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ERLEADA - Androgen Receptor Anomalies

Last Updated: 07/06/2023

SUMMARY

  • In the phase 3 SPARTAN study, which evaluated the efficacy and safety of ERLEADA compared to placebo in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) receiving continuous androgen deprivation therapy (ADT),1 analyses of multiple androgen receptor (AR) aberrations (AR-V7 expression, AR ligand-binding domain [LBD] mutations, and AR amplification) and non-AR aberrations were performed.2
    • The frequency of any AR aberration was significantly higher at end of treatment than at baseline (25.4% vs 13.6%; P=0.019). The difference between the ERLEADA and placebo groups at end of treatment was not statistically significant.
    • In patients who progressed to metastatic castration-resistant prostate cancer (mCRPC) and received abiraterone acetate plus prednisone or enzalutamide as first subsequent therapy, the median second progression-free survival (PFS2) was shorter in patients who were positive than in those who were negative for AR amplification (13.8 months vs 27.6 months; HR, 2.91; 95% CI, 1.62-5.25; P=0.0004) and any AR aberration (15.5 months vs 27.6 months; HR, 1.74; 95% CI, 1.08-2.80; P=0.024).2, 3
  • In the phase 3 TITAN study, which evaluated the efficacy and safety of ERLEADA compared to placebo in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving continuous ADT,4 analyses of detectable/undetectable circulating-tumor DNA (ctDNA), AR aberrations (AR amplification, AR LBD mutations, and AR-V7), and non-AR aberrations were performed.5, 6
    • The frequency of total AR aberrations increased from baseline to end of treatment in both groups; however, the frequency was significantly lower in the ERLEADA group vs placebo group at end of treatment (48% vs 67%; P=0.041). Additionally, the proportion of patients with AR-V7, AR LBD mutations, and AR amplification at end of treatment was not increased in the ERLEADA group vs placebo group.5 Median overall survival (OS) and PFS2 were significantly shorter in patients with detectable ctDNA or AR aberrations at the end of treatment. In patients positive for detectable ctDNA vs negative, the median OS was 12.9 months vs not reached (NR; HR, 7.95; 95% CI, 2.47-25.56; P<0.0001) and the median PFS2 was 11.4 months vs NR (HR, 3.53; 95% CI, 1.60-7.79; P=0.0009). In patients with positive AR aberrations vs negative, the median OS was 11.1 months vs NR (HR, 3.67; 95% CI, 1.83-7.36; P=0.0001) and the median PFS2 was 8.8 months vs 21.1 months (HR, 2.92; 95% CI, 1.64-5.19; P=0.0001).5, 6 Results from an exploratory post-hoc analysis evaluating genomic aberrations associated with OS have also been reported.7
  • In the phase 2 ARN-509-001 study of patients with nmCRPC or mCRPC treated with ERLEADA, the frequency of AR LBD mutations has been reported.8

BACKGROUND

Several potential mechanisms have been proposed to explain resistance to AR-targeted agents, including AR amplification, AR overexpression, AR splice variants such as AR-V7, and altered steroidogenesis.9 Point mutations in the AR LBD, including F877L and T878A (formerly F876L and T877A9, 10), have also been associated with resistance to AR-targeted therapy.9, 11, 12

CLINICAL DATA

AR Aberrations in the Phase 3 SPARTAN Study

Smith et al (2021)2 evaluated AR aberrations at baseline and end of treatment in a subset of patients with nmCRPC who were enrolled in the SPARTAN study. Evaluations included determination of aberrations associated with progression from non-metastatic to metastatic disease in the ERLEADA group and assessment of aberrations longitudinally from non-metastatic disease at baseline to metastatic disease at progression.

