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Baseline ctDNA Analyses and Associations with Outcomes in Taxane-Naive Patients with mCRPC Treated with 177Lu-PSMA-617 Versus Change of ARPI in PSMAfore

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Baseline ctDNA Analyses and Associations with Outcomes in Taxane-Naive Patients with mCRPC Treated with 177Lu-PSMA-617 Versus Change of ARPI in PSMAfore

(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting featured a session on prostate cancer, and a presentation by Dr. Johann De Bono discussing baseline ctDNA analyses and associations with outcomes in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA-617 versus change of androgen receptor pathway inhibitor in PSMAfore.

Initially presented as ESMO 2023, 177Lu-PSMA-617 prolonged radiographic progression-free survival versus androgen receptor pathway inhibitor change in taxane-naive patients with mCRPC. In this exploratory analysis presented at ASCO 2024, associations between baseline circulating tumor DNA (ctDNA) and outcomes were assessed.

Patients were randomized 1:1 to 177Lu-PSMA-617 (7.4 GBq every 6 weeks; 6 cycles) or androgen receptor pathway inhibitor change (abiraterone or enzalutamide). Patients known to have actionable mutations (ie. BRCA) were excluded. The primary endpoint was radiographic progression-free survival and the trial design is as follows:
Baseline plasma ctDNA was analyzed using a customized 585-gene sequencing assay, and the ctDNA fraction was assessed in all samples passing quality control. The design for the exploratory ctDNA analysis was as follows:177Lu-PSMA-617 ctDNA analysis
Alterations in key prostate cancer drivers (prevalent in >10% of participants) were assessed in samples with ctDNA fraction >0.5%. Univariate Cox regression (reference: androgen receptor pathway inhibitor change) was used to assess the association of ctDNA fraction or alterations with radiographic progression-free survival, PSA response (≥50% decline; PSA50), and RECIST response at the June 21, 2023 data cutoff.

Among 360 samples from 468 patients, 255 passed quality control and 156 had ctDNA fraction >0.5% (median 5.85%; range 0–85). Median ctDNA fraction was consistent with profiles of patients with mCRPC at 1st and 2nd line:177Lu-PSMA-617 flow
Higher baseline ctDNA fraction was associated with shorter radiographic progression-free survival regardless of treatment received:

177Lu-PSMA-617 ctdna analysis proportion of patients without rPFS
Additionally, 177Lu-PSMA-617 prolonged radiographic progression-free survival compared with androgen receptor pathway inhibitor change regardless of baseline ctDNA fraction:177Lu-PSMA-617 prolonged radiographic progression free survival compared with androgen receptor pathway inhibitor change regardless of baseline ctDNA fraction
Moreover, ctDNA fraction >0.5% was also associated with worse RECIST response and PSA50 response:ctDNA fraction >0.5% was also associated with worse RECIST response and PSA50 response
Interestingly, early ctDNA clearance was associated with longer radiographic progression-free survival:177Lu-PSMA-617 ctdna clearance was associated with longer radiographic progression free survival
Among the genomic analysis in the targeted sequencing panel (585 genes), 18 genes were selected for genomic features prevalent in >10% of patients. These included known prognostic biomarkers that may influence radiation sensitivity: AR amplification, chromosome 8q and MYC amplifications, TP53 deleterious alterations, and PI3K pathway alterations. The presence of 8q amplifications was associated with shorter radiographic progression-free survival:177Lu-PSMA-617 genomic analysis
Additionally, the presence of AR amplification was also associated with radiographic progression-free survival:177Lu-PSMA-617 presence of AR amplification was also associated with radiographic progression free survival
Finally, the presence of TP53 deleterious alterations was associated with shorter radiographic progression-free survival:177Lu-PSMA-617 the presence of TP53 deleterious alterations
Dr. De Bono concluded his presentation discussing baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of androgen receptor pathway inhibitor in PSMAfore with the following take-home messages:

  • Higher baseline ctDNA fraction was associated with shorter radiographic progression-free survival across both treatment arms
  • Patients receiving 177Lu-PSMA-617 had longer progression-free survival compared with androgen receptor pathway inhibitor change, regardless of baseline ctDNA fraction
  • Early ctDNA fraction dynamics informs on radiographic progression-free survival and tumor response
  • 8q amplifications, AR amplifications, and TP53 deleterious alterations are prognostic biomarkers that were associated with shorter radiographic progression-free survival and decreased tumor response in the 177Lu-PSMA-617 arm

Presented by: Johann S. De Bono, MD, MSc, PhD, FRCP, FMedSci, Professor, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024.

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