In prostate cancer clinical trials, overall survival (OS) can be an impractical endpoint because survival is so long, and so a new one has emerged — metastasis-free survival (MFS).
Indeed, apalutamide (Erleada, Janssen) recently became the first drug approved for treating men with nonmetastatic, castration-resistant prostate cancer (nmCRPC) precisely on the basis of this endpoint.
The US Food and Drug Administration (FDA) provided its reasoning on using MFS as a new endpoint for granting this approval in a article published online June 28 in the New England of Medicine.
Julia A. Beaver, MD, from the FDA's Center for Drug Evaluation and Research, and Paul G. Kluetz, MD, and Richard Pazdur, MD, both from the FDA's Oncology Center of Excellence, were coauthors of the article, which presents the FDA's point of view.
The FDA's approval of apalutamide was based on data from the SPARTAN study, a randomized, placebo-controlled trial that included 1207 men. The trial showed a statistically significant improvement in MFS, defined as the time from randomization to either imaging-detectable distant disease or death.
The recently published PROSPER study, which was similar to SPARTAN, also showed that MFS was significant for patients who received enzalutamide (Xtandi, Pfizer/Astellas). Enzalutamide is now expected to receive approval in a similar population of patients with nmCRPC, as reported by Medscape Medical News.
The Need for a New Endpoint in nmCRPC
nmCRPC is defined by rising levels of prostate-specific antigen (PSA) despite castration levels of testosterone, the absence of radiographic progression, and the absence of distant metastasis, as determined on the basis of imaging.
The FDA authors note that even with early detection and advances in surgical and radiotherapy techniques, disease does recur. After salvage local therapy followed by androgen-deprivation therapy, PSA levels may continue to rise for many patients.
"Yet many years may elapse between detection of rising PSA levels and metastasis or death," the FDA authors write. They cite the example of a trial that evaluated a bone-targeting agent. In that trial, only a third of patients in the control arm experienced progression to metastatic degree by 2 years, and yet median overall survival was not reached.
"Such long survival periods, along with the availability of multiple subsequent therapies that could confound results, render overall survival an impractical end point and have spurred interest in earlier efficacy end points," the FDA authors contend.
The authors note that radiographic progression-free survival is a standardized endpoint in metastatic settings, but previously, there was no earlier endpoint in nmCRPC.
"The FDA had now recognized that a prolonged delay in the development of metastatic disease is an objective and clinically relevant measure," Beaver and colleagues write.
Approached for comment, Anthony D'Amico, MD, PhD, chief of genitourinary radiation oncology at the Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Boston, Massachusetts, concurred with this move. "This is a brand new primary endpoint in prostate cancer clinical trials, and one has to ask why this endpoint can now be used," he commented to Medscape Medical News.
He noted that in prostate cancer, metastasis is nearly always associated with pain and suffering and therefore a diminished quality of life. Moreover, additional therapies are frequently used, and death from prostate cancer often occurs. Therefore, metastasis is a clinically relevant endpoint, he pointed out.
He also pointed out that "the study populations in both PROSPER and SPARTAN had short PSA doubling times (< 10 months and a median of about 4 months), which is known to herald a quicker death from prostate cancer following metastasis, making competing risks less relevant."
The FDA authors also note that in other early-disease settings (eg, in breast and colorectal cancers) in which OS has been problematic, disease-free survival (DFS) or recurrence-free survival has been used as valid endpoints in studying patients at risk for metastatic disease.
"Like metastasis-free survival, these end points mark a transition from nonmetastatic to metastatic disease, which triggers subsequent interventions and is associated with an eventual increase in symptoms, toxic drug effects, illness, and death," the FDA authors write.
The Road to MFS as an Endpoint
In 2011, the FDA brought together a group of experts — the Oncologic Drugs Advisory Committee (ODAC) — to discuss clinical trial designs and endpoints that may support approval of developing therapies for nmCRPC. The ODAC members recognized that transition from nmCRPC to detectable metastatic disease can be associated with pain and illness and can result in the need for additional interventions.
The members concluded that use of MFS as an endpoint would require substantial magnitude of improvement and a favorable benefit-risk evaluation.
In 2012, another ODAC assessed results of the use of denosumab (Prolia, Amgen) from a randomized, placebo-controlled trial that involved 1432 men with nmCRPC. The data showed that median improvement in MFS was 4 months. However, the committee members concluded that this small improvement, coupled with denosumab's safety profile, was not sufficient to grant approval for denosumab. The risk-benefit profile was not favorable, and a longer MFS would be required to justify approval.
In February 2018, the FDA approved apalutamide for the treatment of men with nmCRPC whose PSA level rises despite their receiving androgen-deprivation therapy (ADT). The approval was based on data from the SPARTAN study. In the study, MFS was 40.5 for the patients who received apalutamide and 16.2 months for the patients who received placebo (hazard ratio, 0.28; P < .001). Apalutamide was associated with a 72% reduced risk for metastasis or death.
The FDA authors noted the "robust improvement" in estimated median MFS, time to metastasis, and progression-free survival. Although survival data were immature, they also noted that apalutamide was well tolerated and that the incidence and severity of adverse events were similar to those seen with placebo despite a longer median duration of use of apalutamide compared with placebo.
However, D'Amico pointed out that an analysis of individual patient data from 28 trials, which included 28,905 patients, showed that MFS is a strong surrogate for OS (Xie W et al, J Clin Oncol. 2017;35:3097-3104).
This analysis, which showed that DFS and MFS very closely correlated with OS, concluded that "in a cohort of patients with prostate cancer with an approximate 15% chance of dying of prostate cancer over a 10-year period, DFS and MFS are valid surrogates for OS."
The FDA authors concede that apalutamide was approved for a less restrictive indication. The SPARTAN trial population included a large number of high-risk men (median PSA doubling time, ~4 months), but the drug's benefit was consistent across the quartiles of doubling times studied.
"The trial population is clearly described in the labeling, so decisions about what PSA doubling time justifies treatment are left to physicians and patients," the FDA authors write.
Challenges Ahead for Clinical Trials in nmCRPC
They acknowledge challenges ahead. One of them is prospective specification of imaging methods and assessment frequencies.
Secondly, they note that with increasing sensitivity and specificity of metastases detection, study results may be open to interpretation and may even change the baseline characteristics of enrollment over time.
Thirdly, procedures may be required for addressing the attrition of participants in the face of "PSA anxiety."
Finally, definitions of MFS should ensure that metastatic events exclude local progression, which is not as likely to cause illness and death as distant bone or visceral metastases.
"Efforts are underway to standardize trial design elements including eligibility criteria and end-point definitions in the nmCRPC context," Beaver and colleagues write.
In future head-to-head trials using apalutamide as the control, the clinical gains may be smaller, but a substantial safety profile leading to superior MFS could still meet regulatory approval requirements, the FDA authors note. Another approval scenario includes identifying a subgroup of patients who are more likely to benefit.
For studies designed to determine the benefit of adding a drug to apalutamide, the magnitude of benefit would be weighed against the additive toxicity of the new agent, they note.
"Although the FDA has not required demonstration of improved overall survival, continued follow-up for survival and detrimental effects is expected," the FDA authors write.
N Engl J Med. Published online June 28, 2018. Full text
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