Study Design/Methods

  • SPARTAN (NCT01946204) was a phase 3, randomized, double-blind, placebo-controlled, multicenter study in patients with high-risk (defined as prostate-specific antigen [PSA] doubling time ≤10 months) nmCRPC receiving either ERLEADA 240 mg orally (PO) once daily (QD) or placebo. All patients received continuous ADT throughout the study. The primary endpoint was metastasis-free survival (MFS), defined as the time from randomization to the time of first evidence of detection of blinded independent central review-confirmed distant metastasis, defined as new bone or soft-tissue lesions or enlarged lymph nodes above the iliac bifurcation, or death due to any cause, whichever occurred first. Study treatment was continued until protocol-defined progression, adverse events, or withdrawal of consent occurred.1
  • PFS2, an exploratory endpoint, was defined as the time from randomization to investigator-assessed disease progression (PSA progression, detection of metastatic disease on imaging, symptomatic progression, or any combination) during the first subsequent treatment for mCRPC or death from any cause.1
  • Blood samples were collected in a subset of patients who consented to biomarker analysis at baseline and at end of study treatment (defined as the time of first MFS event or treatment discontinuation) and the following were assessed:
    • AR LBD mutations (L702H, W742C, H875Y, F877L, and T878A)
    • Non-AR aberrations (CDK12, RB1, BRCA1, BCA2, TP53 inactivation and MET, MYC, and PIK3CA activation)
  • Next-generation sequencing of cell-free DNA (cfDNA) isolated from plasma was used to assess ctDNA and genomic AR- and non-AR aberrations. Whole blood-derived quantitative reverse transcription polymerase chain reaction from total RNA was utilized for AR-V7 identification.
  • The biomarker population included patients who had at least 1 biomarker sample collection at end of study treatment and analyzed before the first interim analysis (data cut-off of 19 May 2017).
  • Associations between MFS, PFS2, and OS with biomarker status were assessed in univariate analyses at baseline and multivariate analyses of biomarker status were assessed in pooled patients from both groups who had all biomarkers measured.

Results

  • Patient baseline characteristics were generally similar between the SPARTAN biomarker population (n=247) and the overall SPARTAN population (N=1207). Significant differences were observed in median PSA doubling time which was shorter, and the proportion of patients with PSA doubling time ≤6 months, which was larger. Median MFS, PFS2, and OS were also significantly shorter in the biomarker population compared with the overall population.
  • At the end of the first interim analysis, 247 patients provided blood samples at end of study treatment (193 plasma and whole blood processed samples were from the same patients) and 149 of these patients also provided samples at baseline (110 plasma and whole blood processed samples were from the same patients). A total of 54.6% (131/240) plasma samples and 63.0% (126/200) of whole blood samples at the end of study treatment had matched baseline samples.
  • In the biomarker population, progression of disease was reported in 51% of patients (62/121) in the ERLEADA group and 74% of patients (93/126) in the placebo group.
  • ctDNA-positive samples were obtained from 40.6% of patients at baseline and from 57.1% of patients at end of treatment (P=0.003).3 Refer to Table: AR Aberrations at Baseline and at End of Treatment in the Phase 3 SPARTAN Study.
  • A significantly greater percent of any genomic AR aberrations and AR amplifications were reported in patients at the end of treatment than at baseline (P=0.002 and P=0.013, respectively).3 Refer to Table: Genomic Aberrations at Baseline and End of Treatment in the Phase 3 SPARTAN Study.
  • At the end of study treatment, no significant differences were observed in any type of AR aberration between the ERLEADA and the placebo groups.

AR Aberrations at Baseline and at End of Treatment in the Phase 3 SPARTAN Study3
AR Aberrations
Baseline
n/N
(%)

End of Treatmenta
P-value
BL vs End of Treatment

ERLEADA Group
n/N (%)
Placebo Group
n/N (%)
P-value vs Placebo
Total
n/N (%)

Analyzed cfDNA
133/149
(89.3)

118/121
(97.5)

122/126 (96.8)
240/247 (97.2)
Detected ctDNA
54/133
(40.6)

69/118
(58.5)

68/122 (55.7)
0.697
137/240 (57.1)
0.003
Analyzed whole blood RNA
126/149
(84.6)

96/121
(79.3)

104/126 (82.5)
200/247 (81.0)
AR-V7
8/126
(6.3)

9/96
(9.4)

13/104 (12.5)
0.507
22/200 (11.0)
0.174
Analyzed cfDNA and whole blood RNA
110/149
93/121
100/126
193/247
Any AR aberrations
15/110
(13.6)

20/93
(21.5)

29/100 (29.0)
0.251
49/193 (25.4)
0.019
Abbreviations: AR, androgen receptor; BL, baseline; cf, cell-free; ct, circulating-tumor; MFS, metastasis-free survival.
aEnd of study treatment is at time of first MFS event or treatment discontinuation.


