EURURO Vol. 72 No. 2

alternative adapting mechanisms that can overcome AR

blockade, and these also need to be evaluated

[9] .

The genomic AR aberrations described in this report

appear common in CRPC but seem to be infrequent in

localized prostate cancers before androgen deprivation.

These probably primarily evolve as a result of treatment-

induced selective pressures, although AR splice variants may

be present in untreated prostate tumors

[10] .

Whether these

events appear de novo or are a result of the selection of

subclones that become more prominent after therapy needs

further consideration and may be relevant when selecting

early treatment for both localized and metastatic disease.

The mechanisms resulting in the emergence of these

complex intra-AR rearrangements also merit discussion.

Aberrant DNA damage responses, frequently present in

mCRPC, and the resulting genomic instability may contrib-

ute to the generation of these structural genomic rearran-

gements, particularly when error-prone non-homologous

Table 1 – Studies determining androgen receptor aberrations and their impact on clinical outcome

Assay

Aberration

Treatment

Clinical impact

Plasma DNA

Targeted DNA

sequencing

[3]

AR CN gain (40%)

AR T878A or L702H mutant (5%)

Abiraterone (80 pts)

AR aberration (CN gain and AR mutant) vs AR CN neutral patients

PSA 50% RR: OR 4.9;

= 0.002

PFS: HR 3.73;

= 2 10

b,c

OS: HR 7.33;

= 1.2 10

b,c

CTCs

RT-PCR

[5]

AR-V7 (RNA) positive (19%)

Abiraterone (31 pts)

AR-V7 positive vs AR-V7 negative patients:

PSA 50% RR: 0% vs 68%;

= 0.004

PSA PFS: 1.3 mo vs NR; HR 16.1;

0.001

b,c

Clinical/radiological PFS: 2.3 mo vs NR; HR 16.5;

0.001

b,c

OS: 10.6 mo vs NR; HR 12.7;

= 0.006

b,c

AR-V7 (RNA) positive (39%)

Enzalutamide (31 pts)

AR-V7 positive vs AR-V7 negative patients:

PSA RR: 0% vs 53%;

= 0.004

PSA PFS: 1.4 vs 6.0 mo; HR 7.4;

0.001

b,c

Clinical/radiological PFS: 2.1 vs 6.1 mo; HR 8.5;

0.001

b,c

OS: 5.5 mo vs NR; HR 6.9;

= 0.002

b,c

RT-PCR

[12]

AR-V7 (RNA) positive (46%)

Docetaxel (30 pts) and

cabazitaxel (7 pts)

AR-V7 positive vs AR-V7 negative patients:

PSA 50% RR: 41% vs 65%;

= 0.19

PSA PFS: 4.5 vs 6.2 mo; HR 2.1;

= 0.06

b,c

Clinical/radiological PFS: 5.1 vs 6.9 mo; HR 2.8;

= 0.02

b,c

[11_TD$DIFF]

OS; 9.2 vs 14.7 months; HR 2.5; p=0.11

AR-V7 positive patients demonstrated improved 50% PSA RR

(41% vs 0%;

0.001

a )

PSA PFS (HR 0.22;

0.001

clinical/radiological PFS (HR 0.26;

= 0.001

c )

, and OS

(HR 0.83;

= 0.76

) with taxane treatment compared to

AR-targeted therapies (compared to REF; updated analysis).

There was no benefit of taxane treatment over

AR-targeted therapies in AR-V7 negative patients

[6]

AR-V7 (protein) positive (12.5%)

Abiraterone, enzalutamide,

and apalutamide (128 pts)

AR-V7 positive vs AR-V7 negative patients:

rPFS: 2.3 vs 14.5 mo; HR 2.3;

0.001

b,c

Time on therapy: 2.1 vs 6.8 mo; HR 4.2;

0.001

b,c

OS: 4.6 mo vs NR; HR 11.45;

0.001

b,c

AR-V7 (protein) positive (28.6%)

Docetaxel, cabazitaxel,

and paclitaxel (63 pts)

AR-V7 positive vs AR-V7 negative patients:

rPFS: 5.3 vs 6.6 mo; HR 1.38;

= 0.46

b,c

Time on therapy: 3.0 vs 3.7 mo; HR 1.40;

= 0.23

b,c

OS; 8.9 vs NR; HR 3.74; p=0.001

AR-V7 positive patients had favorable survival on taxane

therapy compared to ARSi (HR 0.24;

= 0.035

[1_TD$DIFF]

)

while

[2_TD$DIFF]

AR-V7

negative patients did not

Targeted RNA

sequencing

[1]

AR-V (RNA) positive (47%)

Abiraterone (15 pts)

and enzalutamide (2 pts)

AR-V positive vs AR-V negative patients:

PSA 50% RR: 44% vs 12.5%;

= 0.29

PFS HR 4.53;

= 0.0105

b,c

Tissue

IHC

[13]

Nuclear AR-V7 (protein) expression Various (37 pts)

Nuclear AR-V7 expression levels by tertiles (3rd vs 2nd vs 1st):

OS from metastatic biopsy: 7.1 vs 10.7 vs 15.6 mo; HR 2.9;

= 0.002

b,c

CTCs = circulating tumor cells; IF = immunofluorescence; IHC = immunohistochemistry; AR = androgen receptor; CN = copy number; pts = patients;

PSA = prostate-specific antigen; RR = response rate; PFS = progression-free survival; OS = overall survival; OR = odds ratio; HR = hazard ratio; RT-

PCR = reverse transcription polymerase chain reaction; AR-V7 = androgen receptor variant 7; AR-V = androgen receptor variant; NR = not reached;

ARSi = androgen receptor signaling inhibitor; rPFS = radiological PFS.

Fisher’s exact test.

Kaplan-Meier method with log-rank test.

Univariate Cox regression analyses.

Multivariate Cox regression analyses.

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