COMMENTARY

Prostate Cancer: A Treatment Renaissance

Johann S. de Bono, PhD, MSc

Disclosures

October 05, 2011

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Introductions

Hello. I am Johann Sebastian de Bono, Professor of Experimental Cancer Medicine at the Institute of Cancer Research and the Royal Marsden Hospital in London in the United Kingdom. I am a clinician scientist. I trained in Europe at the Cancer Therapy and Research Center and in the United States at the Institute for Drug Development in San Antonio. Welcome to Medscape Oncology Insights on Prostate Cancer.

Today, I will discuss some of the exciting and significant data on prostate cancer treatment presented at the 2011 European Multidisciplinary Cancer Congress, [a collaborative meeting of ESMO, the European Cancer Organization (ECCO), and the European Society for Therapeutic Radiology and Oncology (ESTRO)] here in Stockholm. This is truly a renaissance in the development of novel agents for treating advanced prostate cancer. Until 2010, only 2 treatments had a significant impact on overall survival in this disease. The first was therapy that resulted in androgen deprivation, a first-line treatment involved luteinizing-hormone releasing hormone (LHRH) analogues, either agonists or antagonists. The second treatment was docetaxel, given as a 1-hour infusion every 3 weeks.

4 Therapies That Improve Survival

Since 2010, we have had 4 new and very different therapeutic modalities that show an overall survival benefit in phase 3 trials. One is a hormone treatment called abiraterone acetate. The second treatment is a novel cytotoxic tubulin-binding drug -- cabazitaxel -- that may work on the androgen receptor and which in both preclinical and clinical studies clearly has antitumor activity in advanced prostate cancer that is resistant and even refractory to docetaxel. The third treatment that was presented at the Stockholm meeting and which generated much interest and excitement was the alpha-emitting radionuclide radium-223 (Alpharadin; Algeta ASA; Oslo, Norway). These data were presented for the first time at this meeting in Stockholm by my colleague from the Royal Marsden Hospital, Dr. Chris Parker. Finally, we have the dendritic cell infusion therapy, sipuleucel-T, from Dendreon (Seattle, Washington)

I will discuss these 4 different therapeutic modalities that have shown survival benefit. Before I do so, I would like to bring to your attention the increasing evidence and multiple publications from different centers, suggesting that the taxanes actually influence androgen receptor function, and in particular, cytoplasmic to nuclear movement inside the cell, by affecting tubulin and tubulin binding to the androgen receptor. This raises issues about cross-resistance between the taxanes and drugs such as abiraterone.

Abiraterone: Important Antitumor Activity

I will start with abiraterone. At the Royal Marsden Hospital, we have shown in early phase 1 and phase 2 studies[1,2] -- the findings of which are now confirmed by other international, collaborative phase 2 studies -- that this drug has important and significant antitumor activity, resulting in reductions in prostate-specific antigen, RECIST response with tumor shrinkage on scans, reductions in circulating tumor cell counts that we know are associated with survival benefit, and, importantly, symptomatic benefit for many patients by reducing pain and improving symptom control. These phase 2 data show that this drug has substantial activity in the settings of pre-chemotherapy before docetaxel and post-chemotherapy after docetaxel. Of note, the antitumor activity was more marked in the pre-docetaxel setting, in keeping with the concept of cross- resistance between the taxanes and abiraterone. In a large randomized phase 3 trial, which I spearheaded and published in The New England Journal of Medicine,[3] we have shown a significant overall survival benefit in patients treated with abiraterone compared with patients who received placebo, with patients in both arms receiving a low-dose steroid (prednisone or prednisolone, 5 mg twice daily).

At this meeting in Stockholm, we have seen further data from this trial,[4]particularly the second and final analysis for the survival data, which showed an increased survival benefit reaching almost 5 months for the treatment arm vs the control arm. Moreover, we heard data showing that abiraterone improves not only pain and quality of life but also fatigue in patients who received this drug compared with the placebo group.[5]Abiraterone is well tolerated, although it does have some toxicities. These minor and uncommon effects are related to the hypermineralocorticoid state associated with targeting and blocking CYP17, a key enzyme in steroidogenesis. So, abiraterone is now approved both in Europe and in the United States for treating advanced prostate cancer in the postchemotherapy setting. We await the results of the 302 abiraterone trial, which is looking at administering this drug in the prechemotherapy setting, but at present we are unable to recommend administration of this drug in prechemotherapy patients.

Cabazitaxel: Administer With Care

The second drug to show a significant survival benefit is cabazitaxel, a cytotoxic tubulin-binding drug. In the randomized phase 3 study (which I led and published in The Lancet[6] in October 2010) we have shown that cabazitaxel improves overall survival in patients who have previously been treated with docetaxel. Docetaxel-refractory and docetaxel-resistant patients also had a significant overall survival benefit, with more than two thirds of the patients in this trial falling into the category of docetaxel refractory (patients who progressed while on docetaxel) or docetaxel resistant (patients who progressed within 3 months of stopping docetaxel).

Cabazitaxel is associated with less neuropathy than many other tubulin-binding drugs, including ixabepilone and probably docetaxel. Cabazitaxel does, however, induce some myelosuppression, particularly neutropenia, although anemia was uncommon with this drug. It should be administered with care, with monitoring of the neutrophil count, particularly in the first 15 days following treatment, and the drug should be administered with growth factors or a reduced dose if significant neutropenia is seen. This drug should certainly be administered only in cancer centers or in practices where the treatment of neutropenic sepsis can be managed safely.

Radium-223 Targets Bone Metastases

The third drug is radium-223. Studies of this alpha emitter (phase 1 and randomized phase 2) have been previously published in the Clinical Cancer Research Journal[7] as well as more recently in Lancet Oncology[8] by Nilsson and associates. These studies have shown that this drug is very well tolerated with minimal myelosuppression, unlike previous radionuclides studied for treating this disease, such as samarium, strontium, and rhenium. The reason that radium-223 causes less myelosuppression is that alpha emission results in heavy particles that have a very short penetration distance. This radium nucleotide is in the same class in the periodic table as calcium. Osteoblasts in bone take up radium-223 to sites of active disease-induced bone turnover.

In detailed analysis of bone uptake of radium-223, evidence is clear that this is highly selective to areas of disease involvement. My colleague Dr. Parker, from the Royal Marsden Hospital, has shown that radium-223 improves overall survival, by almost 3 months, in patients with advanced prostate cancer.[9]This is the first time in a large randomized phase 3 trial that we have clear evidence that a radionuclide improves survival. This is now the third agent to improve survival for metastatic prostate cancer over the last 2 years. Radium-223 not only causes minimal myelosuppression but in fact is associated with minimal toxicity, as more adverse events were observed in the control arm than in the treatment arm.

Sipuleucel-T: Cancer Immunotherapy

Finally, I should mention the results of the trial of the dendritic cell infusion sipuleucel-T published by Kantoff and associates in The New England Journal of Medicine[10] about a year ago. In the prechemotherapy and postchemotherapy settings, this agent affects both B-cell and T-cell immune responses, as shown in several presentations at this meeting. These presentations showed significant changes in immune biomarker assays that were not influenced by previous docetaxel therapy. Sipuleucel-T improves survival by almost 5 months in late-stage advanced prostate cancer.

Closing Remarks

Further studies with these eagerly anticipated drugs -- sipuleucel-T, abiraterone, and radium-223 will evaluate them in earlier-stage, localized, high-risk disease to try to improve cure rates from this common and invariably lethal disease. Thank you for joining me in this edition of Medscape Oncology Insights. This is Professor Johann de Bono from the Royal Marsden Hospital in London.

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