Impact of clinical versus radiographic progression on clinical outcomes in metastatic castration-resistant prostate cancer

Abstract

Objectives
Unequivocal clinical progression (UCP)—a worsening of clinical status with or without radiographic progression (RAD)—represents a distinct mode of disease progression in metastatic prostate cancer. We evaluated the prevalence, risk factors and the impact of UCP on survival outcomes.

Methods
A post-hoc analysis of the COU-AA-302, a randomised phase 3 study of abiraterone plus prednisone (AAP) versus prednisone was performed. Baseline characteristics were summarised. Cox proportional-hazards model and Kaplan-Meier method were used for survival and time to event analyses, respectively. Iterative multiple imputation method was used for correlation between clinicoradiographic progression-free survival (crPFS) and overall survival (OS).

Results
Of 736 patients with disease progression, 280 (38%) had UCP-only and 124 (17%) had UCP plus RAD. Prognostic index model high-risk group was associated with increased likelihood of UCP (p<0.0001). Median OS was 25.7 months in UCP-only and 33.0 months for RAD-only (HR 1.39; 95% CI 1.16 to 1.66; p=0.0003). UCP adversely impacted OS in both treatment groups. Lowest OS was seen in patients with prostate specific antigen (PSA)-non-response plus UCP-only progression (median OS 22.6 months (95% CI 20.7 to 24.4)). Including UCP events lowered estimates of treatment benefit—median crPFS was 13.3 months (95% CI 11.1 to 13.8) versus median rPFS of 16.5 months (95% CI 13.8 to 16.8) in AAP group. Finally, crPFS showed high correlation with OS (r=0.67; 95% CI 0.63 to 0.71).

Conclusions
UCP is a common and clinically relevant phenomenon in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with AAP or prednisone. UCP is prognostic and associated with inferior OS and post-progression survival. A combination of PSA-non-response and UCP identifies patients with poorest survival. When included in PFS analysis, UCP diminishes estimates of treatment benefit. Continued study of UCP in mCRPC is warranted.