Genomic Aberrations at Baseline and End of Treatment in the Phase 3 SPARTAN Study3
Aberrations
Baseline
(n=54)
End of Treatmentb
P-value
BL vs End of Treatment

ERLEADA Group
(n=69)
Placebo Group
(n=68)
P-value vs Placebo
Total
(n=137)

Any genomic AR aberration
7 (13.0)
25 (36.2)
23 (33.8)
0.858
48 (35.0)
0.002
AR LBD mutation
1 (1.9)
7 (10.1)
5 (7.4)
0.764
12 (8.8)
0.115
AR amplification
6 (11.1)
21 (30.4)
18 (26.5)
0.706
39 (28.5)
0.013
TP53 inactivation
12 (22.2)
27 (39.1)
21 (30.9)
0.372
48 (35.0)
0.118
RB1 inactivation
1 (1.9)
0 (0)
2 (2.9)
0.245
2 (1.5)
>1
BRCA2 inactivation
3 (5.6)
9 (13.0)
12 (17.6)
0.486
21 (15.3)
0.089
PTEN inactivation
1 (1.9)
3 (4.3)
4 (5.9)
0.718
7 (5.1)
0.445
CDK12 inactivation
3 (5.6)
6 (8.7)
6 (8.8)
>1
12 (8.8)
0.563
BRCA1 inactivation
1 (1.9)
2 (2.9)
3 (4.4)
0.681
5 (3.6)
>1
PIK3CA activation
1 (1.9)
5 (7.2)
8 (12)
0.399
13 (9.5)
0.119
MYC activation
0
5 (7.2)
5 (7.4)
>1
10 (7.3)
0.065
MET activation
0
1 (1.4)
0
>1
1 (0.7)
>1
Abbreviations: AR, androgen receptor; BL, baseline; ct, circulating tumor; LBD, ligand-binding domain; MFS, metastasis-free survival.
aGenomic aberrations summarized in patients with detectable levels of ctDNA.
bEnd of study treatment is at time of first MFS event or treatment discontinuation.

No significant associations were observed between AR aberration status at baseline and MFS, PFS2, or OS outcomes. Refer to Table: AR Aberration Status at Baseline and Efficacy Outcomes in the Phase 3 SPARTAN Study. Given the low prevalence of biomarkers at baseline, it is unknown if the lack of association was due to low power or lack of signal.


AR Aberration Status at Baseline and Efficacy Outcomes in the Phase 3 SPARTAN Study2, 3
Efficacy Outcomes
ERLEADA Group
Placebo Group
Total
Biomarker Status
Biomarker Status
Biomarker Status
Positive
Negative
Positive
Negative
Positive
Negative
MFS
Months, median
(95% CI)

14.7
(4.4-NR)

18.2
(12.1-22.1)

7.5
(3.6-10.9)

7.3
(3.8-10.9)

10.9
(3.9-14.7)

11.0
(7.5-15.0)

Events, n/N
3/8
20/42
6/7
38/53
9/15
58/95
HR (95% CI)
0.99 (0.27-3.62)
1.51 (0.61-3.73)
1.17 (0.56-2.45)
P-value
0.992
0.367
0.671
PFS2
Months, median
(95% CI)

34.0
(16.9-NR)

32.1
(25.5-39.1)

27.3
(26.0-NR)

26.1
(23.0-29.7)

34.0
(26.0-43.9)

27.1
(24.7-31.8)

Events, n/N
5/8
24/42
4/7
38/53
9/15
62/95
HR (95% CI)
1.13 (0.40-3.21)
0.67 (0.23-1.99)
0.83 (0.39-1.74)
P-value
0.821
0.473
0.623
OS
Months, median
(95% CI)

NR
(29.9-NR)

45.3
(39.1-NR)

41.1
(37.4-NR)

50.3
(39.7-NR)

NR
(37.4-NR)

47.6
(43.4-52.8)

Events, n/N
2/8
23/42
4/7
27/53
6/15
50/95
HR (95% CI)
0.35 (0.08-1.54)
1.06 (0.36-3.15)
0.67 (0.28-1.60)
P-value
0.165
0.910
0.369
Abbreviations: AR, androgen receptor; CI, confidence interval; HR, hazard ratio; MFS, metastasis-free survival; NR, not reached; OS, overall survival; PFS2, second progression-free survival.

