(apalutamide)
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Last Updated: 07/06/2023
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
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.
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. |
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.
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. |
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 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).
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.
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. |
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. |
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. |
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. |
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. |
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. |
A literature search of MEDLINE®,
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. |
9 | Crona DJ, Whang YE. Androgen receptor-dependent and -independent mechanisms involved in prostate cancer therapy resistance. Cancers. 2017;9(6):67. |
10 | Gottlieb B, Beitel LK, Nadarajah A, et al. The androgen receptor gene mutations database: 2012 update. Hum Mutat. 2012;33(5):887-894. |
11 | Balbas MD, Evans MJ, Hosfield DJ, et al. Overcoming mutation-based resistance to antiandrogens with rational drug design. Elife. 2013;2:e00499. |
12 | Joseph JD, Lu N, Qian J, et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 2013;3(9):1020-1029. |