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New Directions in Castration-resistant Prostate Cancer Management

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 47th Annual Meeting of the American Society of Clinical Oncology (ASCO)

Chicago, Illinois / June 3-7, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Québec

Data from 5 phase III studies for the treatment of castration-resistant prostate cancer (CRPC) were presented during the 2011 ASCO annual meeting. Some evaluated sunitinib, risedronate and estramustine and 1 was a secondary analysis from the recently published COU-AA-301 trial with the androgen biosynthesis inhibitor abiraterone acetate (de Bono et al. N Engl J Med 2011;364:1995-2005). This diversity of approach captures differences in therapeutic targets when the goal is both improved survival and quality of life.

“In advanced-stage CRPC, there has been a lot of debate about whether we should target the cancer, target the bone or target both. In this disease, benefit can be judged by survival, by the way the patient feels or by the way the patient functions. The latest data with androgen deprivation suggest you can have your cake and eat it, too,” stated Dr. Michael J. Morris, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center (MSKCC), New York City. An ASCO-designated discussant who addressed the clinical relevance of several of the new studies, Dr. Morris indicated that the latest data on bone pain from the COU-AA-301 is critical to patient care “because bone metastases in this population are the primary cause of suffering and death.”

In the COU-AA-301 study, 1195 patients with metastatic CRPC and previous treatment with docetaxel were randomized in a 2:1 ratio to abiraterone 1000 mg or placebo. All received prednisone 5 mg. After a median follow-up of 12.8 months, the androgen biosynthesis inhibitor, which provides profound androgen blockade, was associated with a 35% improvement in survival benefit (14.8 vs. 10.9 months, HR 0.65; 95% CI, 0.54-0.77; P<0.001). It was also superior to placebo for every secondary end point, including progression-free survival (PFS) (5.6 vs. 3.6 months; P<0.001), prostate-specific antigen (PSA) response rate (29% vs. 6%; P<0.001) and time to PSA progression (10.2 vs. 6.6 months; P<0.001).

COU-AA-301 Secondary Analysis

A newly reported secondary analysis at ASCO may be even more significant from the patient’s perspective. In those randomized to abiraterone, the time to skeletal-related events (SRE) was doubled (301 vs. 150 days; P<0.0006). Consistent with the benefit on SRE, defined as pathologic fracture, spinal cord compression, or palliative radiation or bone surgery, fewer patients on abiraterone had progression of pain intensity vs. placebo at 6 months (22% vs. 28%), 12 months (30% vs. 38%) and 18 months (35% vs. 46%).

While the major conclusion of the COU-AA-301 study was that inhibition of androgen biosynthesis prolongs survival, the newly derived data from that study demonstrate that “inhibition of intracrine testosterone production is the foundation for bone-targeted therapy,” reported Dr. Christopher J. Logothetis, Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston, Texas.

In this secondary analysis of the COU-AA-301 study, data were available for 797 patients randomized to abiraterone and 398 patients randomized to placebo. In addition to SRE, fewer patients on abiraterone had pain progression, whether measured as palliation/progression of intensity (P-INT) (P=0.0002) or pain interference (P-INF) (P=0.0004). Consistent with the doubling of time to SRE, the androgen biosynthesis inhibitor reduced the median time to pain palliation by almost 50% (169 vs. 312 days; P=0.001).

“The cumulative proportion of patients with an improvement in pain from baseline was consistently in favour of abiraterone, which included both faster and better pain relief,” Dr. Logothetis reported. He suggested that pain relief occuring with protection from SRE provides an important confirmation of the clinical utility of this agent. While the benefits on bone were attributed solely to androgen deprivation, Dr. Logothetis did not rule out further benefit with adjunctive therapy directed at bone production.

Phase III Trials in CRPC

However, a phase III trial testing the benefit of the third-generation bisphosphonate risedronate in combination with docetaxel indicated that benefits are not significant in a first-line regimen when combined with docetaxel. In this study, 592 men with previously untreated CRPC and bone metastases were treated with docetaxel 75 mg.m2 q3 weeks plus prednisone 5 mg. They were randomized to receive risedronate 30 mg q.d. or no bisphosphonate. There was no significant difference after a median of 37 months of follow-up in overall survival (OS) (19.7 vs. 18 months; P=0.6) or PSA response rates (64% vs. 63%), but there was also no benefit in regard to pain response, according to Dr. Hielke J. Meulenbeld, Department of Medical Oncology, Erasmus University, Rotterdam, The Netherlands.

