • More than two-thirds of the men had some reduction in the spread of cancer outside of the bone
  • Side effects included fatigue, gastrointestinal symptoms, and high blood pressure

The results of this study, which were presented at the 2011 Annual Meeting of the American Society of Clinical Oncology, suggest that cabozantinib not only may be helpful for men who have hormone-resistant metastatic prostate cancer, but that it may be especially helpful for men with bone metastases. Cabozantinib is the development pipeline, and additional trials will be conducted.

Orteronel (TAK-700)

Another pipeline prostate cancer drug is orteronel (TAK-700), an oral, nonsteroidal drug that selectively inhibits the activity of a specific enzyme (17,20 lyase) in both the testicles and adrenal glands. The 17,20 lyase enzyme plays a significant role in the production of precursor molecules for both male and female sex steroid hormones, which are made in the testicles and adrenal glands and can contribute to the progression of hormone-resistant prostate cancer.

As of early 2012, two Phase 3 trials were recruiting men with metastatic hormone-resistant prostate cancer to receive orteronel along with prednisone or prednisone with placebo. Previous Phase 1 and 2 studies had indicated that orteronel was associated with a reduction in PSA levels and in testosterone levels.

Read more in our Prostate Cancer Health Center.

Reference

Hussain M et al. Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): results from a phase II randomized discontinuation trial. Paper presented at: 2011 Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, IL. Abstract 4516