JOURNAL OF CLINICAL ONCOLOGY
Curing More Prostate Cancer: Thinking Through
the Options
Oliver Sartor, Tulane Medical School, New Orleans, LA
See accompanying article doi:https://doi.org/10.1200/JCO.2017.76.4126
Phase III clinical trials should generally be simple affairs. The
rule of thumb is that the standard of care should be compared with
a promising intervention among reasonably well-defined patients and
the proposed outcome should be readily measurable, generalizable,
and clinically meaningful. Ideally, the results, if positive, should change
practice and be implemented widely. As a generality, one (and only
one) variable should be changed in the experimental group to facilitate
understanding the intervention and its consequences.
Simplicity, though an oft-stated goal, is not always achieved.
In prostate cancer trials, outcomes will always occur long after the
trial was designed. Trial architects are forced to consider various
future treatment approaches, and the potential future state of
affairs is inherently uncertain. Speculating on future scenarios is
interesting, but even well-informed investigators may have sub-
stantial discordance in their views.
Currently in nonmetastatic prostate cancer, the time to reach
the most relevant clinical end points (metastases or overall sur-
vival) can take a decade or even more. Definitions of prognostic
categories, biomarkers, and treatments are all subject to flux over
time. How to anticipate these changes can determine the success or
failure of a trial. Much is at stake because both research dollars and
trial participants are limited.
In the article that accompanies this editorial, let us examine the
Southwest Oncology Group (SWOG) S9921 trial and the patients
considered to be at high risk of death after radical prostatectomy
(RP).1 First, the investigators should be congratulated for seeing a trial
through to completion, two decades after conception. In SWOG
S9921, patients were randomly assigned to 2 years of androgen-
deprivation therapy (ADT) or 2 years of ADT plus mitoxantrone.
Accrual to the trial was halted prematurely as a result of higher
leukemia risk in the mitoxantrone-treated patients; however, the early
stopping occurred after 961 patients were randomly assigned, thus
providing a valuable and sizable data set with long-term follow-up.
In 1999, the standard of care for most of these patients was
observation because no treatment had level I evidence showing
clear clinical benefit. In 2009, standards changed for many high-
risk patients as adjuvant radiation therapy (in SWOG 8794) was
shown to prolong overall survival (OS).2 Since that time, no new
trials in the adjuvant setting after RP have reported clear clinical
benefit, but the truth is that post-RP patients with high-risk
features rarely receive adjuvant radiation.3 Low use of adjuvant
radiation is in part a result of the availability of prostate-specific
Corresponding author: Oliver Sartor, MD, Tulane Medical School, Box SL-78, 1430 Tulane Ave, New Orleans, LA 70112;
e-mail: osartor@tulane.edu.
Downloaded from ascopubs.org by UNIVERSIDADE DE SO PAULO on April 14, 2018 from 143.107.252.087
Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
E D I T O R I A L
antigen (PSA)–driven salvage treatments.4 Salvage approaches
avoid radiation overuse in patients never destined to experience
relapse, but whether clinical outcomes are similar is not yet clear.
The Radiotherapy and Androgen Deprivation in Combination
After Local Surgery (RADICALS) trial (ClinicalTrials.gov identi-
fier: NCT00541047) will help answer the important question re-
garding the relative merits of adjuvant radiation versus PSA-driven
salvage radiation.
The investigators in SWOG S9921 assessed adjuvant che-
motherapy for patients deemed to be at high risk for death after RP.
