New paper below.
Does improved metastasis-free survival (MFS) translate into longer overall survival (OS)?
What if resistance to a drug that delays metastasis, causes a reduction in post-MFS survival? The result might be a wash or even a shortening of OS.
Metastasis-Free Survival in Prostate Cancer: Faster Drug Approvals, Better Drugs?
Ravi B. Parikh, MD, MPP1 and Vinay Prasad, MD, MPH2
1University of Pennsylvania, Philadelphia, PA
2Oregon Health and Science University, Beaverton, OR
Figures and Tables
On February 13, 2018, the US Food and Drug Administration (FDA) granted marketing authorization to apalutamide for treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). Five months later, the FDA approved enzalutamide for the same indication. The FDA made these approvals on the basis of two randomized trials that showed improved metastasis-free survival (MFS; a novel surrogate end point) when the active agent was compared with placebo.1,2
There is a tradeoff between speed and certainty in drug approvals of antineoplastic agents. Although overall survival (OS) is a clear and important measure of patient benefit, it takes time to demonstrate an OS effect, particularly as advances in standard-of-care therapy improve survival. This has been the case over the last decade with prostate cancer. For this reason, researchers and others sought novel surrogates (such as MFS) that can demonstrate a timelier effect in nmCRPC. In 2011, the FDA Oncologic Drugs Advisory Committee concluded that MFS was a reasonable end point in nmCRPC, also considering the magnitude of improvement and a favorable risk-benefit evaluation of a particular drug.3,4 However, as we make progress in delaying death from intractable cancers such as prostate cancer, clinicians and researchers should ensure that novel end points serve to accelerate bringing efficacious drugs to market—not to justify approvals of drugs with questionable long-term effectiveness.
Moving forward, MFS will probably be the primary end point in the majority of trials that test agents in nmCRPC.3 This will speed the approval of some efficacious drugs in this disease setting, although it may also facilitate the approval of some ultimately ineffective drugs. In addition, although the FDA was quite clear in 2011 that it would consider MFS only in the setting of nmCRPC, MFS has been studied as a surrogate in all localized prostate cancers, which will invite others to use this end point more broadly. In fact, many current phase III studies in earlier states of disease, such as high-risk localized prostate cancer, are using MFS as the primary end point.5,6 It is thus conceivable that the MFS end point may soon be used beyond nmCRPC for regulatory approval. We have three concerns about the relevance and applicability of MFS as a regulatory end point. These concerns provide a broader cautionary lesson for applying surrogate end points in earlier cancer states.
First, evidence that improvements in MFS translate into survival gains comes from clinical trials that are decreasingly relevant to modern prostate cancer care, and the surrogate relationship may have since changed. The largest meta-analysis validating MFS, the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) study, consisted of 28 randomized trials that enrolled nearly 29,000 men with localized prostate cancer between 1987 and 2011.7 The majority of men received radiation as initial therapy (91%) and had high-risk disease (66%). The authors found a strong correlation between change in MFS and change in OS (Kendall’s τ correlation, 0.91) and concluded that MFS met criteria as a strong surrogate for OS. It is important to note that this was an analysis of prospectively conducted adjuvant trials in high-risk patients, and it generated the best available data at the time. But the landscape of metastatic prostate cancer changed in 2011, when abiraterone acetate (with prednisone) became the first second-generation antiandrogen approved to treat metastatic CRPC, demonstrating a 4-month survival benefit over placebo in the second line of treatment. Since then, the FDA has approved four other agents (enzalutamide, cabazitaxel, radium-223, and sipuleucel-T) on the basis of an OS benefit in metastatic prostate cancer. Promising data also exist for other investigational agents in progressive metastatic CRPC. As a result, a prostate cancer metastasis means something very different today than it did in 2011, because there are now many more life-prolonging medications available for treatment of metastatic disease.8
Exclusion criteria of the ICECaP meta-analysis also limit its generalizability. Of 102 eligible studies, the article only included 28 (27%) in its analysis. Only 19 trials (18.6%) were eligible for analysis of MFS. Reasons for exclusion included nonagreement of a study group to participate, failure to collect data on MFS, and withholding of individual patient data (often as a result of lack of resources). The authors should be commended for obtaining individual patient data and including a large number of men in their meta-analysis. However, the FDA and clinicians must question meta-analyses validating surrogate end points in oncology that use convenience sampling and include only a fraction of available data.9
Second, other variables (including prostate-specific antigen [PSA] kinetics) may be more important predictors of mortality in recurrent prostate cancer than whether a metastasis is detected on a scan.10,11 PSA doubling time is also a strong predictor of metastasis and survival in nmCRPC.12 Biochemically recurrent prostate cancer after definitive local therapy is presumed to be metastatic, regardless of whether a metastasis is detected on imaging. Furthermore, MFS may become outdated in the era of advanced nuclear imaging using prostate-specific membrane antigen– and sodium fluoride–based nuclear imaging. These modalities detect more asymptomatic (and possibly clinically trivial) metastases earlier in the disease course, modifying the MFS outcome.13 Finally, MFS ignores other important prognostic variables, such as site of metastasis. For the 17% of patients with metastatic prostate cancer who present with visceral metastases, the median OS is nearly 40% lower than for patients with bone-only metastases.14 In the phase III trial justifying its approval, enzalutamide did not seem to prevent visceral metastases in nmCRPC.2 It is unclear whether PSA doubling time or site of metastasis are stronger surrogates for OS than development of first metastasis, and they may not be easily translatable into reliable study end points. However, they are undoubtedly important prognostic indicators that mediate the impact of a prostate cancer metastasis.