Full text

1
RaoA, etal. ESMO Open 2020;5:e000943. doi:10.1136/esmoopen-2020-000943
Open access
Impact of clinical versus radiographic
progression on clinical outcomes in
metastatic castration- resistant
prostate cancer
Arpit Rao ,1 Howard I Scher,2,3 Peter De Porre,4 Margaret K Yu,5 Anil Londhe,6
Keqin Qi,6 Michael J Morris,2,3 Charles Ryan1
Original research
►Additional material is
published online only. To view
please visit the journal online
(http:// dx. doi. org/ 10. 1136/
esmoopen- 2020- 000943).
To cite: RaoA, ScherHI,
De PorreP, etal. Impact of
clinical versus radiographic
progression on clinical
outcomes in metastatic
castration- resistant prostate
cancer. ESMO Open
2020;5:e000943. doi:10.1136/
esmoopen-2020-000943
Received 23 July 2020
Revised 4 September 2020
Accepted 30 September 2020
1Division of Hematology,
Oncology and Transplantation,
University of Minnesota,
Minneapolis, Minnesota, USA
2Department of Medicine,
Memorial Sloan- Kettering
Cancer Center, New York, New
York, USA
3Weill Cornell Medical College,
New York, United States
4Oncology Development,
Janssen Research &
Development, Beerse, Belgium
5Janssen Research &
Development, Los Angeles,
California, USA
6Oncology Development,
Janssen Research &
Development, Titusville, New
Jersey, USA
Correspondence to
Dr Arpit Rao; raoa@ umn. edu
© Author (s) (or their
employer(s)) 2020. Re- use
permitted under CC BY- NC. No
commercial re- use. Published
by BMJ on behalf of the
European Society for Medical
Oncology.
ABSTRACT
Objectives Unequivocal clinical progression (UCP)—a
worsening of clinical status with or without radiographic
progression (RAD)—represents a distinct mode of disease
progression in metastatic prostate cancer. We evaluated
the prevalence, risk factors and the impact of UCP on
survival outcomes.
Methods A post- hoc analysis of the COU- AA-302, a
randomised phase 3 study of abiraterone plus prednisone
(AAP) versus prednisone was performed. Baseline
characteristics were summarised. Cox proportional-
hazards model and Kaplan- Meier method were used for
survival and time to event analyses, respectively. Iterative
multiple imputation method was used for correlation
between clinicoradiographic progression- free survival
(crPFS) and overall survival (OS).
Results Of 736 patients with disease progression, 280
(38%) had UCP- only and 124 (17%) had UCP plus RAD.
Prognostic index model high- risk group was associated
with increased likelihood of UCP (p<0.0001). Median
OS was 25.7 months in UCP- only and 33.0 months for
RAD- only (HR 1.39; 95% CI 1.16 to 1.66; p=0.0003). UCP
adversely impacted OS in both treatment groups. Lowest
OS was seen in patients with prostate specic antigen
(PSA)- non- response plus UCP- only progression (median
OS 22.6 months (95% CI 20.7 to 24.4)). Including UCP
events lowered estimates of treatment benet—median
crPFS was 13.3 months (95% CI 11.1 to 13.8) versus
median rPFS of 16.5 months (95% CI 13.8 to 16.8) in AAP
group. Finally, crPFS showed high correlation with OS
(r=0.67; 95% CI 0.63 to 0.71).
Conclusions UCP is a common and clinically relevant
phenomenon in patients with metastaticcastration-
resistant prostate cancer (mCRPC) treated with AAP or
prednisone. UCP is prognostic and associated with inferior
OS and post- progression survival. A combination of PSA-
non- response and UCP identies patients with poorest
survival. When included in PFS analysis, UCP diminishes
estimates of treatment benet. Continued study of UCP in
mCRPC is warranted.
INTRODUCTION
Assessing treatment outcomes in prostate
cancer clinical trials is complicated by the
fact that the majority of patients with meta-
static prostate cancer have bone- only or
bone- predominant disease.1 To detect and
monitor these lesions, 99mTc- methylene
diphosphonate radionuclide bone scintig-
raphy remains the most widely used radio-
graphic modality. The validated regulatory
time to event endpoint of radiographic
disease progression in the Prostate Cancer
Working Group (PCWG) consensus guideline
includes an assessment of disease progres-
sion using bone scintigraphy.2 However,
bone scintigraphy provides an imperfect
Key questions
What is already known about this subject?
►Unequivocal clinical progression (UCP)—a worsen-
ing of clinical status with or without radiographic
progression (RAD)—is the frequently observed
mode of metastatic prostate cancer progression in
clinical practice.
►UCP is, in part, a function of limitations of currently
used imaging modalities.
►Physicians change treatment due to UCP, but there’s
lack of consistency in management due to varying
denitions of UCP and knowledge about impact on
outcomes.
What does this study add?
►UCP is more common than previously estimated, oc-
curring in 37% of patients in the COU- AA-302 study.
►Risk of UCP is higher in patients with aggressive dis-
ease biology as captured by prognostic index model
risk group.
►UCP has substantial adverse impact on overall sur-
vival and post- treatment survival; and including
UCP events shortens estimates of treatment benet
(progression- free survival).
How might this impact on clinical practice?
►UCP can be clinically used by itself and in combina-
tion with prostate specic antigen- non- response (a
marker of treatment insensitivity) to identify patients
with poorest prognosis and proactively tailor treat-
ment approach including early genomic testing to
nd targetable alterations.

