Abstract 776: Androgen receptor (AR) and non-AR aberrations associated with outcomes in metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) plus androgen deprivation therapy (ADT) in TITAN
Bibliographic record
Abstract
Abstract Background: In TITAN, APA improved radiographic progression-free survival (rPFS), overall survival (OS), and second progression-free survival (PFS2) vs placebo (PBO) in patients (pts) with mCSPC receiving ADT. We determined the presence of genomic and transcriptional aberrations and evaluated associations of these aberrations with clinical outcomes in TITAN. Methods: Whole-blood samples from 130 pts were collected at baseline (BL, n = 59) and end of treatment (EOT: APA, n = 47; PBO, n = 83). Circulating tumor (ct)DNA and non-AR aberrations (Table) were assessed from isolated cell-free (cf)DNA (n = 129), and AR aberrations at EOT were assessed from cfDNA and cellular RNA (n = 127) using next-generation sequencing and real-time PCR. Detected biomarkers at BL and EOT were assessed for associations with rPFS, OS, and PFS2 and with OS and PFS2, respectively, using Cox proportional hazards model and multivariate analyses (MVA) in pooled APA and PBO pts. Table.Frequency of aberrations and univariate analyses of the association between aberration status at EOT with outcomesAberrationsBL, n (%)EOT, n (%)HR (95% CI) p value for shorter outcomes by aberration-positive vs -negative status (reference)APAPBOOverallAPAPBOOverallPFS2OSn = 15n = 44n = 59n = 47n = 82n = 129ctDNA6 (40)19 (43)25 (42)32 (68)66 (80)98 (76)3.55 (1.59-7.92)7.77 (2.40-25.13)p = 0.002p = 0.001Any AR aberrationa3 (20)10 (23)13 (22)n = 46n = 81n = 1272.82 (1.58-5.03)3.70 (1.85-7.41)22 (48)54 (67)76 (59)p = 0.0002p = 0.0001TP53 inactivationb1 (7)7 (16)8 (14)14 (30)36 (44)50(39)2.42 (1.45-4.04)2.69 (1.54-4.71)p = 0.001p = 0.001RB1 inactivationb2 (13)2 (5)4 (7)13 (28)19 (23)32 (25)1.86 (1.08-3.21)2.08 (1.18-3.66)p = 0.026p = 0.011PIK3CA amplification/SNV2 (13)2 (5)4 (7)13 (28)16 (20)29 (22)2.30 (1.34-3.94)3.06 (1.75-5.36)p = 0.002p < 0.001MYC amplification/SNV1 (7)3 (7)4 (7)6 (13)7 (9)13 (10)1.64 (0.77-3.48)2.35 (1.10-5.02)p = 0.198p = 0.027CDK12 inactivationb01 (2)1 (2)1 (2)5 (6)6 (5)1.54 (0.56-4.28)2.55 (1.00-6.47)p = 0.406p = 0.050MET amplification/SNV0001 (2)9 (11)10 (8)1.59 (0.72-3.52)2.90 (1.28-6.56)p=0.253p=0.010aDefined as AR ligand-binding domain mutations (L702H, W742C, H875Y, F877L, and T878A), or AR copy number gain, or ARv7 transcript detection.bDefined as either heterozygous or homozygous deletion or single nucleotide variant (SNV) with known pathogenic consequence based on ClinVar, an archive of human variations and phenotypes. Results: From BL to EOT, detection of ctDNA increased 1.8-fold and similarly with APA and PBO; detection of AR aberrations increased 2.7-fold and was less frequent with APA vs PBO (Table; p = 0.04, Fisher exact test). Among non-AR aberrations at EOT, those in TP53, RB1, PI3KCA were the most frequent; detection increased ≥ 2.8-fold from BL to EOT and similarly with APA and PBO (Table). Detection of ctDNA, AR aberrations, and aberrations in TP53, RB1, PI3KCA at EOT were associated with shorter PFS2 and OS (Table). Detection of other non-AR aberrations at EOT and of all aberrations at BL was low for robust conclusions. Only detectable ctDNA at EOT maintained association with shorter OS in MVA. Conclusions: In TITAN pts with mCSPC, AR and several non-AR aberrations were most frequent at progression. APA was associated with decreased frequency of AR aberrations at EOT and similar frequency of detectable ctDNA vs PBO. ctDNA was an independent prognostic variable for shorter PFS2 and OS in pts with mCSPC. Citation Format: Kim N. Chi, Shibu Thomas, Michael Gormley, Dong Shen, Neeraj Agarwal, Felix Feng, Gerhardt Attard, Alex Wyatt, Deborah S. Ricci, Angela Lopez-Gitlitz, Julie S. Larsen, Branko Miladinovic, Simon Chowdhury. Androgen receptor (AR) and non-AR aberrations associated with outcomes in metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) plus androgen deprivation therapy (ADT) in TITAN [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 776.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".