In patients who progressed to mCRPC and received abiraterone acetate plus prednisone or enzalutamide as first subsequent therapy, the median PFS2 was shorter in patients who were positive for AR amplification and any AR aberration. Refer to Table: AR Aberration Status at End of Treatment and Efficacy Outcomes in Patients Treated with Androgen Signaling Inhibitors in the SPARTAN Study.


AR Aberration Status at End of Treatment and Efficacy Outcomes in Patients Treated with Androgen Signaling Inhibitors in the SPARTAN Studya2
AR Aberrations
PFS2
OS
Type
Biomarker Status
Months,
median
(95% CI)

Events
n/N

HR
(95% CI)
P-value

Months, median
(95% CI)

Events
n/N

HR
(95% CI)

P-value
AR-V7
positive
22.8
(7.4-29.3)

7/14
0.97
(0.45-2.11)
0.946

24.8
(22.2-NR)

4/7
1.27
(0.45-3.62)
0.652

negative
26.0
(23-28.8)

88/130
47.2
(37.1-55.8)

35/57
AR amp
positive
13.8
(7.8-18.4)

18/24
2.91
(1.62-5.25)
0.0004

23.9
(8.4-33.6)

9/11
1.75
(0.78-3.92)
0.171

negative
27.6
(25.1-31.1)

77/120
51.3
(42.3-62.0)

30/53
AR LBD mutations
positive
10.3
(7.4-26.2)

4/4
2.06
(0.74-5.75)
0.168

18.1
(18.1-NR)

1/3
0.35
(0.05-2.58)
0.301

negative
25.8
(22.8-28.8)

91/140
46.5
(35.9-54.3)

38/61
Any AR aberration
positive
15.5
(11.4-23.0)

25/36
1.74
(1.08-2.80)
0.024

23.9
(8.4-49.4)

10/15
1.14
(0.54-2.40)
0.727

negative
27.6
(24.2-32.8)

70/108
51.3
(42.3-58.6)

29/49
Abbreviations: amp, amplification; AR, androgen receptor; CI, confidence interval; HR, hazard ratio; LBD, ligand-binding domain; OS, overall survival; PFS2, second progression-free survival.
aIncluded only patients who received abiraterone acetate plus prednisone or enzalutamide as first subsequent treatment for metastatic castration-resistant prostate cancer.

Additional Information

Additional information regarding the SPARTAN study, including the clinical study report, protocol, and statistical analysis plan, can be found at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/Erleada_210951_toc.cfm (scroll to the “Sponsor Clinical Study Reports ARN-509-003 SPARTAN NCT # 01946204” section at the bottom of the web page).

AR Aberrations in the Phase 3 TITAN Study

Chi et al (2019)5 and (2020)6 evaluated the levels of ctDNA and frequencies of AR aberrations (including AR amplification, AR LBD mutations, and AR-V7 mutations) at baseline and end of treatment with ERLEADA plus ADT and impact on OS and PFS2 in patients with mCSPC who were enrolled in the TITAN study. Chi et al (2020) additionally evaluated for the presence of ctDNA and non-AR aberrations.

Study Design/Methods

  • TITAN (NCT02489318) was a phase 3, randomized, double-blind, placebo-controlled, multicenter study in patients with mCSPC receiving either ERLEADA 240 mg PO QD or placebo. All patients received ADT via gonadotropin releasing hormone analog or surgical castration. The dual primary endpoints were radiographic progression-free survival (rPFS), defined as time from randomization to first imaging-based documentation of progressive disease (progression of soft tissue lesions measured by computed tomography or magnetic resonance imaging or new bone lesions on bone scan) or death, whichever occurred first, and OS.4
  • PFS2, an exploratory endpoint, was defined as time from randomization to first occurrence of investigator-assessed disease progression (PSA progression, progression on imaging, or clinical progression) while the patient was receiving first subsequent treatment for prostate cancer, or death from any cause, whichever occurred first.4
  • Blood samples were collected in a subset of patients who consented to biomarker analysis at baseline and end of treatment (defined as first rPFS event or treatment discontinuation) and the following was assessed:
    • Detectable ctDNA, AR amplification, AR LBD mutations, and AR-V7 mRNA5
    • Detectable/undetectable ctDNA, AR amplification, AR LBD mutations, non-AR aberrations, and AR-V76
  • Next-generation sequencing was utilized to assess plasma-derived cfDNA for presence of detectable ctDNA, AR amplification, and AR LBD mutations (L702H, W742C, H875Y, F877L, and T878A), and Chi et al (2020) additionally assessed undetectable ctDNA and non-AR aberrations (TP53, RB1, and CDK12 inactivation, and PIK3CA, MYC, and MET activation). Whole blood-derived quantitative reverse transcription polymerase chain reaction from total RNA was utilized for AR-V7 identification.5, 6
  • Associations of PFS2 and OS with biomarker status were assessed in univariate analyses and using multivariate analyses in pooled patients from both groups.6

