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Targeting Androgen Signalling in Metastatic Castration-resistant Prostate Cancer

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 - 48th Annual Meeting of the American Society of Clinical Oncology

Chicago, Illinois / June 1-5, 2012

Chicago - Improved understanding of the mechanisms of castration-resistant prostate cancer (CRPC) has led to the recognition of the key role the androgen receptor (AR) has in disease progression. Accumulating evidence suggests that AR activation and signalling persist after medical or surgical castration, driven by extragonadal androgen production. Though currently incurable, CRPC does respond to second-line hormonally directed therapies, a clinical observation that has stimulated interest in development of agents that target extragonadal androgen production and signalling activation. One such approach centres on inhibition of the CYP17 lyase enzyme, a critical potentiator of androgen biosynthesis. An interim analysis of a follow-up trial of an androgen biosynthesis inhibitor has demonstrated improved outcomes in patients with previously untreated CRPC, including a strong trend toward improved survival. Here at ASCO, this study was among several reflecting the ongoing investigation of AR signalling in CRPC.

Despite recent advances in the development of systemic agents, an unmet therapeutic need persists in the setting of metastatic castration-resistant prostate cancer (CRPC), according to Dr. Charles J. Ryan, University of California, San Francisco. The unmet need arises from the limited scope of currently available therapies which use is restricted to the post-chemotherapy setting. Some therapies might have demonstrated an overall survival (OS) benefit without achieving an objective response or having an impact on symptoms and functionality. Moreover, chemotherapy has achieved limited penetration in clinical practice to date.

“A reality is that much of the life of a patient with metastatic CRPC is lived before chemotherapy and a large proportion of patients never receive chemotherapy,” stated Dr. Ryan.

Recognizing that delay in disease progression and death can be separated by a period that stretches into years, clinical investigators in 12 countries, including Canada, designed the randomized, placebo-controlled COU-AA-302 trial to evaluate the impact of the androgen biosynthesis inhibitor abiraterone acetate on the key primary end points of progression-free survival (PFS) and OS in men with chemotherapy-naive metastatic CRPC. The study involved almost 1100 asymptomatic or mildly symptomatic men randomized to abiraterone 1000 mg/day plus prednisone 5 mg b.i.d. or to a matching placebo and prednisone.

In addition to the co-primary end points, trial outcome assessments included time to opiate use for cancer-related pain, to initiation of chemotherapy, to deterioration of performance status and to prostate-specific antigen (PSA) progression. Investigators assessed progressive disease in bone by means of a radiographic definition of PFS (rPFS), as recommended by the Prostate Cancer Clinical Trials Working Group (J Clin Oncol 2008;26:1148-59). CT or MRI evaluation was used to determine soft-tissue progression.

Treatment arms did not differ significantly with respect to baseline characteristics, including a median age of 70, time from initial diagnosis of 5 to 5.5 years, bone metastases (80-83%), >10 bone lesions (48%) or soft-tissue or nodal involvement (50%). The trial design incorporated 3 interim analyses for early identification of significant benefit or potential harm. These analyses were scheduled to be performed after occurrence of about 15%, 40% and 55% of OS events.

Early Trial Termination Due to Benefit

After the second interim analysis, when 43% of events had occurred, the data and safety monitoring committee recommended unblinding the trial and crossing placebo-treated patients to abiraterone treatment.

The trial had a median follow-up duration of 22.2 months, during which time patients in the abiraterone arm received a median of 15 cycles of therapy compared with 9 in the placebo group. Dr. Ryan reported that 84% of placebo-treated patients discontinued treatment vs. 69% of the abiraterone group. Primary reasons for discontinuation in both groups were radiographic progression, clinical progression or both. The results showed statistically significant improvement in rPFS with the placebo group reaching a median of 8.3 months, whereas it had yet to be reached in the abiraterone group (P<0.0001). The difference translated into a 57% reduction in the hazard for radiographic progression or death.

An extensive subgroup analysis showed a consistent and statistically significant advantage for patients treated with the androgen biosynthesis inhibitor vs. placebo, reported Dr. Ryan.

Strong Survival Trend

Analysis of the co-primary end point showed a median OS of 27.2 months in the placebo arm but had yet to be reached in the abiraterone arm. However, the difference was associated with a P value of 0.0097, which did not meet the required level of significance for the stopping point (P=0.0008). Consequently, the 25% reduction in the mortality hazard constituted a strong trend in favour of abiraterone. Forest-plot representation of the subgroup analysis once again demonstrated a consistent trend toward improved OS.

