In the past year, three treatment modalities have been shown to improve survival in men with metastatic CRPC: cabazitaxel, abiraterone and sipuleucel-T. However, the rapid emergence of effective drugs for patients with CRPC has also resulted in some uncertainly about the optimal sequencing (or combination) of these agents. shows one plausible algorithm for the management of men with metastatic CRPC, although other treatment paradigms (including those recommended by the National Comprehensive Cancer Network)83
may also be reasonable.
Proposed treatment paradigm for metastatic castration-resistant prostate cancer (mCRPC). Note: *Patients with small-cell (and possibly neuroendocrine) carcinoma.
Understanding the natural history of the disease in this post-docetaxel state may help facilitate treatment decisions, and may also provide important prognostic information. To this end, we have previously developed a multivariate prognostic model for men who had progressed following docetaxel chemotherapy, which showed a reasonable predictive accuracy for overall survival after accounting for several important prognostic factors.139
These included traditional prognostic parameters such as performance status and the presence of significant pain, the number of metastatic sites, alkaline phosphatase levels, degree of anemia and the presence/absence of liver metastases. However, we also identified novel prognostic factors that became important in this disease state, including time from original diagnosis (a measure of disease aggressiveness), how progression occurred (on docetaxel or following completion of a planned course), what type of progression was present (pain, radiographic or PSA progression) and the number of docetaxel cycles that a man had received (a measure of progression-free survival with previous docetaxel). Using this nomogram, median overall survival was found to range from 5 to 50 months,139
providing vital prognostic information with reasonable accuracy. Although this model may not directly aid a practitioner in deciding which treatment to use following docetaxel, it may provide useful information on prognosis to help better gauge treatment goals and how to individually tailor either aggressive or palliative therapies to these men.
In our view, sipuleucel-T is most appropriate for patients with asymptomatic to minimally symptomatic bone- or lymph node-metastatic CRPC who have not yet received cytotoxic chemotherapy, although select men may be able to receive this therapy during a prolonged chemotherapy holiday. Abiraterone with prednisone would also be a reasonable choice in this setting, although the results of the COU-AA-302 trial are still awaited, and there is some concern about the use of immunosuppressive corticosteroids early in the disease course, particularly concurrently with immunologic therapies such as sipuleucel-T. Ketoconazole and hydrocortisone (with or without dutasteride) would be an alternative to abiraterone. In patients with symptomatic disease or visceral metastases, or in those who have rapidly progressive disease at imminent risk of symptoms, chemotherapy should be initiated sooner rather than later, and docetaxel with prednisone is the preferred first choice. In men who may not be able to tolerate docetaxel, mitoxantrone may be used, especially in those with bone pain in whom a palliative benefit might be achieved. Alternatively, a platinum-etoposide doublet may be beneficial and palliative for men with metastatic prostatic small cell (or neuroendocrine) carcinoma. In docetaxel-pretreated patients, best evidence supports the use of cabazitaxel or abiraterone (once approved) each given with prednisone, whereas mitoxantrone may be reasonable in men at high risk of neutropenic complications or in those with significant peripheral neuropathy or taxane intolerance. Docetaxel retreatment may also be appropriate, especially in patients with a good initial response to docetaxel and subsequent discontinuation for reasons other than disease progression. Finally, in patients with multiply chemotherapy-refractory disease, treatment with abiraterone may be entertained but, in the absence of life-prolonging therapies in this setting, clinical trial participation should be encouraged in patients with good performance status.
In addition to the above approaches, the use of bone-health-promoting agents such as denosumab or zole-dronate should be strongly considered for men with bone metastatic disease to prevent pathological fractures, spinal cord compression or the need for radiation or surgery for skeletal complications. Palliative radiation or radiopharmaceuticals (for example, samarium, strontium or investigational radium) also have a significant role in the approach to men with symptomatic disease, both before or after systemic therapies. Several additional active agents are currently in phase III development (see the second review in this series), and some of these therapies are also likely to further expand the treatment options for men with metastatic CRPC in the near future.
In summary, cabazitaxel is the first agent to be approved by the FDA for use in men with metastatic CRPC who have progressed after previous docetaxel chemotherapy, and abiraterone acetate is also anticipated to gain FDA approval in this same patient population. In addition, sipuleucel-T may be beneficial in selected docetaxel-pretreated patients, so long as they remain minimally or asymptomatic and do not have visceral (especially hepatic) metastases. Clinical trial participation remains another excellent option for docetaxelrefractory patients.