Prostate cancer is the most common non-cutaneous malignancy diagnosed in men and the second most common cause of cancer death after lung cancer in men in Ireland.¹ The backbone of therapy is androgen deprivation therapy. The duration of response varies, but the vast majority of men with prostate cancer eventually develop progressive disease. Reactivation of the disease despite castrate levels of testosterone represents a transition to castrate resistant prostate cancer (CRPC). The treatment of CRPC is evolving with a number of new and effective modalities becoming available. These include newer chemotherapy agents, immunotherapy, further hormonal manipulation and emerging targeted agents. 

Chemotherapy

Historically, chemotherapy was regarded as ineffective in CRPC. Response rates were low and median overall survival did not exceed 12 months. However, in recent times three agents have shown to have efficacy in CRPC.

The first chemotherapy agent to be approved for the treatment of CRPC was mitoxantrone. Its approval was based on a palliation effect, not on an increase in overall survival (OS). A trial randomly assigned 242 men with metastatic CRPC to mitoxantrone plus hydrocortisone or hydrocortisone alone. There was no difference in survival between the groups, but the PSA response and pain control were better in the mitoxantrone group.² Its use is limited today due to more effective agents, but it is still an option in selected cases. 

The standard chemotherapy in the first-line setting for patients with metastatic CRPC is docetaxel. In the landmark TAX-327 trial, 1,006 men with chemotherapy-naïve metastatic CRPC were randomly assigned to docetaxel (75mg/m² every three weeks); docetaxel (30mg/m² weekly); or mitoxantrone (12mg/m² every three weeks).³ All patients received prednisolone 5mg twice daily. The median OS (trial’s primary endpoint) was 18.9 months in the three-weekly docetaxel arm; 17.4 months in the weekly docetaxel arm; and 16.5 months in the mitoxantrone arm. The difference between the three-weekly docetaxel arm and the mitoxantrone arm was statistically significant and this benefit persisted after 3.5 years of additional follow-up. There was no significant difference in survival between weekly docetaxel and mitoxantrone arms. Therefore three-weekly docetaxel at 75mg/m² is currently the standard of care for men with metastatic CRPC in the first-line setting. The Irish Clinical Oncology Research Group (ICORG) participated in the ‘Prosty’ study that compared two-weekly docetaxel (50mg/m²) to three-weekly docetaxel (75mg/m²). The results showed similar OS but the two-weekly schedule was better tolerated with less grade 3/4 adverse effects.⁴ This is an acceptable regimen for standard care.

Another agent which has shown efficacy in patients who have progressed on docetaxel is cabazitaxel. This drug is a semi-synthetic taxane derivative. The TROPIC trial⁵ randomly assigned 755 men who had progressed on docetaxel to either cabazitaxel (25mg/m²) every three weeks or mitoxantrone (12mg/m²) every three weeks. Overall survival was superior in the cabazitaxel arm (15.1 months versus 12.7 months, [HR] 0.7 95% CI 0.59-0.83). Grade 3 or more neutropenia was seen in 82% and febrile neutropenia in 8% of patients in the cabazitaxel group. As a result GCSF prophylaxis is recommended with its use. Studies are underway to compare cabazitaxel and docetaxel as first-line therapy. 

Immunotherapy

Prostate cancer cells express tumour-associated antigens that can serve as targets for immunotherapy. Sipuleucel-T (Provenge) is an individualised therapeutic dendritic cell vaccine for men with metastatic CRPC. A course of sipuleucel-T treatment consists of three basic steps. A patient’s own white blood cells are extracted by leukapheresis. These cells are then pulsed with a fusion protein made from an immune-signalling factor GM-CF and the antigen prostatic acid phosphatase (PAP). The activated product is then reinfused into the patient to cause an immune response against the cancer cells carrying the PAP antigen. In two randomised phase III trials the primary endpoint was progression-free survival (PFS), which was not met. But the secondary endpoint of overall survival was improved.⁶

The IMPACT trial was a phase III, double-blind placebo controlled trial with OS as its primary endpoint. The study included 512 patients with metastatic CRPC who were asymptomatic or minimally symptomatic. Patients were randomised to sipuleucel-T or placebo. Overall survival was improved by 4.1 months in the sipuleucel-T arm (25.8 months versus 21.7 months [HR] 0.78).⁷ Again there was no difference seen in PFS or PSA response. Further trials are ongoing. The vaccine was approved by the FDA in the US in 2010, but is not available in Ireland at present. 

Abiraterone

The androgen pathway continues to play a significant role in the progression of CRPC. Abiraterone is an oral drug that irreversibly inhibits the product of the CYP17 gene (including both 17-20 lyase and 17-α-hydroxylase). It blocks the synthesis of androgens in the tumour as well as the adrenal gland and testis. The efficacy of abiraterone in metastatic CRPC was established in the COU-AA-301 trial.⁸ This phase III trial randomly assigned 1,195 men with CRPC who had progressed on docetaxel chemotherapy in a 2:1 ratio to abiraterone versus placebo. The primary endpoint was OS. 