“These results were disappointing because there is some experimental evidence of synergy between bisphosphonates and taxanes, but we found no benefit of adding risedronate to docetaxel in this population,” Dr. Meulenbeld told delegates.

Adding estramustine to docetaxel in another phase III study of CRPC did provide a signal of benefit, but the study did not meet its end point of improved PFS. In that study, which was conducted in 413 patients with localized CRPC, patients were randomized to goserelin 10.8 mg q3 months alone or to the same dose of goserelin plus 4 cycles of docetaxel 70 mg/m2 q3 weeks plus estramustine 10 mg/kg/day for the first 5 days of the cycle. With a median follow-up of 4.6 years, the PFS rates were 81% for goserelin alone vs. 85% for the combination including estramustine (P=0.26).

“We did see a significant improvement in the PSA response rate [34% vs. 15%; P<0.0001] and the addition of estramustine was well tolerated, but we have not seen a difference in the primary end point in follow-up to date,” reported Dr. Karim Fizazi, Institut Gustave Roussy, Villejuif, France, here at ASCO. Although the event rates in both arms were lower than anticipated, the benefit, if any, from the addition of estramustine appears to be modest.

A third phase III trial tested the tyrosine kinase inhibitor (TKI) sunitinib in combination with prednisone vs. prednisone alone in metastatic CRPC patients previously treated with docetaxel. The randomization was performed in a 2:1 ratio to sunitinib 37.5 mg or placebo. All patients received prednisone 5 mg. Although 873 men were randomized, the study was stopped at the second interim analysis for lack of efficacy. Although there was a significant improvement in PFS among those randomized to sunitinib (5.6 vs. 3.7 months; P=0.0077), the primary end point was survival, and the interim analysis projected no benefit. At the time that the study was closed, median OS was 13.1 months on sunitinib vs. 12.8 months on prednisone alone (P=0.518). Although there were more discontinuations for lack of efficacy in the prednisone-only arm (41% vs. 28%), there were more discontinuations for adverse events (21.4% vs. 5.9%) in the TKI arm.

“Based on the improvement in PFS rates, we are going back to the data to look for subpopulations who might benefit from sunitinib, but this agent was found to have limited efficacy in an unselected population of patients with metastatic CRPC,” reported Dr. M. Dror Michaelson, Massachusetts General Cancer Center, Harvard Medical School, Boston.

Circulating Tumour Cell Levels: Potential Surrogate Marker of Activity

While this study suggests that the MEK/ERK kinases inhibited by sunitinib do not play an important mediating role in the pathways involved in late-stage, metastatic CRPC, a late-breaking abstract looked at circulating tumour cell (CTC) levels as a way to predict benefit from abiraterone. In this study, CTC counts were evaluated at baseline in 972 of the 1195 participating patients and then again at 4 weeks in 838 patients and 12 weeks in 723 patients. When using a definition of <5 cells/mL as favourable, a low CTC count was strongly correlated with OS.

“In this analysis, a low CTC count was predictive of survival after only 4 weeks on therapy with a very high correlation value overall [r=0.83],” reported Dr. Howard I. Scher, Chief, Genitourinary Oncology Service, MSKCC, New York City. While he said that the reduction in CTC might provide an explanation of the survival benefit associated with the androgen biosynthesis inhibitor in the COU-AA-301 trial, he also suggested to ASCO delegates that this might be a highly useful surrogate marker of activity to more rapidly test efficacy with experimental agents.

Summary

New information about the treatment of metastatic CRPC has been provided by an uncommonly large series of both encouraging and negative trials presented at this year’s ASCO. The data overall have generated a new standard of treatment for this disease and have helped draw attention to the importance of patient well-being independent of objective improvements in survival duration. According to Dr. Morris, there are now opportunities for patients “not just living longer but living better,” which he identified as an important advance in a disease for which OS remains short.

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