EURURO Vol. 72 No. 3

324 476

conditions, AR can repress a number of genes, including AR
and those involved in androgen synthesis, DNA synthesis,
and proliferation. Therefore, high-dose T may lead castra-
tion-resistant cells to transition from a more oncogenic
transcriptome associated with castrate T levels to a high-
androgen transcriptome that does not support cancer
proliferation.
To exploit these mechanistic findings, we developed a
mode of intermittent high-dose T therapy in the clinic
termed BAT. We hypothesized that rapidly cycling between
the polar extremes of near-castrate and supraphysiologic
serum T (SPT) levels would prevent adaptive changes in AR
expression, prolonging the length of time during which
patients respond to this therapy. Furthermore, because
recent studies have shown that the dsDNA breaks and
apoptosis induced by high doses of androgens are transient,
rapid cycling of T could result in repeated rounds of DNA
damage, enhancing antitumor effects .
To date, BAT has yielded encouraging preliminary results
in CRPC patients. In our first pilot study testing BAT
combined with etoposide, we found that of the 14 patients
completing at least the first 3 mo of therapy (response-
evaluable cohort), 50% had PSA declines and 5/10 RESICT-
evaluable patients had an objective soft-tissue response
. It is also notable that there was a high rate of response
to subsequent ARS inhibitors (eg, abiraterone, antiandro-
gens), potentially indicating that BAT could effectively
resensitize tumors to drugs inhibiting ARS. This observation
provided justification for a study (NCT02090114; RESTORE)
evaluating BAT in men after abiraterone or enzalutamide,
with the co-primary endpoints of (1) response to BAT and
(2) response to rechallenge with either abiraterone or
enzalutamide. Preliminary results from the enzalutamide
armof the study have demonstrated a >50% PSA decline and
an objective response in approximately one-third of
patients. BAT was well tolerated, with low-grade musculo-
skeletal pain and breast tenderness being common side
effects. On rechallenge with enzalutamide, 50% of patients
had a >50% PSA response. BAT is also able to suppress AR-V7
expression in most men with detectable AR-V7 in baseline
CTC samples .
At present, BAT is being definitively tested in a large
(n = 180) randomized trial (NCT02286921; TRANSFORMER)
in asymptomatic CRPC patients who have failed on
abiraterone. In this study, BAT is being compared to
enzalutamide for the primary endpoint of progression-free
survival. Patients are notably allowed to cross over
following progression to the first therapy, with an impor-
tant secondary endpoint being PSA progression-free sur-
vival on the second agent in order to further examine the
question of the ability of BAT to resensitize tumors to ARS
inhibitors.
As it stands, not all men respond favorably to treatment,
and there is an urgent need to develop biomarkers able to
discriminate between BAT responders and nonresponders.
Candidate predictive biomarkers include high AR/AR-V7
expression and the presence of mutations in genes involved
in DNA repair (eg, BRCA1/2, ATM and others). The case report
of an extreme BAT responder with germline BRCA2 and ATM
mutations supports DNA damage as one potential mecha-
nisms underlying response to high-dose T, while a second
case report showing eradication of an AR copy gain
(detected from ctDNA) and a clinical response to high-dose
T supports AR levels as an important mediator of BAT’s
efficacy . These hypotheses are actively being
investigated in the RESTORE and TRANSFORMER trials.
Optimization of SPT-based therapies is still needed.
While there is a strong rationale for an intermittent
approach (ie, BAT), preclinical studies have demonstrated
that continuous exposure to supraphysiologic androgen
levels also has a robust antitumor effect. Clinical trials
testing different dosing schedules are needed to determine
if better modes for administration of SPT-based therapy
exist. It also stands to reason that combinatorial SPT-based
therapies may produce better outcomes. An emerging
understanding of the mechanism of BAT inhibition have
suggested that potential combinatorial strategies (eg, with
PAPR inhibitors, platinum agents, proteasome inhibitors,
immune checkpoint inhibitors) may be warranted, as are
rational sequencing strategies (time-sequential therapies).
Conflicts of interest: The authors have nothing to disclose.
Acknowledgments: This work was supported by DOD awards
W81XWH-15-PCRP-PRTA (M.T.S.) and W81XWH-14-2-0189 (S.R.D.);
NIH award R01CA184012 (S.R.D.); and a Prostate Cancer Foundation
Young Investigator Award (M.T.S.).
References
[1]
[2]
.
[3]
[4]
[5]
.
[6]
[7]
[8]
[9]
[10]
.
E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 3 2 3 – 3 2 5 324