Investigators also analyzed subsequent treatment following discontinuation of randomized therapy and 60.3% of placebo-treated patients received additional treatment, primarily docetaxel (53%), compared with 44.3% of the abiraterone arm (37.9% docetaxel). “Notably, abiraterone was administered to 10% of patients in the control arm and in 5% of those in the abiraterone arm,” Dr. Ryan told delegates.

Analysis of response data showed that more than twice as many patients in the abiraterone arm achieved objective responses (36% vs. 16%, P<0.0001), including complete responses in 11%, partial responses in 25% with an additional 61% achieving stable disease, resulting in a disease control rate of 98% compared with 85% in the placebo arm. Biochemical response, defined as a PSA decline ³50%, was reported in 62% of abiraterone-treated patients and in 24% of the placebo arm (P<0.0001).

“These data suggest that prednisone served as an active control and does have antitumour activity,” Dr. Ryan commented. “Further, it suggests that prior docetaxel is not required for abiraterone to produce clinical activity. “

Consistent Advantage

Analysis of secondary end points demonstrated significant improvement across the board for patients treated with abiraterone (P=0.0053 to P<0.0001). The most common adverse events (AEs) were fatigue, fluid retention, hypokalemia, hypertension, cardiac disorders and transient elevation of liver enzymes. In general, AEs occurred in a similar proportion of patients in each group. Grade 3/4 AEs were uncommon in both groups.

“In summary, in patients with asymptomatic and mildly symptomatic, chemotherapy-naive metastatic CRPC, treatment with abiraterone/prednisone delays disease progression, increases survival, extends the time with minimal or no symptoms, and is associated with no new important safety signals,” Dr. Ryan concluded.

Ongoing Therapeutic Developments

Update of the current status of therapeutic development in the field of metastatic CRPC at other ASCO sessions also reflected the ongoing investigation of the androgen receptor as a therapeutic target.

A phase I study of the androgen signalling inhibitor ARN-509 demonstrated safety and preliminary evidence of efficacy. Only one of 30 patients had a serious adverse event, and treatment at varying doses was associated with ³50% reduction in PSA levels in 42% of cases, reported Dr. Dana E. Rathkopf, Memorial Sloan-Kettering Cancer Center, New York, New York.

An international phase III randomized trial showed that treatment with the androgen receptor signalling antagonist enzalutamide was associated with significant improvement in OS. Half of the 1200 patients had received ≥3 prior regimens. Treatment with enzalutamide was associated with a median OS of 18.4 months vs. 13.6 months with placebo, reported Dr. Johann S. de Bono, Royal Marsden Hospital, Surrey, UK.

Treatment with the oral quinoline-3-carboxamide derivative tasquinimod demonstrated a significant delay in the time to symptomatic progression in a placebo-controlled trial involving 201 patients with metastatic CRPC (HR 0.42, P=0.039). OS did not differ between treatment groups. However, patients who met the Prostate Cancer Working Group 2 criteria for progression had a median OS of 34.2 months vs. 25.6 months in the placebo group, a survival that exceeds previously reported rates in similar populations, remarked Dr. Andrew J. Armstrong, Duke University, Durham, North Carolina, and colleagues.

Patients with bone-metastatic CRPC had almost a 3-month improvement in OS when treated with the alpha-pharmaceutical radium-223 (Ra-223) vs. placebo in a phase III trial (P=0.00185). Moreover, Ra-223 was associated with significant delay in the time to first skeletal-related event (13.6 vs. 8.4 months; P=0.00046), reported Dr. Oliver Sartor, Tulane University, New Orleans, Louisiana. The agent had a favourable safety profile and outperformed placebo for preservation of performance status.

A phase I clinical trial provided preliminary evidence of anticancer activity with ASG-5ME, a monoclonal antibody-drug conjugate that targets SLC44A4, a protein expressed by 95% of primary prostate tumours. PSA declines >50% were observed in 4 of 8 patients with metastatic CRPC treated at the 2 highest doses of ASG-5ME. Clinical investigation will continue with the maximum tolerated dose of 2.4 mg/kg.

Summary

Androgen receptor signalling has emerged as a key driver of metastatic CRPC and is a target of ongoing therapeutic development. Currently available therapies are limited in scope and activity. An international placebo-controlled trial of the androgen biosynthesis inhibitor abiraterone demonstrated significant improvement in rPFS and a strong trend toward improved OS in patients with chemotherapy-naive metastatic CRPC and was associated with significant improvement in all secondary end points, including time to initiation of chemotherapy.  

 

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