Controversially, they chose 2 years of ADT as the control arm
despite the fact that no prior study supported the use of 2 years of
ADT for these patients. The best supportive data for adjuvant ADT
after RP come from the 1999 study by Messing et al5 performed in
node-positive men. That small study (n 5 100) used lifelong ADT
and enrolled patients beginning in 1988 (the pre-PSA era). OS
benefit was seen for adjuvant versus delayed ADT. Today, lifelong
ADT is rarely used in such patients. Multiple studies of radiation
plus ADT demonstrate positive benefit,6 but ADT plus radiation is
not the same as ADT after RP. The combination of ADT and
radiation seems to be synergistic, whereas data to support synergy
between ADT and RP is sparse. Perhaps newer neoadjuvant studies
can result in change (ClinicalTrials.gov identifier: NCT00430183).7
What do the authors of SWOG S9921 conclude? First,
mitoxantrone provided no benefit. Second, the observed OS was
improved relative to pretrial estimates. Third, only approximately
20% of the deaths were attributable to prostate cancer. Whether
these better than expected observations were a result of patient
selection, 2 years of ADT, stage migration, or various postprotocol
therapies cannot be ascertained.
Should SWOG S9921 change practice? At this time, without
the appropriate control group, one cannot conclude that these
better than expected outcomes were attributable to ADT. Are they
provocative? Yes. Are they practice changing? No. The control arm
assignment to ADT for 2 years was a controversial choice; data to
support 2 years of ADT after RP as a standard therapy were not
available then (or now).
So how do we proceed? How can we cure more men with high-
risk prostate cancer? How do we design trials that read out more
quickly? First, we have to stage patients better. Many failures from
local treatment are simply a result of inadequate staging. In fact,
one might conjecture that the majority of patients with high-risk
© 2018 by American Society of Clinical Oncology 1
 Editorial
localized disease who eventually experience progression do so
because of a failure to detect metastatic disease with bone scans,
computed tomography scans, and magnetic resonance images,
given these imaging tests have poor sensitivity for detecting me-
tastases. Notably, a 1-cm diameter tumor contains approximately
1,000,000,000 cells, and detecting , 1-cm tumors by conventional
imaging is not consistently feasible.
Newer positron emission tomography scans (prostate-specific
membrane antigen, choline, and fluciclovine) are more sensitive
than conventional imaging,8 although more sensitive does not
mean perfect. Clearly, we need trials that divide the current high-
risk patients into those with and without metastatic disease after
being imaged with state-of-the-art scans. Better imaging will likely
subdivide high-risk patients into new higher and lower risk cat-
egories. What is the best imaging? That is a debatable question
given the lack of comprehensive comparative studies, especially for
patients imaged before initial treatments. Some initial data suggest
that prostate-specific membrane antigen positron emission to-
mography may have superior sensitivity.9
Second, it is likely that molecular risk stratification can pro-
vide additional benefits. For years, we have risk stratified patients
by using a combination of TNM staging, Gleason score, and PSA.
Incorporation of newer molecular and genetic analyses can provide
more effective risk stratification.10 By using a combination of both
imaging and genetics, what today looks like a monolithic group of
high-risk patients may be subcategorized more accurately. It is
obvious that higher and lower risk patients may benefit from more
or less intensive therapies. For higher risk patients, it is likely that
most benefits will come from more effective systemic therapies.
Overall, for prostate cancer, we still have problems regarding
overtreating low-risk disease and undertreating high-risk disease.
Taking molecular biomarkers from prognostic to predictive is
another task at hand. Certain alterations, such as mutations in
mismatch or DNA repair genes, may suggest alternative thera-
peutic choices.11,12 Today, our discussions often revolve around
hormones, better hormones, longer hormones, shorter hormones,
or no hormones. Tomorrow, with better understanding of mo-
lecular categorization and targeted treatments, we will likely have
more personalized choices to consider. Newer trials should take
fuller advantage of the newly appreciated molecular heterogeneity
by broadening the current therapeutic spectrum. Targeted radia-
tion (stereotactic body radiation therapy and targeted systemic
radiation) may also play an important therapeutic role.13,14
What type of end points should be used in our future trials?
Waiting for men to die (OS) seems extreme, yet that is the current
gold standard. The Intermediate Clinical Endpoints in Cancer of
the Prostate group has done important work that suggests that
metastasis-free survival is a reasonable surrogate for OS (even
without testosterone measurements).15 Metastasis-free survival
can be reached more or less quickly given cancer aggressiveness,
treatment effects, and the timing of deaths. Patients with more
aggressive disease and fewer comorbidities are the best candidates
for trials. Older and sicker patients are less likely to benefit from
cancer therapies given the inevitable competing mortality risks in
this patient population.