The trial was terminated based on an interim analysis, which showed improved OS in the abiraterone arm (14.8 months versus 10.9 months [HR] 0.65 p < 0.001).⁸ In addition, several secondary endpoints were also significantly better in the abiraterone arm including PFS (5.6 versus 3.6 months); PSA response (29% versus 6%); and time to first skeletal event (301 versus 150 days). Based on this trial abiraterone was approved by the European Medicines Agency in September 2011, but is currently not available in Ireland. ICORG sites have, however, been able to access this agent for a time on an expanded access basis. Abiraterone is also being investigated in the first-line setting of CRPC (COU-AA-302 trial) and early phase data are encouraging for the use of abiraterone before docetaxel and in earlier hormone-sensitive disease.

Enzalutamide

The recent publication of the AFFIRM trial⁹ has shown enzalutamide to be another drug that is effective in CRPC post-failure of docetaxel chemotherapy. Enzalutamide is an androgen receptor signalling inhibitor. It inhibits nuclear translocation of the androgen receptor, DNA binding and co-activator recruitment.⁹ The AFFIRM study was a phase III randomised double-blind placebo controlled trial. All patients had metastatic CRPC and previous docetaxel chemotherapy. In the trial, 1,199 patients were randomly assigned in 2:1 ratio to enzalutamide 160mg daily versus placebo. The primary endpoint was OS. The study was stopped after a planned interim analysis. The median OS was 18.4 months versus 13.6 months in the placebo group (HR 0.63, 95% CI 0.53-0.75 p < 0.001). 

All secondary endpoints, including reduction in PSA level 50% or more, response rate and quality of life response, were superior in the enzalutamide arm. The drug appears to be well tolerated. It shows promise and is likely to be an addition to the arsenal against CRPC. It is also under investigation in the PREVAIL trial, looking at enzalutamide in the chemotherapy-naïve population with CRPC (NCT01212991). It is available for suitable Irish patients on an expanded access basis, after failure of docetaxel.

Emerging agents

Abnormalities in growth factor-signalling pathways that control cell cycle and apoptosis are seen in prostate cancer. Drugs targeting these pathways may prove beneficial. Cabozantinib is an oral small molecule inhibitor of multiple kinase signalling pathways including c-MET, VEGFR2 and RET. Results from a phase II randomised discontinuation trial involving 171 patients were promising.¹⁰

In this trial, after 12 weeks of treatment patients with a partial response continued open-label cabozantinib. Those with stable disease were blindly randomised to cabozantinib versus placebo; and those who progressed were taken off protocol. Results showed that 74% of patients had evidence of tumour regression. PFS was significantly longer compared to placebo (21 versus six weeks). Improvement in bone pain was seen in 67% of patients.¹⁰

Based on these results two phase III trials are under way in patients who have had previous treatment including docetaxel and either abiraterone and/or enzalutamide. The first trial (NCT01522443) has mitoxantrone/prednisolone as the control arm with relief of bone pain as the primary endpoint. A second trial (NCT01665227) comparing cabozantinib versus prednisolone had an overall survival as the primary endpoint. The COMET study will shortly open for Irish patients with bone-dominant disease. It should be an option for suitable patients with limited access to other effective agents.

Another tyrosine kinase inhibitor under investigation in CRPC is dasatinib. This is an Src family/abl inhibitor with pre-clinical activity in prostate cancer. Two phase II studies showed the drug to be active.^11,12 A phase III trial in men with CRPC is closed to accrual, in which patients are randomly assigned to docetaxel plus dasatinib versus docetaxel plus placebo (NCT00744497); results are imminent. ICORG sites recruited strongly to this trial. 

Conclusion

Chemotherapy with docetaxel is still the standard of care in the first-line setting for patients with CRPC. But when patients progress on docetaxel there are now a number of newer agents with activity that offer a survival advantage. Chemotherapy, immunotherapy and further hormonal manipulation all show promise in a disease that until recently had no meaningful treatment option after docetaxel-based therapy. Currently in Ireland two of these agents (abiraterone and cabazitaxel) have not been approved for reimbursement, but are under review with a hope of being made available in the not-too-distant future. The newer agent enzalutamide, which very recently was shown to offer a survival advantage, shows great promise. The results from early trials involving tyrosine-kinase inhibitors (TKIs; cabozantinib and dasatinib) are interesting and we await the outcome of the larger phase III trials to see if these results can be reproduced. 

Many of these drugs are being investigated in earlier stages of prostate cancer. Access to clinical trials at an ICORG site should be encouraged. Drugs available against CRPC are increasing at a rate never experienced before in this condition. This can only prove to be beneficial to the many men who are diagnosed with the disease each year. 

References 

1. www.ncri.ie/pub/pubfiles/Annualreport2011.pdf.
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