Abstract 359: Molecular signatures associated with long-term response to apalutamide (APA) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) in TITAN
Bibliographic record
Abstract
Abstract Background: TITAN, a phase 3 placebo (PBO)-controlled study in a broad population of pts with mCSPC (NCT02489318), demonstrated that the addition of APA to androgen deprivation therapy (ADT) significantly improved radiographic progression-free survival (rPFS) (median rPFS in the APA and PBO groups was not reached and was 22.1 months, respectively) and overall survival (OS) compared with PBO + ADT (Chi N Engl J Med 2019). This exploratory analysis investigated molecular signatures of pts with mCSPC who had long-term responses to APA. Methods: Pts (n = 222) in the biomarker cohort of TITAN were characterized as long-term responders (LTR) or early progressors (EP) by separating rPFS into quartiles. The last quartile with longest rPFS (APA, n = 28; PBO, n = 28) represented LTR. The first quartile, with shortest rPFS (APA, n = 17; PBO, n = 21) represented EP. Gene expression profiles of TITAN pts were generated from archival primary prostate tumors; data were summarized based on 110 predefined gene signatures. Mean signature scores between LTR and EP groups were compared within treatment groups using 2 sample t tests to evaluate whether effects were prognostic or specific to APA treatment. Signatures were also evaluated for association with outcome using Cox proportional hazard models in each treatment group. Results: At primary analysis, with median 22.7 months follow-up, median rPFS was, respectively, not reached and 32.9 months in APA and PBO pts in the LTR group, and 10.9 and 3.7 months in APA and PBO pts in the EP group. A higher level of expression (above median) of either polycomb repressor complex 2 activation or the Decipher signature was more frequently associated with EP in both groups. LTR in the APA treatment group, but not those in the PBO group, had lower expression of transcriptional signatures describing myeloid-derived suppressor cells (MDSCs) and cell cycle progression. These results suggest that pts with mCSPC who have relatively lower levels of MDSCs in the tumor, indicative of a less immune-suppressed tumor microenvironment, may have long-term benefit from treatment with APA. Conclusions: Consistent clinical benefit was observed with the addition of APA to ADT in both EP and LTR. Although the data require confirmation in larger studies, these molecular signatures may have utility in selecting pts with mCSPC who may derive the most benefit from APA and other androgen signaling inhibitors. Citation Format: Justin Lucas, Neeraj Agarwal, Felix Feng, Clemente Aguilar-Bonavides, Shibu Thomas, Michael Gormley, Suneel Mundle, Sabine Brookman-May, Sharon A. McCarthy, Anders Bjartell, Hirotsugu Uemura, Simon Chowdhury, Kim N. Chi. Molecular signatures associated with long-term response to apalutamide (APA) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) in TITAN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 359.
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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".