What about PSA as an end point? PSA nadir (even for patients
with an intact prostate), time to PSA recurrence, and PSA doubling
time all carry important prognostic information.16-18 All PSA end
2 © 2018 by American Society of Clinical Oncology
Downloaded from ascopubs.org by UNIVERSIDADE DE SO PAULO on April 14, 2018 from 143.107.252.087
Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
points are dependent on the androgen axis. Furthermore, re-
currences after androgen-axis manipulation are potentially distinct
from recurrences occurring without such intervention. PSA re-
currences after extreme ADT (ie, abiraterone and enzalutamide)
may be quite different from those without such treatments. Simply
stated, time to PSA progression may be longer, but time from PSA
progression to metastasis or death may be shorter for patients
treated with newer hormonal therapies. Thus, PSA measurements
are clearly imperfect.
A possible solution is to measure the PSA in men with a normal
(or noncastrate) testosterone level.19 This is not perfect, but an
undetectable PSA with a normal testosterone level potentially signals
a cure. Cures are forever, but the meaning of no PSA and normal
testosterone can change over time. A no PSA and normal testos-
terone state can mean one thing after extreme androgen deprivation
and another after no ADT or lesser forms of ADT. A no PSA and
normal testosterone state can have one meaning 1 year after therapy
and a different meaning 10 years later. The distinction between
noncastrate and normal testosterone is complex, and variations in
this range represent a spectrum of values with incompletely defined
meaning and consequences. Perhaps landmark analyses are best
used in such endeavors.
Approximately 27,000 men died of prostate cancer in the
United States this past year, and approximately 300,000 died
worldwide. Curing more patients should be a priority for all in the
field. Better risk assessment, better clinical trial end points, and
better therapies are all part of the solution.
AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at
jco.org.
REFERENCES
1. Hussain M, Tangen CM, Thompson IM, et al: Phase III intergroup trial of
adjuvant androgen deprivation with or without mitoxantrone plus prednisone in
patients with high-risk prostate cancer after radical prostatectomy: SWOG S9921.
J Clin Oncol doi:10.1200/JCO.2017.76.4126
2. Thompson IM, Tangen CM, Paradelo J, et al: Adjuvant radiotherapy for
pathological T3N0M0 prostate cancer significantly reduces risk of metastases and
improves survival: Long-term followup of a randomized clinical trial. J Urol 181:
956-962, 2009
3. Kalbasi A, Swisher-McClure S, Mitra N, et al: Low rates of adjuvant radiation
in patients with nonmetastatic prostate cancer with high-risk pathologic features.
Cancer 120:3089-3096, 2014
4. Rodriguez JF, Liauw SL, Eggener SE: Managing cancer relapse after radical
prostatectomy: Adjuvant versus salvage radiation therapy. Urol Clin North Am 44:
597-609, 2017
5. Messing EM, Manola J, Sarosdy M, et al: Immediate hormonal therapy
compared with observation after radical prostatectomy and pelvic lymphadenec-
tomy in men with node-positive prostate cancer. N Engl J Med 341:1781-1788, 1999
6. Yang DD, Nguyen PL: Optimizing androgen deprivation therapy with radi-
ation therapy for aggressive localized and locally advanced prostate cancer. Urol
Oncol 10.1016/j.urolonc.2017.10.020 [epub ahead of print on December 15, 2017]
7. McKay RR, Montgomery B, Xie W, et al: Post prostatectomy outcomes of
patients with high-risk prostate cancer treated with neoadjuvant androgen
blockade. Prostate Cancer Prostatic Dis 10.1038/s41391-017-0009-6 [epub ahead
of print on December 20, 2017]
