Current Therapy For Castration Resistant Prostate Cancer Biology Essay

One in seven Canadian men are diagnosed with prostate cancer which leads to the most common cancer in men. Prostate cancer proliferates in the presence of androgens mainly testosterone. For these tumours, blockade of androgens typically inhibits tumour growth. Treatments typically include hormonal manipulation to remove or reduce androgens in the system. This may involve orchiectomy, antiandrogens (flutamide, bicalutamide), luteinizing-releasing hormone antagonists (leuprolide), and androgen synthesis inhibition (ketoconazole, progesterone). However, in advanced stages of prostate cancer, cells are able to survive and proliferate without signalling from androgens and are no longer sensitive to androgen blockade resulting in resistance to therapy. Originally, this type of condition was known as hormone-resistant prostate cancer or androgen sensitive prostate cancer, however it is now known as castration resistant prostate cancer due to the fact that prostate cancer proliferation was in part due to overexpression of the androgen receptor. Enzalutamide is an androgen-receptor signalling inhibitor and was chosen as an agent to combat against CRPC on the basis that it has high activity towards overexpression of androgen receptors.

Castration resistant prostate cancer (CRPC) may be defined as a progression of disease despite the use of androgen depletion therapy. It may be presented as a rise in prostate serum antigen (PSA), progression of the disease, and the presence of metastases.

Current Guidelines on CRPC

Based on the Canadian Urological Association guidelines, the first line therapy for CRPC involves a second attempt at hormonal treatment. Currently there is no evidence on the survival benefit of secondary hormonal treatment, however the studies done in this area have been small and confounded. Typically patients are treated with luteinizing-releasing hormone agonist as monotherapy or those with orchidectomy a total androgen blocker (eg. bicalutamide) may be used. These treatments may offer PSA reduction in about 30-35%. Corticosteroid therapy is also offered with low dose prednisone or dexamethasone to help improve PSA and palliative outcomes in 30% of men. Steroids also may have anti-neoplastic effects on CRPC.

In patients with advanced prostate cancer with metastatic disease is generally considered a candidate for chemotherapy. Docetaxel and prednisone combination is the current standard of care for CRPC based on two large randomized controlled trials compared to the traditionally used mitoxantrone and prednisone. Docetaxel had improved survival over mitoxantrone when given with prednisone. Therefore, current second line chemotherapy when docetaxel has failed is mitoxantrone, but this agent has limited activity and increased toxicity in CRPC patients. Therefore treatment algorithms in the Canadian Urological Association guidelines suggests clinical trials in situations where docetaxel has had no response and failed as treatment.

Mechanism of Enzalutamide in CRPC

As mentioned earlier, enzalutamide (MDV3100) is an androgen receptor antagonist, however it possesses the unique ability compared to current androgen antagonists that it inhibits nuclear translocation of the androgen receptor, DNA binding, and coactivator recruitment. It also has greater affinity for androgen receptors without any agonistic activity.

AFFIRM trial

A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100 (AFFIRM) was an international phase 3, randomized, double-blinded, placebo-controlled study that evaluated the use of enzalutamide in patients with castrate resistant prostate cancer who have been previously treated with one or two chemotherapy regimens, with at least one that contained docetaxel. The primary endpoint was to determine overall survival defined as time from randomization to death of any cause. Secondary endpoints measured response (PSA level, soft tissue, and quality-of-life score (based on the FACT-P questionnaire) ) and progression (time to PSA progression, radiographic progression-free trial, and time to first skeletal-related event).

This study enrolled 1199 patients which were randomly assigned in a 2:1 ratio to receive enzalutamide (800 patients) 160 mg orally once daily or placebo (399 patients). The study was halted after planned interim analysis with 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) and 13.6 months (95% CI, 11.3 - 15.8) for enzalutamide and placebo respectively. Hazard ratio for death was 0.63 (95% CI, 0.53 - 0.75; P< 0.001). Secondary endpoints were in favour of enzalutamide with all aspects which include patients with a reduction in PSA level (54% vs. 2%, P< 0.001), soft tissue response rate (29% vs. 4%, P< 0.001), quality-of-life response rate (43% vs. 18%, P< 0.001), time to PSA progression (8.3 vs 3.0 months; hazard ratio 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and time for the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). The authors of this study conclude that enzalutamide was able to significantly prolong survival in metastatic castrate resistant prostate cancer after chemotherapy with docetaxel use.

This study was important in determining new therapies after failure of docetaxel in CRPC. This study lead to the approval by the US Federal and Drug Administration (FDA) for its use in men with late-stage or metastatic CPRA despite medical or surgical intervention to minimize testosterone. Although there is strong evidence for its use, there are considerations to take with this study. AFFIRM was stopped on an interim analysis and was not carried to completion which would have inflated the mortality benefits of enzalutamide.

Side Effects of Enzalutamide

Enzalutamide is generally well tolerated. The AFFIRM trial reported the most common side effects (>5%) were fatigue, diarrhea, muscloskeletal pain, and headache. Other more serious common side effects include hypertension, spinal cord compression, and upper/lower respiratory infections. Seizures were reported in 0.6% of patients. Enzalutamide is a strong inducer of CYP3A4 and moderate inducer of CYP2C9 and CYP2C19 and is metabolised by CYP2C8 and CYP3A4. Precautions should be taken if enzalutamide or other medications interact with these enzymes.

Future use and other available treatments

There are two other agents that have the indication for CRPC which was approved while the AFFIRM trial was in process. These agents are cabazitaxel and abieraterone both in combination with prednisone. The benefits of enzalutamide is its use as monotherapy without the need of prednisone. Over time, with the availability of this agent, other factors such as patient appropriateness and cost-effectiveness will be factors in choosing the right medications for the patient.

Conclusion

Although this agent is not available in Canada to date, this may be a suitable option for patients that have metastatic CRPC that have failed docetaxel therapy and other treatment options are not appropriate. More studies high quality studies may have to be completed to determine its efficacy and safety, however currently seems like a viable option to look out for in the future.

As pharmacists, it is important to know available treatments to be used in specific settings in oncology. Having knowledge of a new medication for specific indications allows for optimizing patient treatment regimens to improve patient care.