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2RaoA, etal. ESMO Open 2020;5:e000943. doi:10.1136/esmoopen-2020-000943
assessment of disease burden and treatment response3 4
and in virtually all contemporary metastatic castration-
resistant prostate cancer (mCRPC) trials, a subset of
patients experienced clinical deterioration in the form
of new pain, worsening performance status and so on
without meeting PCWG criteria for radiographic progres-
sion. The type of disease progression—serologic alone,
radiographic or clinical—has been shown to impact the
choice of subsequent therapy in clinical practice.5 The
clinicopathological factors associated with such clinical
progression and the relationship between the occur-
rence of clinical progression and overall survival has not
been well studied.
COU- AA-302 was a phase 3, randomised, double- blind,
multinational registration clinical trial in which asymp-
tomatic or mildly symptomatic patients with progres-
sive chemotherapy- naïve mCRPC were randomised to
receive abiraterone acetate 1000 mg daily plus predni-
sone 5 mg two times per day (AAP group) or placebo
plus prednisone 5 mg two times per day (prednisone
group). The results showed the superiority of AAP over
prednisone in both co- primary endpoints of radio-
graphic progression free survival (rPFS) and overall
survival (OS) despite the availability and use of effec-
tive agents after discontinuation of protocol therapy.6 7
The trial results led to the expansion of the indication
of AAP to include all patients with progressing mCPRC
independent an individual’s taxane exposure history.8
A subsequent analysis showed a high degree of correla-
tion between rPFS and OS (Spearman’s correlation
coefficient, 0.72).9 Demonstration of similarly high
correlation between rPFS and OS in COU- AA-302 and
other prospective randomised controlled trials formed
the basis for acceptance of rPFS as a surrogate endpoint
for clinical trials in mCRPC.2 9–11
An important feature of the COU- AA-302 trial was that
the discontinuation of study therapy was not required
at serological or radiographic progression. As a result,
many patients continued protocol therapy beyond radio-
graphic progression or until they experienced unequiv-
ocal clinical progression (UCP), an indication that, based
on physician judgement, they were ‘no longer clinically
benefitting’ from the treatment.2 UCP was prespecified
in the protocol by any one of the following: the occur-
rence of cancer pain requiring chronic opiate analgesia, a
decline in Eastern Cooperative Oncology Group (ECOG)
performance status to 3 or greater, or an immediate need
to initiate cytotoxic chemotherapy, radiation therapy or
surgical intervention for disease- related events. We eval-
uated the relationship between UCP and radiographic
progression, the characteristics of patients experiencing
UCP and the association of UCP with survival outcomes.
Because patients with non- radiographic progression
are excluded from rPFS analyses, we also evaluated if
a composite clinicoradiographic PFS endpoint would
improve on the correlation between rPFS and OS in
mCRPC.
METHODS
A post- hoc retrospective analysis was performed using
the data from COU- AA-302 trial. Patients discontinuing
the trial therapy due to disease progression were catego-
rised into three cohorts based on the event that resulted
in treatment discontinuation—UCP- only, radiographic
progression (RAD)- only and UCP plus RAD. Baseline
clinicopathological factors including Gleason grade,
AJCC TNM stage, prostate specific antigen (PSA) level at
initial diagnosis and time from initial diagnosis to initia-
tion of protocol therapy and the prognostic index model
(PIM)- risk groups were evaluated for association with
UCP. PIM was created using patient- level data from COU-
AA-302 trial and has been associated with overall survival
in this setting.12 The model incorporates four baseline
variables: Brief Pain Inventory score, lactate dehydroge-
nase level, alkaline phosphatase level and presence of
≥10 bone metastases. Because higher PIM scores corre-
late with a higher bone metastatic tumour burden and
clinically- symptomatic disease at presentation, we hypoth-
esised that PIM poor- risk patients would be more likely to
have UCP than PIM good or intermediate- risk patients.
Descriptive analyses were performed for baseline demo-
graphics and clinicopathological characteristics including
the PIM- risk group.
OS was defined as the time from randomisation to
death from any cause; rPFS as time from randomisation
to radiographic disease progression or death; and the
duration of subsequent survival (DSS) as the time from
study therapy discontinuation to death. Notably, after the
interim OS analysis, the study’s independent data moni-
toring committee allowed patients in the prednisone
group to cross- over to treatment with AAP on disease
progression. DSS was calculated from the time of discon-
tinuation of the first therapy in such cases. The relation-
ship between treatment sensitivity (using PSA response;
defined as >=50% PSA reduction from baseline per
PCWG2) and mode of disease progression was explored
with the hypothesis that a combination of PSA- non-
response and UCP- only progression would predict the
worst survival outcomes. Median overall survival with 95%
CIs was estimated using the Kaplan- Meier method. The
Cox proportional- hazards model was used to estimate the
HR and its associated 95% CI.
In COU- AA-302 study, a proportion of patients discon-
tinued protocol- specified assessments for radiographic
progression after occurance of UCP and were censored
from the rPFS analyses. A composite endpoint of clini-
coradiographic PFS (crPFS), defined as the time from
randomisation to discontinuation of therapy due to UCP,
RAD progression or both or death, was created to capture
the disease progression outcomes of these patients. We
performed an exploratory analysis of crPFS and OS for
the study population and individual treatment groups
using an iterative multiple imputation method, where the
censored times are iteratively augmented. This method is
similar to Spearman’s rank correlation, but incorporates