The SPARTAN (A Study of Apalutamide [ARN-509] in Men With Non-Metastatic Castration-Resistant Prostate Cancer) and PROSPER (Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer) trials, which led to the two recent approvals, suggest that it is beneficial to initiate earlier treatment of the small but real number of patients with rapid PSA doubling times, regardless of whether a metastasis is detected. However, the FDA indications for apalutamide and enzalutamide in nmCRPC do not take PSA doubling times into account, risking indication drift to lower-risk populations with indolent disease.
Third, MFS does not account for many meaningful patient-centered outcomes among men with localized prostate cancer. A metastasis is most relevant when symptomatic. Among survivors of metastatic prostate cancer, patient-reported health utilities for asymptomatic prostate cancer are more than 25% higher than for symptomatic disease.15 In fact, utilities for asymptomatic metastatic prostate cancer closely approximate utilities for nonmetastatic prostate cancer.16 However, the MFS end point does not discriminate between asymptomatic and symptomatic metastases. Although the SPARTAN trial shows that antiandrogen therapy improves time to symptomatic progression, the median time to symptomatic progression was not reached for either the treatment or placebo arm after 20 months of follow-up; thus, the clinical benefit of early antiandrogen treatment is unclear.1 Furthermore, time to cytotoxic chemotherapy (an arguably more important end point for many men with asymptomatic metastases) was not significantly different between the antiandrogen and placebo arms. Finally, the effect of timing of antiandrogen initiation in nmCRPC on MFS is unclear.
MFS has the merit of biologic plausibility and a demonstrated association with OS. The FDA approvals of apalutamide and enzalutamide in nmCRPC were made on the basis of an unprecedented but well-considered end point. It is reasonable to think that gains in MFS may lead to gains in survival or quality of life for patients with nmCRPC, although this remains a hypothesis to be verified. At the same time, MFS lends itself to be used earlier in the course of prostate cancer and even casts implications for other tumor types. In balancing speed of approval with safety and efficacy, the FDA has shown a willingness to tolerate greater speed. However, this comes at the price of greater uncertainty of clinical benefit. Indeed, surrogate end points that are used to justify drug approvals in many other cancers have been found to be poor correlates for OS.10 In addition, traditional surrogate end points (eg, overall response rate and progression-free survival) that are used to prioritize phase III testing may not apply for novel therapies (including most PD-L1 inhibitors), for which these surrogates are a poor correlate for OS.17,18
Therapeutic advances in prostate cancer are a harbinger for advances in other malignancies. Indeed, survival gains in metastatic non–small-cell lung cancer and melanoma have dramatically improved over the last 5 years. As outcomes in metastatic cancer improve, the use of tenuous surrogate end points for drug approval carries the risks of overtreatment and commitment to an indefinite duration of therapy with considerable adverse effects. Indeed, approvals for apalutamide and enzalutamide in nmCRPC were made without knowledge of long-term risks to bone and sexual health. This is relevant because most individuals with nmCRPC will be on novel antiandrogen therapy with traditional androgen-deprivation therapy for years. We hope that these areas will be studied to allow critical evaluation of MFS postapproval. Yet, because apalutamide and enzalutamide received regular (not accelerated) approval on the basis of MFS, the sponsor does not face postmarketing commitments for additional efficacy end points.
Recent FDA approvals reveal a greater appetite for novel end points that enable faster antineoplastic approvals. The benefit may be the use of active drugs earlier in disease that improve long-term outcomes. At the same time, using uncertain end points may result in higher drug spending and large market shares, and limited postmarket studies only compound the problem. In an era of longer cancer survival and many novel agents, that may be too much cost for our health system and patients to bear.
© 2018 by American Society of Clinical Oncology
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST AND DATA AVAILABILITY STATEMENT
Disclosures provided by the authors and data availability statement (if applicable) are available with this article at DOI doi.org/10.1200/JCO.18.01092.
Conception and design: All authors
Administrative support: Vinay Prasad
Provision of study material or patients: Vinay Prasad
Collection and assembly of data: Ravi B. Parikh
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Metastasis-Free Survival in Prostate Cancer: Faster Drug Approvals, Better Drugs?
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to asco.org/rwc or ascopubs.org/jco/site/ifc.
Ravi B. Parikh
Stock and Other Ownership Interests: Merck, Google, GNS Healthcare
Consulting or Advisory Role: GNS Healthcare
Travel, Accommodations, Expenses: Conquer Cancer Foundation
Honoraria: Northwestern University, Methodist Hospital, Northwest Biomedical Society, ASTRO, American College of Physicians, Providence Health Services, University of Alberta, Dutch Oncology Association, Stonybrook University, University of Barcelona, University of Louisville, Massachusetts Dermatology Medical Society, Baycare Medical Center, Leigh Valley Medical Center, and Kaiser Sunnyside; receive payments for contributions to Medscape.
Patents, Royalties, Other Intellectual Property: Receive royalties from Johns Hopkins University Press for the book titled Ending Medical Reversal.
Supported by the Laura and John Arnold Foundation (V.P.).
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