Abstract
This randomized clinical trial explores whether hormone intensification at start of androgen deprivation therapy alters selection of androgen receptor (AR) gene alterations within the gene body and/or enhancer region.
We previously reported that abiraterone acetate and prednisolone (hereafter abiraterone) added at initiation of androgen deprivation therapy (ADT) improved survival of metastatic and very high-risk locally advanced prostate cancer and that combining with enzalutamide did not change efficacy.1 Using next-generation sequencing on plasma DNA, we previously showed that genomic alterations of the androgen receptor (AR) gene contribute to resistance to abiraterone or enzalutamide when initiated for metastatic castration-resistant prostate cancer after progression with ADT alone.2 It is unknown whether hormone intensification at start of ADT alters selection of AR alterations within the gene body and/or enhancer region.3
Methods
Details of the STAMPEDE platform protocol (NCT00268476) have been published elsewhere1 and are included in Supplement 1. Blood was collected at trial-defined progression from patients who consented to this optional donation. Patients were followed up to July 2022, and we also included deaths recorded in national registries in England and Wales to February 2024. Biomarker analysis was approved by an independent research ethics committee (REC18/LO/1235). Plasma DNA was analyzed using the PCF-SELECT test (eMethods in Supplement 2).4 Based on a decrease in ESR1 alterations with early aromatase inhibitors for breast cancer,5 the null hypothesis defined prior to initiation of sample collection was that early hormone intensification would not affect the prevalence of AR gene alterations. This study followed CONSORT reporting guidelines.
Results
Between March 2016 and January 2020, plasma at progression was collected from 110 patients who between August 2014 and March 2016 were randomly allocated 1:1 to ADT (58 patients [controls]) or ADT with enzalutamide and abiraterone (52 patients) (Table). Among 108 patients with plasma samples that passed quality control, 44 of 57 (77%) samples from controls and 46 of 51 (90%) samples from patients in the intensification arm had detectable circulating tumor DNA (ctDNA).
Table. Patients Characteristics.
| Characteristic | No. (%) | ||
|---|---|---|---|
| Substudy cohort (n = 110) | Patients from ITT with an FFS event within 48 mo (n = 760) | Overall ITT (N = 1976) | |
| Treatment arm by metastatic stage | |||
| M0 | |||
| Standard of care | 9 (8) | 133 (18) | 533 (27) |
| Standard of care + AAP + ENZ | 5 (5) | 57 (7) | 527 (27) |
| M1 | |||
| Standard of care | 50 (45) | 363 (48) | 454 (23) |
| Standard of care + AAP + ENZ | 46 (42) | 207 (27) | 462 (23) |
| Disease burden | |||
| M0N+ | 6 (5) | 112 (15) | 391 (20) |
| M0N0 | 8 (7) | 77 (10) | 667 (34) |
| M1, high volume | 29 (26) | 187 (25) | 219 (11) |
| M1, low volume | 18 (16) | 126 (17) | 162 (8) |
| Unknown | 49 (45) | 258 (34) | 537 (27) |
| Tumor stage | |||
| T0-T2 | 14 (13) | 53 (7) | 145 (7) |
| T3 | 63 (57) | 467 (61) | 1409 (71) |
| T4 | 27 (25) | 187 (25) | 317 (16) |
| TX | 6 (5) | 53 (7) | 105 (5) |
| Gleason score | |||
| ≤7 | 18 (16) | 117 (15) | 366 (19) |
| 8 | 14 (13) | 131 (17) | 452 (23) |
| 9-10 | 74 (67) | 489 (64) | 1124 (57) |
| Unknown | 4 (4) | 23 (3) | 34 (2) |
| Age ≥70 y | 52 (47) | 321 (42) | 871 (44) |
| Cancer presentation | |||
| De novo | 106 (96) | 724 (95) | 1885 (95) |
| Relapsed | 4 (4) | 36 (5) | 91 (5) |
| Planned radiotherapy | 9 (8) | 140 (18) | 942 (48) |
| Planned docetaxel treatment | 9 (8) | 41 (5) | 103 (5) |
| PSA, median (IQR), ng/mL | 119 (52-392) | 80 (24-270) | 48 (17-134) |
| Death from any cause | 88 (80) | 568 (75) | 691 (35) |
Abbreviations: AAP, abiraterone acetate and prednisolone; ENZ, enzalutamide; FFS, failure-free survival; ITT, intention to treat; PSA, prostate-specific antigen.
SI conversion factor: To convert PSA to micrograms per liter, multiply by 1.
At least 1 AR alteration was identified in 11 of 44 control samples (25%; 95% CI, 13%-40%), and there was a statistically significant higher proportion of AR alterations in the hormone intensification arm (22 of 46 samples [48%; 95% CI, 33%-63%]), leading to a rejection of the null hypothesis (χ2 test: P = .03; Figure, A). The odds of AR alteration were higher for patients allocated to intensification vs control (odds ratio, 0.36; 95% CI, 0.15-0.89). The median (IQR) time from randomization to sample collection was 20 (14-24) months among controls and 20 (14-27) months among patients in the intensification arm, but shorter among samples with AR alterations (Wilcoxon test: P = .03).
Figure. Plasma Androgen Receptor (AR) Gene Alterations and Patient Survival.
A, AR alterations identified in plasma DNA collected at progression among patients, divided by arm. Estimated tumor content fraction in the plasma DNA sample is indicated by the continuous white-red scale. B, Kaplan-Meier curves displaying overall survival from time of sample collection to death, with patients split by circulating tumor DNA (ctDNA) and AR status (partial deviance test: P = .004). Shaded areas represent 95% CIs. AAP indicates abiraterone acetate and prednisolone; ENZ, enzalutamide; SOC, standard of care; TC, tumor content.
There was a high correlation for AR and AR enhancer copies (Pearson correlation: r = 0.94; P < 2.2 × 1016), suggesting that AR amplification commonly involves both regions regardless of treatment. No notable differences in the prevalence of non-AR gene alterations by treatment allocation were identified, although the sensitivity of this analysis is limited by the sample size.
Hazards of death from time of first-line progression were greater in patients with AR alterations compared to wild-type AR or no ctDNA (Figure, B). This was consistent in multivariable analyses adjusted for baseline TNM staging, treatment allocation, and type of progression (wild-type AR vs no ctDNA: hazard ratio, 2.09; 95% CI, 1.00-4.39; AR alterations vs no ctDNA: hazard ratio, 3.92; 95% CI, 1.68-9.15; P < .001).
Discussion
Given that hormone intensification at start of ADT is now standard of care, there are limited opportunities to investigate differences in the genomic landscape at progression with first-line therapy in directly randomized patients. We focused on plasma samples collected until the start of the COVID-19 pandemic, when sample collection decreased dramatically. It is possible that longer responders, who have not been included, have a lower prevalence of AR alterations. However, we confirmed high selective pressures for genomic alterations involving AR following abiraterone and/or enzalutamide, with a similar distribution detected at progression with enzalutamide initiated for metastatic castration-resistant prostate cancer in the phase 3b PRESIDE trial analyzed using the same pipeline.6 This supports using the same treatment paradigms at progression on AR pathway inhibitors, regardless of timing of initiation.
Trial Protocol
eMethods
Nonauthor Collaborators. The STAMPEDE collaborators
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eMethods
Nonauthor Collaborators. The STAMPEDE collaborators
Data Sharing Statement
