At present, the main end point for clinical trials in metastatic castration-resistant prostate cancer (mCRPC) is overall survival, but the availability of multiple life-prolonging therapies for this indication makes overall survival a formidable hurdle in current drug development.
Results from the COU-AA-302 study, published onlineJanuary 26 in the Journal of Clinical Oncology, suggest that radiographic progression-free survival (rPFS) is a promising end point for clinical trials of mCRPC.
In the study, a highly positive association was reported between overall survival and rPFS, defined using Prostate Cancer Working Group 2 (PCWG2) criteria. This is the first in a series of prospective randomized trials in which this biomarker is undergoing preplanned prospective validation.
However, the investigators are cautious. They conclude that "these data make no surrogate claims of rPFS and do not provide support for the use of rPFS to serve as a substitute for overall survival at this juncture."
For COU-AA-302 investigator Michael J. Morris, MD, from the Memorial Sloan Kettering Cancer Center in New York City, this is the first evidence linking the modified PCWG2 definition of rPFS and overall survival.
"There has been a coordinated effort among all the stakeholders in prostate cancer to establish a clinically meaningful end point that is a shorter readout than overall survival," he told Medscape Medical News.
"Overall survival is becoming a less meaningful end point in clinical trials of mCRPC, given that there are now six drugs in the standard armamentarium for mCRPC that a patient can receive after a protocol, each of which singly or in combination can impact overall survival," he added.
"This is a landmark study, as it provides validation for this modified definition of rPFS in this setting," write Andrew J. Armstrong, MD, ScM, FACP, associate professor of medicine and surgery from the Duke Cancer Institute, and Susan Halabi, PhD, from the Department of Biostatistics at Duke University in Durham, North Carolina, in an accompanying editorial.
"There is widespread interest in employing surrogate end points such as rPFS to make timely decisions about the efficacy of certain drugs, as well-powered comparative trials with overall survival as the primary end point will become increasingly challenging given approvals of multiple new effective agents and lengthening survival," they write.
"This is the first trial to show a robust and reliable association between rPFS and overall survival. Previous studies using older definitions of rPFS demonstrated more modest associations, and thus this represents an advance toward an intermediate end point for drug development in this disease," Dr Armstrong told Medscape Medical News.
He explained that the rPFS definition has been carefully refined to account for bone scan flare, a healing reaction commonly seen with effective hormonal therapies that target metastatic disease in bone. In COU-AA-302, therefore, updated PCWG2 guidelines were used (J Clin Oncol. 2008;26:1148-1159)
Dr Morris said he agrees: "The PCWG2 arrived at a new definition for bone progression and control of flare."
"In mCRPC, the need for validating such definitions is crucial, given the bone tropism of metastatic disease and the nonmeasurability of bone metastases," Dr Morris added. Most men with mCRPC have bone-predominant metastases without significant soft tissue components in many cases, he explained.
COU-AA-302 was the first double-blind, placebo-controlled, phase 3 study to look at the correlation between rPFS and overall survival. It also looked at the use of abiraterone prior to chemotherapy in mCRPC and showed a survival benefit in this setting.
In 2011, abiraterone was approved by the US Food and Drug Administration (FDA) for use in mCRPC after chemotherapy. In 2012, it was approved for use prior to chemotherapy in combination with prednisone.
The indication of use before chemotherapy was added on the basis of data from the COU-AA-302 study. "Full approval was granted on the basis of a large magnitude of effect on rPFS, a favorable trend in overall survival, and internal consistency across multiple secondary end points and exploratory patient-reported pain data. This is the first drug approval for mCRPC to use rPFS as the primary end point, " FDA officials explain in a report on the approval (Clin Cancer Res. 2013;19:6650-6656).
They add that this "this approval was granted in the context of a prior statistically significant overall survival benefit that formed the basis of the original 2011 approval of abiraterone acetate for patients with mCRPC who had received prior chemotherapy containing docetaxel."
In the COU-AA-302 study, 1088 patients with chemotherapy-naïve mCRPC were randomly assigned to receive abiraterone and prednisone (n = 546) or placebo and prednisone (n = 542) twice daily.
During the first 24 weeks of the study, patients underwent bone and CT scans every 8 weeks; thereafter, they underwent scans every 12 weeks.
The 2+2 rule that was used controls for flare when defining bone progression — a new time-to-event progression end point. With this rule, the PCWG2 proposes that progression be defined as at least 2 new lesions on an initial post-treatment bone scan followed by at least 2 lesions on the subsequent scan, or at least 2 new confirmed lesions on a scan performed after the flare period.
With these criteria, new lesions associated with healing are not mistaken for lesions associated with successful therapy, also called flares or pseudoprogression
Bone Scan Readings Made Uniform
In this study, a bone scan data capture tool was used, for the first time, to standardize the interpretation of the scans at participating centers, Dr Morris noted.
"The study operationalized PCWG2 and furnished the initial validation of the tool and the criteria tool analytically and clinically," he explained.