Results


AR Aberrations at Baseline and End of Treatment in the Phase 3 TITAN Study5
AR Aberrations, n (%)
Baseline
End of Treatment
ERLEADA Group
(n=15)
Placebo Group
(n=44)
Overall (n=59)
ERLEADA Group
(n=46)
Placebo Group
(n=81)
Overall
(n=127)
Detectable ctDNA
6 (40)
19 (43)
25 (42)
32 (70)
66 (81)
98 (77)
AR-V7
2 (13)
6 (14)
8 (14)
9 (20)
29 (36)
38 (30)
AR LBD mutations
0
0
0
4 (9)
7 (9)
11 (9)
AR amplification
1 (7)
6 (14)
7 (12)
19 (41)
42 (52)
61 (48)
Any AR aberrationa
3 (20)
10 (23)
13 (22)
22 (48)
54 (67)
76 (60)
Abbreviations: AR, androgen receptor; ct, circulating tumor; LBD, ligand-binding domain.
aAny AR aberration was defined by the presence of at least 1 aberration.


Genomic Aberrations at Baseline and End of Treatment in the Phase 3 TITAN Study6
Aberrations, n/N (%)
Baseline
End of Treatment
ERLEADA Group
Placebo Group
ctDNA
25/60 (42)
32/46 (70)
66/82 (80)
cfDNA
60/60 (100)
46/46 (100)
82/82 (100)
Whole blood RNA
60/60 (100)
46/46 (100)
82/82 (100)
Any genomic AR aberrationa
7/25 (28)
20/32 (62)
45/66 (68)
AR-V7
8/60 (13)
9/46 (20)
30/82 (37)
TP53 inactivation
8/25 (32)
14/32 (44)
36/66 (55)
RB1 inactivation
4/25 (16)
13/32 (41)
19/66 (29)
PIK3CA activation
4/25 (16)
13/32 (41)
16/66 (24)
MYC activation
4/25 (16)
6/32 (19)
7/66 (11)
CDK12 inactivation
1/25 (4)
1/32 (3)
5/66 (8)
MET activation
0
1/32 (3)
9/66 (14)
Abbreviations: AR, androgen receptor; cf, cell-free; ct, circulating tumor; LBD, ligand-binding domain.
aAR LBD mutation or amplification.


Change in AR Aberrations from Baseline to End of Treatment in the Phase 3 TITAN Study5
ERLEADA Group
(n=15)
Placebo Group
(n=44)
AR Aberration Type, n (%)
Sustained
AR-V7
1 (7)
2 (5)
AR LBD mutations
0
0
AR amplifications
1 (7)
6 (14)
Acquired
AR-V7
3 (20)
13 (30)
AR LBD mutations
2 (13)
3 (7)
AR amplification
5 (33)
19 (43)
Lost
AR-V7
1 (7)
4 (9)
AR LBD mutations
0
0
AR amplification
0
0
No Aberrations, n (%)
AR-V7
10 (67)
25 (57)
AR LBD mutations
13 (87)
41 (93)
AR amplification
9 (60)
19 (43)
Abbreviations: AR, androgen receptor; LBD, ligand-binding domain.

Detectable ctDNA and AR Aberrations and Overall Survival in the Phase 3 TITAN Studya5, 6
End of Treatment
Median Overall Survival, months
HR (95% CI)
P-Value
Positive
Negative
Detectable ctDNA
12.9
NR
7.95 (2.47-25.56) <0.0001
Any AR aberration
11.1
NR
3.67 (1.83-7.36) 0.0001
Abbreviations: AR, androgen receptor; ct, circulating tumor; HR, hazard ratio; NR, not reached; PFS2, second progression-free survival.
aTo remove bias for outcome analyses of biomarker status, patients were only considered to be at risk once they reached end of treatment.