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the censoring information which is better suited to assess
the relationship between two ‘time- to- event’ variables.13
RESULTS
The final analysis of COU- AA-302 was conducted at 96% of
planned deaths, with a median follow- up of 49.2 months.
Study treatment was discontinued by 500 (92%) patients
in the AAP group and 540 (100%) in the prednisone
group. Of the 736 patients who discontinued treatment
for a protocol- defined progression measure, 280 (38%)
discontinued for UCP- only, 332 (45%) for RAD- only and
124 (17%) for UCP plus RAD. These proportions were
balanced between the two treatment groups (table 1).
The most common UCP events were the need to initiate
chemotherapy (50% in AAP group vs 53% in predni-
sone group) and need to initiate radiation therapy (36%
in AAP group vs 27% in prednisone group). As previ-
ously published, 522 of 532 (99%) patients in the AAP
group, and 506 of 522 (97%) patients in the prednisone
group had no or minimal pain at study entry.6 However,
increased cancer pain requiring chronic opiate therapy
was the cause for treatment discontinuation in 45 of 366
(12.3%) patients in the AAP group and 51 of 370 (13.8%)
patients in the prednisone group.
Predictors of unequivocal clinical progression
The clinicopathological characteristics were compa-
rable in the UCP- only, RAD- only and UCP plus RAD
cohorts (online supplemental table 1). Notably, 126 of
280 (45.0%) patients in UCP- only, 195 of 332 (58.7%) in
RAD- only and 71 of 124 (57.3%) in UCP plus RAD had
visceral metastatic disease. PIM- risk group was associ-
ated with a higher risk of UCP in our analysis. Patients in
poor- risk group had higher rate of UCP- only progression
compared with the other two risk groups (46% vs 21% in
good- risk and 30% in intermediate- risk; p<0.0001).
Unequivocal clinical progression as a negative prognostic
marker for survival
UCP was associated with inferior survival outcomes inde-
pendent of the treatment arm. In the study population,
median OS was 25.7 months in UCP- only cohort and
26.9 months in UCP plus RAD cohort, compared with
33.0 months for RAD- only cohort, translating into a 39%
higher likelihood of death in UCP- only cohort (HR 1.39;
95% CI 1.16 to 1.66; p=0.0003) and a 36% higher like-
lihood of death in the UCP plus RAD cohort (HR 1.36;
95% CI 1.08 to 1.71; p=0.0079) (figure 1).
The deleterious effect of UCP was also seen in each of
the treatment groups. In the AAP group, the median OS
was 27.7 months in UCP- only cohort (HR 1.36; 95% CI
1.04 to 1.76; p=0.0224) and 26.9 months in UCP plus
RAD cohort (HR 1.53; 95% CI 1.11 to 2.11; p=0.0091),
compared with 34.9 months in RAD- only cohort. In the
prednisone group, the median OS was 23.4 months in
UCP- only cohort (HR 1.44; 95% CI 1.13 to 1.84; p=0.003)
and 27.0 months in UCP plus RAD cohort (HR 1.23;
95% CI 0.88 to 1.71; p=0.219), compared with 30.3
months in RAD- only cohort (figure 2).
In the study population, the median DSS was 15.8
months for UCP- only cohort compared with 19.0 months
for RAD- only cohort (HR 1.27; 95% CI 1.06 to 1.51;
p=0.0092), translating into a 27% higher risk of death
after treatment discontinuation for patients with UCP-
only progression. Median DSS was 13.4 months in the
UCP plus RAD cohort, translating into a 31% higher risk
of death after treatment discontinuation compared with
RAD- only cohort (HR 1.31; 95% CI 1.04 to 1.65; p=0.02).
Similarly, UCP- only progression appeared to have an
adverse impact on DSS in both treatment groups, but
these differences did not reach statistical significance.
Taken together, these results suggest that UCP is asso-
ciated with an inferior overall and post- treatment survival
regardless of therapy.
Unequivocal clinical progression events lower the estimates
of treatment benet
Consistent with our hypothesis, incorporation of UCP
events diminished the magnitude of PFS in both treat-
ment arms. In the AAP group, the median crPFS was 13.3
months (95% CI 11.1 to 13.8) and median rPFS was 16.5
months (95% CI 13.8 to 16.8). In the prednisone group,
the median crPFS was 6.0 months (95% CI 5.5 to 8.2) and
median rPFS was 8.3 months (95% CI 8.0 to 9.7). However,
AAP treatment was associated with an improvement in
both crPFS (HR 0.55, 95% CI 0.48 to 0.64, p<0.0001) and
rPFS (HR 0.56, 95% CI 0.49 to 0.65, p<0.0001) compared
with prednisone suggesting that occurrence of UCP does
not selectively diminish benefit from either of these ther-
apies.
Table 1 Summary of treatments and modes of disease
progression
Abiraterone
plus prednisone
(n=546)
Placebo plus
prednisone
(n=542)
Patients treated, n (%) 542 (100) 540 (100)
Treatment
discontinued
500 (92) 540 (100)
Treatment ongoing 42 (8) 0 (0)
Reasons for
discontinuation, n (%)
366 (68) 370 (69)
UCP- only 138 (26) 142 (26)
RAD- only 160 (30) 172 (32)
RAD plus UCP 68 (13) 56 (10)
Adverse event 50 (9) 33 (6)
Other 42 (8) 30 (6)
Withdrawal of consent 41 (8) 56 (10)
Lost to follow- up 1 (0.2) 0
All values are n (%).
RAD, radiographic progression; UCP, unequivocal clinical
progression.

