PERS PE C T IV E
highly disadvantaged neighbor-
Metastasis-free Survival — A New End Point
Metastasis-free Survival — A New End Point
in Prostate Cancer Trials
Julia A. Beaver, M.D., Paul G. Kluetz, M.D., and Richard Pazdur, M.D.​​
2458
disparities-focused research. Data School of Medicine and Public Health
hoods. Multiple state-based pub-
lic health organizations and health
systems are already employing
Neighborhood Atlas data for this
purpose.
Policymakers and payers could
use atlas data to inform risk-
adjustment strategies, financial
incentives, payment reform, infra-
structure targeting, benefits deci-
sions, and program eligibility. For
example, the Maryland Health
Services Cost Review Commis-
sion, the state’s all-payer hospital
rate-setting author-
An audio interview
with Dr. Kind is
ity, is using these
metrics in its deci-
available at NEJM.org
sions with regard to
hospital-level quality measure-
ment and policy. The Atlas could
also be harnessed to advance
E arlier this year, the Food and
Drug Administration (FDA)
approved apalutamide, an andro-
gen receptor inhibitor, for treat-
ment of patients with nonmeta-
static castration-resistant prostate
cancer (nmCRPC). The approval
was based on SPARTAN, a ran-
domized, placebo-controlled trial
involving 1207 patients that dem-
onstrated a statistically signifi-
cant improvement in metastasis-
free survival, defined as the time
from randomization to either
imaging-detectable distant disease
or death.1 It was the first drug
approval for nmCRPC and the
first use of metastasis-free sur-
vival as a primary end point to
support drug approval.
n engl j med 378;26  nejm.org  June 28, 2018
The New England Journal of Medicine
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Copyright © 2018 Massachusetts Medical Society. All rights reserved.
Making Neighborhood-Disadvantage Metrics Accessible
could be used to inform study
design, recruitment and reten-
tion of participants, and analysis
and dissemination of results for
translational, clinical, and com-
munity-based research.
The Neighborhood Atlas makes
neighborhood-disadvantage met-
rics accessible to everyone. We
hope that improving the accessi-
bility of these data will serve as a
catalyst for the kinds of policy
efforts, research studies, resource
alignment, and clinical interven-
tions that are desperately needed
to eliminate health disparities in
the United States.
Disclosure forms provided by the authors
are available at NEJM.org.
From the Division of Geriatrics, Depart-
ment of Medicine, University of Wisconsin
Nonmetastatic CRPC is a dis-
ease state defined by rising levels
of prostate-specific antigen (PSA)
despite castrate levels of testos-
terone and the absence of radio-
graphic evidence of distant meta-
static disease. The U.S. incidence
of nmCRPC is estimated to be
50,000 to 60,000 cases per year.2
PSA screening is common in the
United States, and most men with
prostate cancer are initially diag-
nosed with localized asymptom-
atic disease. Despite early detec-
tion and advances in surgical
and radiation techniques, disease
can recur, and many patients
continue to have rising PSA levels
after salvage local therapy and
subsequent androgen-deprivation
(A.J.H.K.), the Department of Veterans Af-
fairs Geriatrics Research Education and
Clinical Center (A.J.H.K.), and the University
of Wisconsin Applied Population Laboratory
(W.R.B.) — all in Madison.
1. Link BG, Phelan J. Social conditions as
fundamental causes of disease. J Health Soc
Behav 1995;​Spec No:​80-94.
2. Ludwig J, Sanbonmatsu L, Gennetian L,
et al. Neighborhoods, obesity, and diabetes
— a randomized social experiment. N Engl
J Med 2011;​365:​1509-19.
3. Kind AJ, Jencks S, Brock J, et al. Neigh-
borhood socioeconomic disadvantage and
30-day rehospitalization: a retrospective co-
hort study. Ann Intern Med 2014;​161:​765-74.
4. Lantos PM, Hoffman K, Permar SR, et
al. Neighborhood disadvantage is associated
with high cytomegalovirus seroprevalence
in pregnancy. J Racial Ethn Health Dispari-
ties 2017 August 24 (Epub ahead of print).
5. Hu J, Kind AJH, Nerenz D. Area Depriva-
tion Index predicts readmission risk at an
urban teaching hospital. Am J Med Qual
2018 January 1 (Epub ahead of print).
DOI: 10.1056/NEJMp1802313
Copyright © 2018 Massachusetts Medical Society.
Making Neighborhood-Disadvantage Metrics Accessible
therapy. Yet many years may elapse
between detection of rising PSA
levels and metastasis or death. In
one trial of a bone-targeted agent,
only a third of control patients
had progression to radiographi-
cally detectable metastatic disease
by 2 years, and median survival
was not reached.3 Such long sur-
vival periods, along with the avail-
ability of multiple subsequent
therapies that could confound
results, render overall survival an
impractical end point and have
spurred interest in earlier efficacy
end points.
