The kinase inhibitor cabozantinib (Cabometyx) failed to significantly improve overall survival (OS) versus prednisone in heavily treated patients with metastatic castration-resistant prostate cancer (mCRPC), a 14-country phase III study has reported in the Journal of Clinical Oncology.
The 1,028-patient randomized trial found a median OS of 11.0 months (range: 10.1-11.6) in the cabozantinib arm (n=682) and 9.8 months (9.0-11.5) in the prednisone arm (n=346), for a hazard ratio (HR) of 0.90 (95% CI 0.76-1.06).
And although cabozantinib also failed to improve prostate-specific antigen (PSA) levels, the drug was related to notable improvements in several other study endpoints, showing activity for bone scan response (BSR), radiographic progression-free survival (rPFS), symptomatic skeletal events (SSEs), and circulating tumor cell (CTC) conversions, reported Matthew Smith, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, and colleagues.
"It is unclear why improvements in BSR, rPFS, SSEs, CTC conversions, and bone biomarkers with cabozantinib did not translate into significantly improved OS in this population of patients with late-stage mCRPC," the researchers wrote. "The successful development of cabozantinib in mCRPC may require a specific biomarker evaluation to identify patients with a high likelihood of treatment benefit."
Participants, mainly from Europe and enrolled during 2012-2014, had progressive disease after treatment with docetaxel and abiraterone and/or enzalutamide. Median ages in the cabozantinib and prednisone arms were 69.5 and 69.0 years, respectively; 76% and 77% of patients were white, with time from diagnosis in both groups about 7 years.
BSR at week 12 favored the cabozantinib arm: 42% (95% CI 38-46) versus 3% (95% CI 1% to 5%). The median duration of BSR from first scan to progression was 5.8 months (95% CI 5.5-8.3) with cabozantinib and 1.8 months with prednisone.
In other response markers, rPFS was superior in the cabozantinib group: median 5.6 versus 2.8 months (HR 0.48; 95% CI 0.40-0.57).
Cabozantinib was also associated with a longer time to first SSE, for an HR of 0.62 (95% CI 0.48-0.81). SSE rates during the study period were lower in the cabozantinib than the prednisone arm: 14% versus 21%, with bone radiotherapy being the most common SSE in both groups, at 12% and 18%, respectively.
Grade 3-4 adverse events and related discontinuations were markedly higher with cabozantinib than with prednisone: 71% versus 56%, and 33% versus 12%, respectively.
The researchers speculated that the lack of a significant overall survival benefit despite improvement in other intermediate outcomes may have been due in part to the high rate of treatment discontinuation because of adverse events. Other factors could be the confounding effects of subsequent salvage therapies, the study's active comparator, unidentified imbalances in prognostic factors between the study arms, and the limitations of using intermediate endpoints for assessing targeted therapies.
They noted that the study's primary results are consistent with previous results for the oral tyrosine kinase inhibitor sunitinib (Sutent), which has shown modest effects on bone scans and bone biomarkers.
Commenting on the paper in a related editorial, Joshi J. Alumkal, MD, and Tomasz M. Beer, MD, both from Oregon Health & Science University in Portland, agreed that other factors not unique to cabozantinib may have contributed to the negative outcome of this phase III trial. These might include the molecular and clinical heterogeneity of the unselected patient population studied, access to post-protocol life-prolonging therapies, and, as noted by the authors, the more frequent early discontinuation of cabozantinib because of toxicity.
"However," Alumkal and Beer asked, "even if the trial proved to be positive in a statistical sense, would it have produced a clinically meaningful result? Would it have yielded a new, well-tolerated treatment option that patients with mCRPC and their providers would embrace?"
In their view the study is emblematic of problems with the design of contemporary clinical trials and their failure to define clinically meaningful benefit to patients. The commentators expressed concern at the magnitude of OS improvement the study was designed to detect, noting that the sample size was based on the assumption that median survival in the control arm would be 7 months, and success was defined as a 25% reduction in mortality risk. While that might be meaningful to a patient with a life expectancy of 3 years, they pointed out, it translates to an only minimal improvement in median survival for the population tested.
"Even acknowledging that treatment benefit varies considerably between patients, one is left to ask: Is this a bar worth jumping over?" Alumkal and Beer asked.
They added that if the trial's 90% power were recalculated with the commonly used 80%, it would be adequately powered to detect an even smaller improvement. And while a high power reduces the risk that a true benefit is missed, it also requires more participants, costs more, takes longer, and exposes more patients to potentially useless therapy. "Also, a high level of power makes it possible to detect even smaller and less clinically meaningful differences than those highlighted in the statistical design."
The editorial called for a raising of the bar in clinical trial design, with consensus to establish what the minimum improvement in overall survival or quality of life should be, as well as the acceptable risks of toxicity for the disease state in which a trial is being considered. Such as consensus should also consider what the minimum evidence from early-stage trials should be to allow further drug trials to move forward.
"We have seen too many failures in mCRPC phase III clinical trials to justify continuing with the same paradigm for clinical trial design," Alumkal and Beer wrote. "Rethinking clinical trial design will not be easy, and the urge to move a marginal drug forward will not entirely go away."
With dialog about meaningful clinical benefit in mCRPC and other diseases long overdue, they added, "Such a discussion would greatly facilitate rapid development of treatments that have the greatest likelihood of significantly improving the lives of patients."
Smith did not respond to emails asking for a response to the editorial.
The study was supported by Exelixis. Several study authors and both editorial commentators disclosed financial relationships with industry.
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