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4RaoA, etal. ESMO Open 2020;5:e000943. doi:10.1136/esmoopen-2020-000943
Clinicoradiographic progression-free survival and overall
survival
In the study population, we found a high but similar
correlation between crPFS and OS (r=0.67; 95% CI 0.63
to 0.71) and between rPFS and OS (r=0.63; 95% CI 0.58
to 0.67). This finding is consistent with comparable HRs
seen in the crPFS and rPFS analyses above.
Treatment insensitivity and unequivocal clinical progression
In the study population, patients with a combination of
PSA- non- response and UCP- only progression had infe-
rior survival (median OS 22.6 months (95% CI 20.7 to
24.4)) than those with PSA- non- response and RAD- only
progression (median OS 27.7 months (95% CI 24.2 to
30.1)), PSA response and UCP- only progression (median
OS 33.2 months (95% CI 28.5 to 36.3)) and PSA response
and RAD- only progression (median OS 40.2 months
(95% CI 36.6 to 45.6)) (online supplemental figure 1).
DISCUSSION
In this post- hoc analysis of a large phase 3 trial, we showed
that unequivocal clinical progression is a common event
in men receiving abiraterone or prednisone therapy
for mCRPC, and that a high- risk PIM score that reflects
a higher mortality risk and disease burden is associated
with a higher likelihood that treatment will be discon-
tinued because of an UCP event. We found that inclusion
of UCP as a progression measure lowers the estimates of
benefit from treatment, and that the survival benefit from
an effective treatment for patients who have UCP is less
than for those who only show radiographic progression,
particularly when combined with PSA- non- response as a
marker of treatment insensitivity.
A substantial proportion (38%) of patients in COU- AA-
302 trial discontinued treatment for non- radiographic
progression including approximately 12% of patients
who had no or minimal pain at study entry who eventu-
ally discontinued treatment due to cancer- related pain
requiring chronic opiate analgesia. The overall rate of
UCP is higher than reported in a sensitivity analysis of
phase 3 trial of enzalutamide versus placebo in first- line
mCRPC (PREVAIL), where 6.9% patients in enzalut-
amide group and 20.9% in the placebo group discon-
tinued treatment due to clinical progression.10 These
Figure 1 Kaplan- Meier plots of overall survival by the type of disease progression in the study population. OS,overall
survival; RAD, radiographic progression;UCP, unequivocal clinical progression.