8. Li R, Ravizzini GC, Gorin MA, et al: The use of PET/CT in prostate cancer.
Prostate Cancer Prostatic Dis 10.1038/s41391-017-0007-8 [epub ahead of print on
December 11, 2017]
9. Calais J, Fendler WP, Herrmann K, et al: Head-to-head comparison of
68
Ga-PSMA-11 PET/CT and 18F-Fluciclovine PET/CT in a case series of 10 patients
with prostate cancer recurrence. J Nucl Med 10.2967/jnumed.117.203257 [epub
ahead of print on December 14, 2017]
JOURNAL OF CLINICAL ONCOLOGY
 Editorial

10. Spratt DE, Zhang J, Santiago-Jiménez M, et al: Development and validation
of a novel integrated clinical-genomic risk group classification for localized prostate
cancer. J Clin Oncol 36:581-590, 2018
11. US Food and Drug Administration: FDA grants accelerated approval to
pembrolizumab for first tissue/site agnostic indication. https://www.fda.gov/
Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm
12. Goodall J, Mateo J, Yuan W, et al: Circulating cell-free DNA to guide
prostate cancer treatment with PARP inhibition. Cancer Discov 7:1006-1017,
2017
13. Muldermans JL, Romak LB, Kwon ED, et al: Stereotactic body radiation
therapy for oligometastatic prostate cancer. Int J Radiat Oncol Biol Phys 95:
696-702, 2016
14. Rahbar K, Ahmadzadehfar H, Kratochwil C, et al: German multicenter study
investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer
patients. J Nucl Med 58:85-90, 2017
15. Xie W, Regan MM, Buyse M, et al: Metastasis-free survival is a strong
surrogate of overall survival in localized prostate cancer. J Clin Oncol 35:
3097-3104, 2017
16. D’Amico AV, Chen MH, de Castro M, et al: Surrogate endpoints for prostate
cancer-specific mortality after radiotherapy and androgen suppression therapy in
men with localised or locally advanced prostate cancer: An analysis of two
randomised trials. Lancet Oncol 13:189-195, 2012
17. Freedland SJ, Humphreys EB, Mangold LA, et al: Risk of prostate cancer-
specific mortality following biochemical recurrence after radical prostatectomy.
JAMA 294:433-439, 2005
18. Freedland SJ, Humphreys EB, Mangold LA, et al: Death in patients with
recurrent prostate cancer after radical prostatectomy: Prostate-specific antigen
doubling time subgroups and their associated contributions to all-cause mortality.
J Clin Oncol 25:1765-1771, 2007
19. O’Shaughnessy MJ, McBride SM, Vargas HA, et al: A pilot study of
a multimodal treatment paradigm to accelerate drug evaluations in early-stage
metastatic prostate cancer. Urology 102:164-172, 2017
DOI: https://doi.org/10.1200/JCO.2018.78.4835; published at jco.org on
April 6, 2018.

nnn

jco.org © 2018 by American Society of Clinical Oncology 3

Downloaded from ascopubs.org by UNIVERSIDADE DE SO PAULO on April 14, 2018 from 143.107.252.087
Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
 Editorial

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Curing More Prostate Cancer: Thinking Through the Options
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I 5 Immediate Family Member, Inst 5 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 www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Oliver Sartor
Consulting or Advisory Role: Bayer, Bellicum Pharmaceuticals, Johnson
& Johnson, Sanofi, AstraZeneca, Dendreon, Endocyte, Constellation
Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers
Squibb, Bavarian Nordic, Oncogenex, EMD Serono, Blue Earth
Research Funding: Bayer (Inst), Johnson & Johnson (Inst), Sanofi (Inst),
Endocyte (Inst), Innocrin Pharma (Inst), Merck
Travel, Accommodations, Expenses: Bayer, Johnson & Johnson,
Medivation, Sanofi, AstraZeneca, Progenics, Blue Earth

© 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Downloaded from ascopubs.org by UNIVERSIDADE DE SO PAULO on April 14, 2018 from 143.107.252.087
Copyright © 2018 American Society of Clinical Oncology. All rights reserved.