In their report on the approval of abiraterone before chemotherapy, FDA officials explain that the COU-AA-302 data increased their confidence that the improvement in rPFS is likely to be predictive of meaningful clinical benefit.
An independent interim analysis of those data demonstrated that abiraterone was associated with a 57% reduction in radiographic progression or death, compared with placebo. Median rPFS was not estimable in the abiraterone group and was 8.3 months in the placebo group.
On investigator-assessed interim analysis, the reduction was 51%, and median rPFS was better with abiraterone than placebo (13.7 vs 8.3 months).
There was general agreement between the independent and investigator reviews with respect to the occurrence and timing of radiographic progression; at the first preplanned analysis, it was 79% for the abiraterone group and 76% for the placebo group.
This "is critical because if agreement is weak, then the entire end point becomes questionable; establishing agreement provides an objective validation to the PCWG2 criteria that can be built on in future guidelines, " Drs Armstrong and Halabi write in their editorial.
Confirmation of radiographic progression with the 2+2 rule to control for flare was significant. The investigators showed that 15% of the total population would have been misclassified as having progressed had just the first scan been used.
Moreover, median overall survival was longer in patients who did not meet the criteria for radiographic progression on their subsequent bone scan than in those who did (24.4 vs 18.5 months).
In a statistical analysis, rPFS was positively correlated with overall survival.
"We lack a surrogate end point that captures the overall survival benefit of systemic agents used to treat men with mCRPC. This study does not claim rPFS is a surrogate, but it is highly prognostic and reproducible," Dr Armstrong told Medscape Medical News.
"It is a reliable end point," he added. "The ability to significantly delay radiographic progression — particularly if that translates into less pain, improved quality of life, and a delay in the onset of symptoms — represents a clinically meaningful finding."
In fact, the significant association between time to radiographic progression and time to opiate use, time to chemotherapy, and time to deterioration in performance status contributed to the decision to approve abiraterone in the prechemotherapy setting.
Is rPFS Ripe for Drug Approval?
This is the first study to show a positive correlation between rPFS assessed with PCWG2 criteria and overall survival. However, it is not yet ready for regulatory use in the approval of new drugs, the investigators note.
"We need to conduct a broader surrogacy analysis across multiple CRPC treatment settings and across different therapies with unique mechanisms of action, including hormonal, immunologic, targeted, and cytotoxic therapies," Dr Armstrong told Medscape Medical News.
"We need to show that improvement in rPFS reproducibly translates into clinical benefit and improved overall survival, and is independent of the mechanism of action of the drug," he added.
He noted that a prospective study might not be needed because a retrospective surrogacy analysis can be done if trial databases captured rPFS and overall survival in similar manners using similar definitions.
"What is required is an analysis across all positive studies that have applied the PCWG2 criteria. This is the first study; there are ongoing studies using the same approach," he explained.
However, Dr Morris said a retrospective analysis would be a challenge.
"The PCWG2 criteria ensured that patients did not come off clinical trials based on PSA alone. In older studies, patients did come off treatment due to biochemical progression. There are limited older studies examining large groups of patients who were maintained on therapy until radiographic progression, as we currently define it. We need to take that into consideration," Dr Morris said.
Dr Armstrong cautioned that this surrogacy measure, when met, might not be a surrogate end point for all drugs. We might need other surrogate end points for other drugs with other unique mechanisms, such as immunotherapies, he suggested.
Dr Armstrong noted that rPFS can be incorporated into controlled phase 2 studies to determine which agents should move forward to phase 3 trials.
For newer hormonal agents, chemotherapy, and most targeted therapies, rPFS might be applicable. However, for antiangiogenic agents such as bevacizumab, which has shown a delay in radiographic progression but no improvement in overall survival, it might not be applicable, Dr Armstrong told Medscape Medical News.
"This is the first real analysis of PSWG2's new definition of radiographic progression, but these data cannot be extrapolated to all drugs and all settings in prostate cancer," Dr Armstrong said.
"Having an objective measure of rPFS is critical in this setting. Currently, the only FDA-approved end point is overall survival. A shorter-term end point would be a win–win situation for both patients and drug companies that are developing these therapies," he told Medscape Medical News.
According to Dr Morris, the FDA is not ready to accept rPFS as a standalone end point, but might accept it as a supportive end point.
"Approval based on this end point will rely on a large absolute and relative magnitude of effect as well as internal consistency among carefully selected key secondary end points in the context of an acceptable safety profile," FDA officials explain in their report on the approval of abiraterone before chemotherapy. "Regardless of the primary end point selected, an analysis of overall survival should be included in any clinical trial intended to support regulatory approval in patients with CRPC."
The study was supported by Janssen Pharmaceuticals, the Prostate Cancer Clinical Trials Consortium, and the Department of Defense. Some of the COU-AA-302 investigators are employees of Janssen Pharmaceuticals. Several of the investigators and Dr Armstrong report financial relationships with pharmaceutical companies.
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