Abstract 4133: High prevalence and heterogeneity of emergence of <i>BRCA</i> reversion mutations at progression on niraparib treatment in <i>BRCA</i>-mutant metastatic castration-resistant prostate cancer (mCRPC) patients
Bibliographic record
Abstract
Abstract In the phase 2 GALAHAD study (NCT02854436), the PARP inhibitor (PARPi) niraparib, was evaluated in heavily pre-treated patients with mCRPC and DNA-repair gene defects (DRD) who progressed after androgen-receptor (AR) targeted therapy and taxane-based chemotherapy. The results showed that objective response rate (ORR) was 34.2% for patients with measurable disease having biallelic BRCA1/2 alterations (n=76). The development of BRCA reversion mutations, a type of secondary mutation that restores protein function, has been proposed as a key resistance mechanism to PARP inhibition. We aimed to evaluate the relationship between reversion mutations and treatment response in BRCA1/2 altered patients treated with niraparib in the GALAHAD study. Thirty-three patients with biallelic BRCA alterations (excluding patients with homozygous deletions) had donated an end-of-treatment (EOT) ctDNA sample. We performed sequencing to detect reversion mutations using the Resolution Bioscience ctDx-HRD assay. Mutation patterns at baseline included splice site, nonsense, missense, and frameshift mutations, with the latter being the most common (24/33; 73%). No reversions were detected at baseline and the baseline BRCA alterations were detected at EOT for every patient. Most BRCA patients (28/33; 85%) had at least 1 reversion mutation (range: 1-38 different BRCA alterations) at EOT. Of the 28 patients with reversions, 5 were classified as low reversions: 3 patients had only one reversion mutation, 1 patient had 2 reversions at low allele frequency and 1 patient had 4 reversions at low allele frequency. Patients with reversion mutations showed better composite response (defined as ORR by RECIST 1.1, or CTC conversion to <5/7.5 mL blood, or ≥50% decline in prostate specific antigen) (74.2% vs 25.8%, p=0.01) and longer duration on treatment (median 6.9 vs 3.7 mo, p<0.05) compared to those without or low reversions. Additionally, patients with reversions trended to have longer median radiographic progression-free survival compared to those without or low reversions (8.1 vs 5.5 mo, p=0.12). In conclusion, the high prevalence of patients with BRCA reversion mutations and the displayed longer benefit from niraparib underscores the dependence of these tumors on BRCA mutation as an oncogenic driver and reversion mutations as a marker of secondary resistance to niraparib treatment. Citation Format: Karen Urtishak, Gerhardt Attard, Tokuwa Kanno, Shibu Thomas, Gary E. Mason, Byron Espina, Eugene Zhu, Natalie Hutnick, Mary Guckert, Adam del Corral, Mark Li, Angela Lopez-Gitlitz, Kim Chi, William Kevin Kelly, Evan Y. Yu, Karim Fizazi, Matthew Smith. High prevalence and heterogeneity of emergence of BRCA reversion mutations at progression on niraparib treatment in BRCA-mutant metastatic castration-resistant prostate cancer (mCRPC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4133.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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".