Detectable ctDNA and AR Aberrations and PFS2 in the Phase 3 TITAN Studya5, 6
End of Treatment
Median PFS2, months
HR (95% CI)
P-Value
Positive
Negative
Detectable ctDNA
11.4
NR
3.53 (1.60-7.79) 0.0009
Any AR aberration
8.8
21.1
2.92 (1.64-5.19) 0.0001
Abbreviations: AR, androgen receptor; ct, circulating tumor; HR, hazard ratio; NR, not reached; PFS2, second progression-free survival.
aTo remove bias for outcome analyses of biomarker status, patients were only considered to be at risk once they reached end of treatment.


Association Between Aberrations at End of Treatment and Outcomes in the Phase 3 TITAN Study6
Aberration, HR (P-Value)
Univariate
Multivariate
PFS2
OS
PFS2
OS
ctDNA
3.5
(0.0009)

8.0
(<0.0001)

1.6
(0.349)

3.0
(0.093)

Any AR aberration
2.9
(0.0001)

3.7
(0.0001)

1.9
(0.066)

1.9
(0.088)

TP53 inactivation
2.8
(0.0001)

2.9
(0.0001)

1.6
(0.185)

1.3
(0.468)

RB1 inactivation
2.1
(0.010)

2.3
(0.004)

1.0
(0.932)

1.1
(0.723)

PIK3CA activation
2.5
(0.001)

3.2
(<0.001)

1.4
(0.314)

1.7
(0.121)

MYC activation
1.8
(0.113)

2.5
(0.018)

1.0
(0.923)

1.3
(0.566)

CDK12 inactivation
1.6
(0.367)

3.0
(0.016)

1.2
(0.720)

2.1
(0.147)

MET activation
1.6
(0.263)

2.6
(0.022)

1.1
(0.846)

1.8
(0.202)

Abbreviations: AR, androgen receptor; ct, circulating tumor; HR, hazard ratio; OS, overall survival; PFS2, second progression-free survival.

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 29 June 2023. Summarized in this response are relevant data limited to the phase 3 SPARTAN and TITAN studies in patients with nmCRPC and mCSPC, respectively.

References

1 Smith MR,  Saad F,  Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408-1418.
2 Smith MR,  Thomas S,  Gormley M, et al. Blood biomarker landscape in patients with high-risk nonmetastatic castration-resistant prostate cancer treated with apalutamide and androgen-deprivation therapy as they progress to metastatic disease. Clin Cancer Res. 2021;27(16):4539-4548.
3 Smith MR,  Thomas S,  Gormley M, et al. Supplement for: Blood biomarker landscape in patients with high-risk nonmetastatic castration-resistant prostate cancer treated with apalutamide and androgen-deprivation therapy as they progress to metastatic disease. Clin Cancer Res. 2021;27(16):4539-4548.
4 Chi KN,  Agarwal N,  Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381:13-24.
5 Chi KN,  Thomas S,  Gormley M, et al. Androgen receptor aberrations in patients with metastatic castration-sensitive prostate cancer treated with apalutamide plus androgen deprivation therapy in TITAN. Poster presented at: European Society for Medical Oncology (ESMO) Congress; September 27-October 1, 2019; Barcelona, Spain.
6 Chi KN,  Thomas S,  Gormley M, et al. Androgen receptor and non-androgen receptor aberrations associated with outcomes in metastatic castration-sensitive prostate cancer treated with apalutamide plus androgen deprivation therapy in TITAN. Poster presented at: American Association for Cancer Research (AACR) 2020 Virtual Meeting II; June 22-24, 2020.
7 Agarwal N,  Lucas J,  Bonavides CA, et al. Genomic aberrations associated with overall survival (OS) in metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) or placebo (PBO) plus androgen deprivation therapy (ADT) in TITAN. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL and online.
8 Rathkopf DE,  Smith MR,  Ryan CJ, et al. Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide. Ann Oncol. 2017;28(9):2264-2271.
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