Recognizing growing inter-
est in developing therapies for
nmCRPC, the FDA convened an
Oncologic Drugs Advisory Com-
 PE R S PE C T IV E
mittee (ODAC) meeting in 2011 to
discuss clinical trial end points
and trial designs that might be
used to support drug approval.4
The committee examined the risks
for metastases, symptoms, com-
plications, and medical interven-
tions associated with disease pro-
gression and the practicality of
using an overall survival end
point in nmCRPC trials. Com-
mittee members recognized that
the transition from nmCRPC to
detectable metastatic disease is a
clinically relevant event that can
be associated with pain and ill-
ness and result in the need for
additional interventions. Their rec-
ommendations emphasized that
though metastasis-free survival
is a reasonable end point, ensur-
ing clinical benefit of a drug
would require a substantial mag-
nitude of improvement and a fa-
vorable benefit–risk evaluation.
In 2012, another ODAC exam-
ined the results of denosumab
use in a randomized, placebo-
controlled trial involving 1432 men
with nmCRPC. This trial demon-
strated an estimated median im-
provement of only 4 months in
bone-only metastasis-free survival.
The committee concluded that this
improvement coupled with deno-
sumab’s safety profile did not
amount to a favorable risk–bene-
fit profile.4 ODAC members com-
mented that longer metastasis-
free survival would be required
to justify approval. Subsequently,
multiple companies designed tri-
als examining systemic therapies
in nmCRPC using metastasis-free
survival as the primary end point
with overall survival as a coprima-
ry or secondary end point. In ad-
dition to SPARTAN, the PROSPER
trial evaluated the use of the an-
drogen receptor inhibitor enzalu-
tamide for treatment of nmCRPC;
n engl j med 378;26  nejm.org  June 28, 2018
The New England Journal of Medicine
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Copyright © 2018 Massachusetts Medical Society. All rights reserved.
Metastasis-free Survival — A New End Point
Hussain et al. now report their
results in the Journal (pages
2465–74).
Apalutamide was approved on
the basis of SPARTAN’s results,
which addressed the ODACs’ con-
cerns about the end point. There
was a robust improvement in esti-
mated median metastasis-free sur-
vival, from 16.2 months to 40.5
months. In addition, time to
metastasis and progression-free
survival (time from randomization
to local or distant metastasis or
death) were improved. Results for
overall survival were immature at
the time of approval but revealed
no detriment associated with
apalutamide treatment. Apaluta­
mide was well tolerated, and de-
spite a longer median duration of
use than placebo, the incidence
and severity of adverse reactions
were similar to those in the pla-
cebo group, with serious adverse
events experienced by 25% and
23% of patients, respectively, and
grade 3 to 4 adverse events by
45% and 34%. Apalutamide’s tol-
erability was further supported by
patient-reported outcomes reveal-
ing no notable adverse signals in
symptom or functional effects de-
spite the long treatment duration.
The FDA concluded that apalu-
tamide was safe and effective in
nmCRPC. Although the trial pop-
ulation was enriched with pa-
tients deemed to have high risk
given their PSA doubling time,
the large benefit, consistent effi-
cacy across the quartiles of dou-
bling times studied, and favorable
safety profile led to recommen-
dations for a less restrictive indi-
cation statement. The trial popu-
lation is clearly described in the
labeling, so decisions about what
PSA doubling time justifies treat-
ment are left to physicians and
patients.
Using metastasis-free survival
in nmCRPC trials can present
challenges, including prospective
specification of imaging methods
and assessment frequencies. The
end point is assessed with medi-
cal imaging, whose increasing
sensitivity may increase the sen-
sitivity and specificity of metas-
tasis detection, potentially affect-
ing the interpretation of study
results and even changing the
baseline characteristics of enroll-
ees over time. In addition, proce-
dures are required for mitigating
attrition of participants in the
face of “PSA anxiety” caused by
rising PSA values. Finally, defini-
tions of metastasis-free survival
have been designed to ensure that
metastatic events exclude local
progression, which is not consid-
ered as likely to cause illness and
death as are distant bone or vis-
ceral metastatic disease. Defin-
ing local progression requires
careful delineation of methods
for evaluating changes in lymph
nodes on computed tomography.
Since not all studies have exclud-
ed local progression in their defi-
nitions of metastasis-free survival,
the contribution of such progres-
sion to overall results must be
carefully examined. Efforts are
under way to standardize trial
design elements including eligi-
bility criteria and end-point defi-
nitions in the nmCRPC context,5
and the FDA will continue to col-
laborate with the drug-develop-
ment community to address these
issues.
