Moving Forward in Hormone-Refractory Prostate Cancer: From Understanding Biology to Advancing Therapy

Prostate cancer is currently the leading cancer diagnosis for men in the United States and the second leading cause of male cancer-related death. The incidence of prostate cancer increases rapidly with age (from ~30% in men over age 50 years to 80% by age 80), and with increasing life expectancy and the long natural history of the disease, the numbers of men who are diagnosed with and die from prostate cancer will grow. In this succinct, comprehensive review, Drs. Ross and Kantoff link the biologic basis of the disease to advances in the field designed to overcome biologic mechanisms of resistance and progression.

Treatment Shortcomings

Prostate carcinogenesis is a multistep process, with precancerous cells progressing to cells that proliferate and eventually metastasize. The initial growth and development of prostate cancer is androgen-dependent, as illustrated by Huggins and Hodges, who demonstrated the therapeutic benefits of castration for control of metastatic prostate cancer in the 1940s. Suppression of androgens with orchiectomy or medical castration, often in combination with competitive androgen-receptor antagonists, remains the mainstay of initial therapy.

Although castration leads to a median progression-free survival of 12 to 18 months, progression of disease with increasing prostate-specific antigen (PSA) levels inevitably occurs even in the face of maximal androgen ablation. Antiandrogen withdrawal and third-line hormonal therapies such as corticosteroids, ketoconazole, or estrogen-based agents only achieve low response rates with little or no demonstrated survival benefit. No treatment thus far has been effective in reversing the sequence of events leading to the lethal hormone-refractory stage of prostate cancer.

Docetaxel-Based Therapy

The two randomized trials that supported the approval of docetaxel (Taxotere) for hormone-resistant prostate cancer (HRPC) treated a heterogeneous group of patients, approximately 30% of whom had symptomatic bone pain. Because of known toxicities, chemotherapy had traditionally been administered to those patients with symptomatic HRPC. The concept of the earlier use of chemotherapy in asymptomatic patients intuitively makes sense. For patients with early HRPC (ie, rising PSA in the face of castrate testosterone levels and no overt metastatic disease) who are asymptomatic, the toxicities of chemotherapy may not be warranted.

Unfortunately, a subgroup analysis of TAX 327 did not demonstrate any difference in the hazard ratios for survival. Nonetheless, biochemical recurrence following androgen ablation is a harbinger of clinical metastatic disease, and thus, such patients could greatly benefit from innovative therapeutic approaches that have minimal toxicity. Although preliminary results are promising, we await larger studies evaluating the use of vaccine therapies for use in early HRPC.

The proven survival benefit of docetaxel-based therapy provides a framework for the development of new combination regimens These new treatments are focused on improving survival while maintaining or improving toxicity. Crucial to the development of rational therapy for hormone-resistant prostate cancer is the fact the major phase III studies combine docetaxel with therapies targeted at different aspects of prostate cancer biology. Ongoing studies are combining docetaxel with targeted agents such as vascular endothelial growth factor (VEGF, in a Cancer and Leukemia Group B [CALGB] -trial); bone-targeted therapy with atrasentan (Xinlay, in a Southwest Oncology Group [SWOG] trial); and calcitriol (DN-101, in a pharma-sponsored trial). In contrast to the TAX 327 and SWOG 9916 studies, refined clinical prognostic models are being utilized to better stratify patients in these studies. Biologic approaches to identifying subsets of patients likely to respond to one treatment or another are still sorely needed.

Older Patients

Because prostate cancer patients tend to be elderly and are at risk for competing causes of morbidity and mortality, treatments that delay progression without significant toxicity would be of value in this subset of the population. Although elderly patients who are asymptomatic may benefit from a delay in chemotherapy initiation, age alone should not be prohibitive for therapy initiation in
older patients who are symptomatic from their cancer and are without significant comorbidity or disability. Although there are clearly several adverse prognostic factors for survival of patients with advanced HRPC, increasing age has not been consistently associated with worse outcomes. Therefore, rather than age, perhaps level of comorbidity or impairment in function should be used to help with decision-making for treatment.

Room for Improvement

Given the recognition of a survival benefit with chemotherapy, new therapies are now needed for patients whose disease progresses on docetaxel. As more patients are being treated with chemotherapy earlier in the disease process, many are still without significant objective tumor burdens even after chemotherapy. On the other hand, many patients have significant symptoms and poor quality of life due to cancer progression after docetaxel. There is currently no standard of care for these patients. The authors review a few therapies on the horizon, including epothilone analogs and the third-generation platinum analog satraplatin.

Although care for the HRPC patient has improved over the past few years with the advent of docetaxel, there is still much room for improvement. As the authors state, HRPC is indeed a heterogeneous and lethal disease. The importance of pharmacogenetics in defining patient subsets cannot be overstressed. Discoveries in the lab must be translated into direct patient care quickly and efficiently in order to benefit the tens of thousands of men who are currently suffering from HRPC.

—Supriya G. Mohile, MD, MS
—Daniel P. Petrylak, MD

Disclosures:

Dr. Petrylak has received research support from and is a consultant for Aventis, Celgene, Abbott, Dendreon, and Cell Genesys.