BERKELEY, CA (UroToday.com) - For men with metastatic castrate-resistant prostate cancer (mCRPC), the prognosis is often poor and death typically occurs within 24 to 48 months after the onset of castration resistance.
For these men who have not undergone chemotherapy, there are a few treatment options available in the form of second-line hormonal manipulations. Many patients get a response to this treatment but none of these treatments have shown to delay progression of the disease or prolong life. After this second-line therapy, docetaxel chemotherapy is available and it has shown survival benefits. However, many patients with mCRPC never receive chemotherapy and the limited use is either by patient choice or physician choice, due to the toxicity of the treatment. Therefore, there is an unmet need for an effective treatment that delays or prevents the landmark events associated with deterioration of overall health and worsening symptoms in these men with mCRPC.
Just in recent years, there has been a development in the treatment options for these patients and a few new products have been approved with promising results. One is an immunotherapy with sipuleucel-T (Provenge®) and it has shown a modest survival benefit but no effect on tumor regression, delay on disease progression, or symptom relief.
As demonstrated in a previous study (COU-AA-301), abiraterone acetate (AA) 1 000 mg once daily plus prednisone 5 mg twice daily improve overall survival in patients with mCRPC who have received prior chemotherapy with docetaxel. For this indication, AA plus prednisone received FDA approval in April 2011. The next step was to evaluate this treatment with AA plus prednisone in patients who had not received previous chemotherapy. Earlier phase I and phase II studies in this group of chemo-naïve patients have shown promising results with a high proportion of durable responses, suggesting that the treatment benefits of AA plus prednisone might be optimal in this group of patients.
In this phase III study (COU-AA-302), AA plus prednisone was compared to placebo plus prednisone in patients with mCRPC who were chemo naïve. The total number of patients randomized was 1 088, with 546 randomized to receive AA 1 000 mg once daily plus 5 mg prednisone twice daily, and 542 randomized to receive placebo once daily plus 5 mg prednisone twice daily. As in the previous study, the medication was administered as four 250mg tablets in the AA group and four placebo tablets in the placebo group, once daily at least one hour before a meal and two hours after a meal. All patients received 5 mg prednisone orally twice daily.
The co-primary efficacy endpoints were radiographic progression-free survival (rPFS) and overall survival. One reason for the co-primary endpoint was that many of these patients have an expected survival that can be fairly long, and, therefore, measuring only overall survival as an endpoint can be quite complicated. One other note is that changes in PSA level were not included in the definition of rPFS in this study.
The pre-specified secondary endpoints were: time to opiate use for cancer pain, time to initiation of chemotherapy, time to a decline in ECOG performance status, and time to PSA progression (PCWG2 criteria).
For the co-primary endpoint of rPFS, a single analysis was planned based on the review by a central radiologist after 378 progression-free events. Subsequent analyses of this endpoint were reported based on investigator assessment. For the co-primary endpoint of overall survival, three interim analyses were planned. The first one was planned after 15% of the required 773 events were observed, and this was supposed to be in conjunction with the independent review of the rPFS. The second interim analysis was planned after 40% of the events and the third after 55% of the events had occurred. A final analysis was planned for when all 773 events had occurred.
The first interim analysis (December 20, 2010) showed a 57% reduction in the risk of radiographic progression or death for the patients in the AA group, based on the blinded central radiologic review. For the AA group, median was not reached vs. median of 8.3 months in the placebo group (HR=0.43; 95% CI; 0.35 to 0.52; p < 0.001). At the time of the second interim analysis (December 20, 2011), median time to rPFS based on investigator assessment was 16.5 months in the AA group and 8.3 months in the placebo group (HR=0.53; 95% CI; 0.45 to 0.62; p < 0.001). The treatment effect of AA on rPFS was consistently favorable across all pre-specified groups (all HR < 1.0).