Going forward, apalutamide’s
approval will make placebo-con-
trolled trials in nmCRPC more
difficult to conduct, heralding an
era of active controls and add-on
trial designs. The magnitude of
benefit in a head-to-head trial
using apalutamide as a control is
2459
PERS PE C T IV E
likely to be smaller, yet substan-
tial evidence that a similarly safe
drug leads to superior metastasis-
free survival could still meet reg-
ulatory approval requirements. For
drugs with greater toxicity, larger
improvements in metastasis-free
survival should be demonstrated,
or a subgroup of patients who
are more likely to benefit should
be identified. For add-on trial de-
signs, the magnitude of benefit
that would be required when com-
bining a new agent with apalu-
tamide would have to be weighed
against additive toxicity. Although
the FDA has not required demon-
stration of improved overall sur-
vival, continued follow-up for sur-
vival and detrimental effects is
expected.
Other end points have been
used in early-disease settings in
which an overall survival end
point is problematic. In adjuvant
breast- and colon-cancer trials,
disease-free or recurrence-free sur-
vival is used in studying patients
at risk for metastatic disease,
and improvements are used to
approve drugs while patients are
followed for overall survival (in
which improvement is not re-
quired). Like metastasis-free sur-
vival, these end points mark a
transition from nonmetastatic to
metastatic disease, which triggers
subsequent interventions and is
associated with an eventual in-
crease in symptoms, toxic drug
effects, illness, and death. But
though all patients entered into
2460
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Copyright © 2018 Massachusetts Medical Society. All rights reserved.
Metastasis-free Survival — A New End Point
adjuvant breast- or colon-cancer
trials are at risk for recurrence,
some are cured by local therapy
alone and would not otherwise
have required treatment; in con-
trast, men with nmCRPC with
rising PSA levels are generally
not considered disease-free, and
the assumption is that metastatic
disease will ultimately be found
if they are followed long enough
and don’t die from another cause.
Moreover, drugs studied for adju-
vant treatment of breast or colon
cancer have generally already
been approved for more advanced
disease, whereas apalutamide’s
nmCRPC approval was its first.
Previous therapies for meta-
static prostate cancer were ap-
proved on the basis of survival
advantage. Using overall survival
as a primary end point will be
increasingly difficult, since mul-
tiple drugs can be used sequen-
tially for advanced disease, neces-
sitating larger and longer trials
and potentially confounding inter-
pretation of results. Similarly, co-
existing conditions can influence
survival, and non–cancer-related
deaths make isolating drug ef-
fects problematic unless coexist-
ing conditions are meticulously
balanced at randomization.
Whereas radiographic progres-
sion-free survival has been stan-
dardized as an end point in meta-
static settings, there was previously
no earlier end point for nmCRPC
trials. The FDA has now recog-
nized that a prolonged delay in
n engl j med 378;26  nejm.org  June 28, 2018
The New England Journal of Medicine
development of metastatic dis-
ease is an objective and clinically
relevant measure. Future agents
may be approved on the basis of
metastasis-free survival only if
substantial effects on this transi-
tion are demonstrated and the
safety profile is acceptable for a
medication taken long-term.
Disclosure forms provided by the authors
are available at NEJM.org.
From the Office of Hematology and Oncol-
ogy Products, Center for Drug Evaluation
and Research (J.A.B.), and the Oncology
Center of Excellence (P.G.K., R.P.), U.S. Food
and Drug Administration, Silver Spring,
MD; and the Johns Hopkins Sidney Kimmel
Cancer Center at Sibley Memorial Hospital,
Washington, DC (J.A.B.).
1. Smith MR, Saad F, Chowdhury S, et al.
Apalutamide treatment and metastasis-free
survival in prostate cancer. N Engl J Med
2018;​378:​1408-18.
2. Scher HI, Solo K, Valant J, Todd MB,
Mehra M. Prevalence of prostate cancer clin-
ical states and mortality in the United
States: estimates using a dynamic progres-
sion model. PLoS One 2015;​10(10):​e0139440.
3. Smith MR, Kabbinavar F, Saad F, et al.
Natural history of rising serum prostate-
specific antigen in men with castrate non-
metastatic prostate cancer. J Clin Oncol
2005;​23:​2918-25.
4. FDA Center for Drug Evaluation and
Research. Oncologic Drugs Advisory
Committee (https:/​/​w ww​.fda​.gov/​Advisory
Committees/​CommitteesMeetingMaterials/​
Drugs/​OncologicDrugsAdvisoryCommittee/​
default​.htm).
5. Scher HI, Morris MJ, Stadler WM, et al.
Trial design and objectives for castration-
resistant prostate cancer: updated recom-
mendations from the Prostate Cancer Clin-
ical Trials Working Group 3. J Clin Oncol
2016;​34:​1402-18.
DOI: 10.1056/NEJMp1805966
Copyright © 2018 Massachusetts Medical Society.
Metastasis-free Survival — A New End Point