The article by Ruch and Hussain provides a comprehensive overview of the progress that has been made in translating basic science findings in prostate cancer biology to clinical trials. Targets that have been identified as having the potential to improve survival in patients with castration-resistant prostate cancer stem from research in angiogenesis, bone metabolism, immunotherapy, androgen metabolism and receptor regulation, and apoptosis. Some of the approaches incorporating these targets have already translated to measurable clinical benefit: sipuleucel-T (Provenge) and cabazitaxel (Jevtana) have demonstrated improvements in median survival of 4.1 and 2.4 months, respectively, in different populations of men with castration-resistant disease.[1,2] Advances have also been made in supportive care: denosumab (XGEVA) demonstrated improvement in skeletal-related events in patients with castration-resistant prostate cancer compared to the standard of care, zoledronic acid (Zometa). On April 28, 2011, abiraterone, a 17,20 lyase inhibitor that can induce the near total abrogation of testosterone, was approved for patients with chemoresistant disease. In addition to these agents, several new drugs, targeting angiogenesis (aflibercept, lenalidamide [Revlimid]), the bone matrix (atrasentan [Xinlay], zibotentan, dasatinib [Sprycel]), the androgen axis (TAK-700 and MDV3100), and apoptosis (custirsen) are in phase III clinical trials that either are currently accruing patients or have completed accrual. Thus, after a seven-year drought following the approval of docetaxel (Taxotere)/prednisone, we are experiencing a windfall in new treatments for a disease that only ten years ago was considered untreatable.
The authors conclude that identification of new targets creates the opportunity for greater personalization of therapy. However, while our knowledge of biology has enabled us to design more specific treatments, patients are still entered in phase III trials based on clinical rather than molecular parameters. Clinical trial design, and eventually clinical practice, needs to focus on using biological phenotype rather than symptoms or number of prior chemotherapeutic regimens as the basis for selecting the proper treatment for a patient. Achievement of this goal is difficult because of problems in performing correlative studies. The predominance of patients with metastatic disease in bone has made it difficult to acquire sufficient tissue to perform correlative studies. Circulating tumor cells may circumvent the problem of tissue acquisition, but the validity of using these cells to determine the molecular phenotype remains to be demonstrated.
New imaging studies using positron emission tomography (PET) along with novel tracers such as F-18 choline, 2-[18F]-fluoro-2-deoxy-D-glucose, and [18F]-dihydrotestosterone also are demonstrating promise as imaging agents in bone. However, these will require prospective evaluation in phase 3 studies before being adopted for general use as a measure of treatment efficacy. Since the current gold standard for approval of drugs in castration-resistant prostate cancer is based on overall survival, prospective evaluation of these types of markers as a surrogate for survival is clearly needed, particularly with the plethora of new agents.
The dilemma in treatment selection is best exemplified in the treatment of patients in whom prior chemotherapy has failed. Cabazitaxel, a semi-synthetic taxoid, has been approved for use as a second-line chemotherapeutic agent in patients whose disease has progressed on docetaxel-based therapy. It has been postulated that the activity of cabazitaxel is due to the fact that it is not a substrate for P-glycoprotein, which is responsible for multi-drug resistance. A survival benefit of 2.4 months was seen in patients treated with cabazitaxel/prednisone compared with mitoxantrone/prednisone. The combination of abiraterone and prednisone improves survival by 3.9 months compared with prednisone alone in men who have failed no more than two chemotherapeutic regimens for castration-resistant prostate cancer. The putative mechanism of action of abiraterone is its ability to abrogate the low intracellular levels of androgen can that can activate the androgen receptor, thereby providing the impetus for castration-resistant growth. Although taxanes may interfere with the translocation of the androgen receptor across the nucleus, both abiraterone and cabazitaxel probably are acting by different mechanisms. With both drugs potentially available, selection of the appropriate treatment is difficult in the absence of direct comparison in randomized trials or biological markers that can determine which patients are more likely to respond to a given drug. Since there is no clear way to determine the likelihood of response, drug selection will most likely be made based on the route of administration and tolerability.
Another problem that has developed in sequencing novel drugs, particularly those that target the immune system, is a disconnect between improvements in overall survival and progression-free survival. Sipuleucel-T is approved for patients with asymptomatic or minimally symptomatic castration-resistant disease. Although an improvement in median survival of approximately 4 months has been seen with sipuleucel-T, there has been no significant improvement in progression-free survival. A similar pattern has been observed in patients treated with PROSTVAC, a PSA-directed vaccine. Because progression has driven changes in treatment in the past, this has proved a perplexing dilemma for both the design of clinical trials and patient care. The dilemma is complicated by the fact that corticosteroids, a necessary component of chemotherapy and some new hormonal therapies, abrogates the effect of immunotherapy. Clearly, a biological marker that could be used to select patients for immune therapy, or that signals that it is safe to observe a patient through biochemical progression treatment, would be extremely helpful in managing patients’ treatment sequences.
Significant progress has been made over the past 20 years in the treatment of prostate cancer, and with these new agents we expect to be able to further extend the survival of patients with castration-resistant disease. Reviews of single-agent chemotherapy treatment in this patient population in the 1990s demonstrated survivals of 12 months. We now routinely expect survivals of between 23 and 30 months from the first initiation of therapy. Although this improvement may be due in part to stage migration, a clear impact has been made. Biologically driven therapy, improved patient selection, and novel agents will hopefully extend survival even further.
Financial Disclosure: The author has served on advisory boards or as a consultant for Amgen, Novartis Otsuka, Egenix (where he is Chair of the Scientific Advisory Board), Bellicum, Ferring, AstraZeneca, Johnson and Johnson, Dendreon, and Millineum; has received research support from Progenics, Celgene, sanofi-aventis, Dendreon, Pfizer, GlaxoSmithKline, Boehringer Ingelheim, Medivation, Esai, Abbott, and Johnson and Johnson; and is a Board Member of the Prostate Cancer Education Council.
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2. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomized open-label trial. Lancet. 2010;376:1147-54.
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