As far as overall survival, a planned interim analysis was performed after 43% of the required 773 events had occurred. More deaths were observed in the placebo group compared with the AA group, 34% vs. 27%. Median overall survival was not reached for the AA group while it was 27.2 months for the placebo group. There was a 25% decrease in the risk of death in the AA group compared with the placebo group (HR=0.75; 95% CI; 0.61 to 0.93; p=0.01). This indicates a strong trend toward improved overall survival but the significance (p>0.001) was not reached at the observed number of events. The treatment effect of AA on overall survival was consistently favorable across all pre-specified groups (all HR < 1.0). At this point (February 2012), the independent data and safety-monitoring committee recommended the study be unblinded. There will be further analysis of overall survival as the study goes on and at that point, the true statistical difference between the two groups will be known.
All the secondary endpoints confirmed the superiority of AA compared with placebo. This included time to decline in ECOG performance score, 12.3 months vs. 10.9 months (HR=0.82; 95% CI; 0.71 to 0.94; p=0.005), an 18% reduction in risk. Median time to initiation of chemotherapy was 25.2 months vs. 16.8 months (HR=0.58; 95% CI; 0.49 to 0.69; p < 0.001), a 42% reduction in risk. Time to opiate use for cancer pain showed a significant delay for the AA group, median time was not reached vs. 23.7 months in the placebo group (HR=0.69; 95% CI; 0.57 to 0.83; p < 0.001). Median time to PSA progression was 11.1 months vs. 5.6 months (HR=49; 95% CI; 0.42 to 0.57; p < 0.001), a 51% reduction in risk.
In summary, this shows that the patients can live longer without disease progression, can live longer without symptoms, can live longer until performance status deteriorates, can live longer until receiving chemotherapy, can live longer until starting opiates for pain, and probably live longer overall.
The most common adverse events were fatigue (AA 39% vs. P 34%), back pain (32% for both), arthralgia (28% vs. 24%), nausea (22% for both), and constipation (23% vs. 19%). Patients in the AA group experienced more mineralocorticoid-related adverse events than patients in the placebo group due to blocking of CYP17. However, when taking low-dose prednisone, the mineralocorticoid excess is reduced. Most frequent were fluid retention and edema (28% vs. 24%), hypertension (22% vs. 13%), and hypokalemia (17% vs. 13%). Cardiac events occurred at a similar rate in both groups (19% vs. 16%). Liver-function test abnormalities also occurred at a similar rate in both groups (8% vs. 3%). Serious adverse events were reported in 33% vs. 26% and adverse events resulting in treatment discontinuation occurred with similar frequency in both groups (10% vs. 9%). Adverse events resulting in death also occurred with similar frequency in both groups (4% vs. 2%).
In summary, this study demonstrated benefit from the use of AA in patients with asymptomatic or mildly symptomatic mCRPC who are chemo naïve. These findings include a prolonged rPFS and a strong trend for overall survival in this patient population, as well as clinically meaningful secondary endpoints, such as extended time until use of opiates for pain, until treatment with chemotherapy, and until a decline in performance status plus delays in PSA progression, onset of pain, and decline in health-related quality of life. As a result, abiraterone acetate was approved by the FDA on December 10, 2012 for the treatment of mCRPC patients prior to receiving chemotherapy.
This shows that abiraterone acetate (brand name ZYTIGA®) is a well-tolerated, oral therapy that delays progression, improves survival, and helps to maintain the general well-being in men with mCRPC.
Charles J. Ryan, et al. (for the COU-AA-302 Investigators). Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy. N Engl J Med. 2013; 368:138-48 doi: 10.1056/NEJMoa1209096
Johann S. de Bono, et al. (for the COU-AA-301 Investigators). Abiraterone and Increased Survival in Metastatic Prostate Cancer. N Engl J Med. 2011; 364:1995-2005 doi: 10.1056/NEJMoa1014618
Written by Anna Forsberg, medical director for UroToday.com. Anna received a BSc in zoology from Louisiana State University, and a BSc in biomedicine and MSc in clinical drug development from Uppsala University in Sweden. She has worked almost 20 years in the global pharmaceutical and medical device world, involved with clinical research management and as a Medical Science Liaison (MSL) before joining UroToday as Medical Director. Her focus in clinical research and as a MSL has mainly been in the fields of urology and oncology.