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RaoA, etal. ESMO Open 2020;5:e000943. doi:10.1136/esmoopen-2020-000943 RaoA, etal. ESMO Open 2020;5:e000943. doi:10.1136/esmoopen-2020-000943
differences could be explained by inclusion of patients
who experienced RAD progression and then continued
treatment until UCP progression in the COU- AA-302
trial; and the stricter definition of UCP in the PREVAIL
trial, where UCP was as a combination of a skeletal- related
event AND either initiation of cytotoxic chemotherapy
or initiation of an investigational agent for treatment of
prostate cancer.
UCP occurred at a similar frequency in both treatment
groups suggesting that it is independent of the antian-
drogen therapies used in the COU- AA-302 trial. PIM- risk
group was associated with an increased likelihood of UCP.
Because PIM comprises of several clinical parameters that
are associated with a higher tumour burden, this correla-
tion between an increased risk of UCP in men with poor-
risk disease is hypothesis- generating.
In our analysis, patients who experienced UCP- only
progression uniformly had a shorter overall survival as
well as the time from study therapy discontinuation to
death compared with patients with RAD- only progression
strongly suggesting that this mode of disease progression
has important prognostic implications. Furthermore,
when clinical progression events were incorporated into
PFS analysis, it diminished the PFS benefit in both AAP
and placebo groups. Our findings could help refine esti-
mates of treatment benefits with AAP therapy in routine
clinical practice. Despite this, AAP treatment demon-
strated improvement in outcomes compared with pred-
nisone. A similar effect was observed in the sensitivity
analyses of rPFS in the PREVAIL trial of enzalutamide.
We found that a composite end point of crPFS failed to
demonstrate a higher correlation with OS compared with
rPFS. This may be due to lack of sufficient sample size
in the post- hoc analysis as a whole, or because clinicians
decided to continue treatment beyond UCP due to lack
of subsequent effective treatment options, thus increasing
the proportion of patients in the UCP plus RAD group
at the cost of UCP- only group. Notably, the correlation
Figure 2 Kaplan- Meier plots of overall survival by the type of disease progression in each of the treatment groups.
AAP,abiraterone acetate and prednisone; OS, overallsurvival; Pred, prednisone; RAD, radiographicprogression; UCP,
unequivocal clinical progression.

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between rPFS and OS also appears to be lower in our
study than previously reported,9 possibly due to our use
of data from the final cut- off (2014) and differences in
method of statistical analysis.
It is possible that inclusion of clinical progression events
in PFS analysis may not build on the work that has gone
into establishing rPFS as a surrogate endpoint in pros-
tate cancer.11 14 However, crPFS can serve an as a clinically
meaningful endpoint within the framework of the ‘no
longer clinically benefitting’ (NLCB) time- to- event measure
introduced in PCWG3 that promotes assessment of clinical
need for changing the treatment rather than strictly at the
first evidence of radiographic progression.2 Thus, our study
provides support for development of a unified definition of
UCP and incorporation of crPFS in mCRPC clinical trials.
The finding that a combination of PSA- non- response and
UCP are correlated with the worst survival outcomes could
have important consequences as well. The use of these two
easily evaluable treatment response variables can identify
the group of patients at the highest risk of poor outcomes in
routine clinical practice.
Our study shares some of the limitations of exploratory
subgroup analyses.15 Further, the definition of UCP used in
COU- AA-302 trial could have arguably adversely impacted
survival by allowing patients to continue on treatment until
significant worsening of clinical status. At the time that
COU- AA-302 was designed, there were few effective treat-
ment options for mCRPC and this definition of UCP, while
somewhat subjective and clinician judgement- dependent,
was clinically appropriate. In contemporary clinical prac-
tice with availability of several therapies in post- abiraterone
setting, the construct of NLCB that allows for continuation
of therapy until the clinical status remains stable (rather than
UCP which requires treatment until clinical deterioration)
may be better suited to assist clinicians with the decision to
switch therapies. The relatively narrow definition of UCP
also has the potential to miss a subset of patients with other
clinical findings of progression (eg, worsening quality of life
scores). Importantly, while abiraterone is now widely used
for men with metastatic hormone- sensitive prostate cancer
(mHSPC), because of differences in clinical characteristics
of mHSPC and mCRPC patients, it is unknown if our results
can be applied to patients treated with abiraterone acetate
plus prednisone for mHSPC. Additionally, generalisation of
findings to patients receiving non- androgen receptor (AR)
targeted therapies such as docetaxel or radium-223 may be
limited.
CONCLUSIONS
UCP is a clinically- significant phenomenon that occurred
independently of radiographic progression in a high propor-
tion of patients with chemotherapy- naïve mCRPC in COU-
AA-302 trial. Risk of UCP was highest in patients with poor
baseline PIM- risk group, suggesting a correlation of UCP
with adverse biology. UCP is prognostic, with occurrence
associated with inferior OS and DSS, independent of treat-
ment group. Further, a combination of PSA- non- response, a
marker of treatment insensitivity, and UCP can be used to
identify patients with poorest survival. Incorporating clin-
ical progression events in PFS analysis resulted in decreased
magnitude of benefit, further underscoring the prognostic
significance of UCP. While crPFS failed to show a better
correlation with OS than rPFS, our findings support further
development of crPFS within the framework of NLCB as
proposed in PCWG3. Future clinical trials should report the
outcomes for patients with UCP to help validate our findings
and inform subsequent treatment strategies in this group of
patients.
Twitter Arpit Rao @drarpitrao
Acknowledgements Janssen research team's assistance with analysis and
drafting of this manuscript.
Contributors Conception or design of the work - AR, HIS, MJM, CR. Data collection
- KQ, PDP, MKY, AL. Data analysis and interpretation - AR, KQ, AL, CR. Drafting the
article - AR, KQ, CR, Critical revision of the article - HIS, MJM, PDP, MKY, AL, CR.
Final approval of the version to be published - All authors.
Funding The authors have not declared a specic grant for this research from any
funding agency in the public, commercial or not- for- prot sectors.
Disclaimer Arpit Rao Consulting or Advisory Role - Eli Lilly and Co; Clovis
Oncology; Sano- Genzyme; QED Therapeutics Research Funding - Eli Lilly and
Co (Inst); Clovis Oncology (Inst); Genentech- Roche (Inst); Pzer (Inst); Foundation
Medicine (Inst) Howard I Scher Leadership - Asterias Biotherapeutics Stock and
Other Ownership Interests - Asterias Biotherapeutics Consulting or Advisory Role
- Ambry Genetics Corporation, Konica Minolta, Inc; Amgen; Bayer; ESSA; Janssen
Biotech, Inc; Janssen Research & Development; Menarini Silicon Biosystems;
Sano Aventis; WIRB- Copernicus Group Research Funding - Epic Sciences (Inst);
Illumina (Inst); Innocrin Pharma (Inst); Janssen (Inst); Menarini Silicon Biosystems
(Inst); Thermo Fisher Scientic Biomarkers (Inst) Travel, Accommodations, Expenses
- Amgen; Asterias Biotherapeutics; Bayer; ESSA; Konica Minolta, Inc; Menarini
Silicon Biosystems; Prostate Cancer Foundation; Sano Aventis; WIRB- Copernicus
Group Peter De Porre Employment - Johnson and Johnson Stock and Other
Ownership Interests - Johnson and Johnson Margaret K Yu Employment - Janssen
Pharmaceutical Co Stock and Other Ownership Interests - Janssen Pharmaceutical
Co Patents, Royalties or Other Intellectual Property - Janssen Pharmaceutical
Co Travel, Accommodation, Expenses - Janssen Pharmaceutical Co Anil Londhe
Employment - Johnson and Johnson Stock and Other Ownership Interests-
Johnson and Johnson Keqin Qi Employment - Johnson and Johnson Stock or Other
Ownership Interests - Johnson and Johnson; BMY Michael J Morris Consulting
or Advisory Role - Advanced Accelerator Applications; Astellas Pharma; Bayer;
Blue Earth Diagnostics; Endocyte; ORIC Pharmaceuticals; Tokai Pharmaceuticals;
Tolmar Pharmaceuticals Research Funding - Bayer (Inst); Corcept Therapeutics
(Inst); Endocyte (Inst); Progenics (Inst); Roche/Genentech (Inst); Sano (Inst) Travel,
Accommodations, Expenses - Bayer; Endocyte Charles Ryan Honoraria - Janssen
Pharmaceutical Co; Bayer Consulting or Advisory Role - Bayer; Dendreon; AAA
Research Funding - Clovis Oncology (Inst); Sano Genzyme (Inst) I = Immediate
Family Member, Inst = Institution.
Competing interests PDP, MKY, AL and KQ are employed by Janssen Research
and Development.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. All data
relevant to the study are included in the article or uploaded as supplementary
information. Patient- level data is proprietary (owned by trial sponsor) and not
available for third- party review. To request relevant data including statistical les
used for the analyses in this article, please contact the corresponding author via
email.
Supplemental material This content has been supplied by the author(s). It has
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
peer- reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability

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RaoA, etal. ESMO Open 2020;5:e000943. doi:10.1136/esmoopen-2020-000943 RaoA, etal. ESMO Open 2020;5:e000943. doi:10.1136/esmoopen-2020-000943
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
Open access This is an open access article distributed in accordance with the
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See:http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.
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