Nivolumab in Patients with Metastatic Castration-Resistant Prostate Cancer with and Without DNA Repair Defects - Beyond the Abstract

The introduction of immune checkpoint inhibitors (ICIs) has transformed cancer treatment but has shown limited success in metastatic castration-resistant prostate cancer (mCRPC). DNA repair defects (DRDs) were hypothesized as potential predictors for increased responsiveness to nivolumab. This commentary explores the findings of our phase II trial evaluating nivolumab's efficacy in mCRPC patients, highlighting the significance and implications for future research.

Our multicenter phase II trial employed a single-arm design to assess nivolumab in mCRPC patients following docetaxel therapy. We utilized plasma circulating tumor DNA (ctDNA) to identify DRDs. The primary endpoint was PSA50 response, with secondary endpoints including objective response rate (ORR), radiographic progression-free survival (rPFS), and overall survival (OS). We also performed exploratory genomic profiling and evaluated PD-L1 expression.

Among 38 patients, DRDs were detectable in 30.5%. However, the PSA50 response was modest at 10.5%, with no significant difference between patients with and without DRD. The median PSA-PFS and rPFS showed no statistical difference across groups. Notably, DRDs did not reliably predict response, underscoring the need for new predictive markers.

Discussion:

  1. Clinical Implications: Our findings suggest that while a subset of mCRPC patients can benefit from nivolumab, DRDs are not sufficient predictors for response. This finding contrasts with the benefits seen in other cancers, highlighting the complexity of applying ICI therapies to mCRPC.
  2. Comparison with Other Studies: Previous studies like STARVE-PC and CheckMate 650 explored ICI efficacy in similar contexts, yet our results echo the challenge of identifying reliable biomarkers in mCRPC. Despite attempts to link DRDs with improved outcomes, consistent predictive markers remain elusive.
  3. Biomarker Challenges: The use of plasma ctDNA proved inadequate in revealing comprehensive genomic alterations, often compounded by poor tissue quality and bone-predominant disease characteristics. Our exploratory use of whole-exome sequencing (WES) offered insights but was feasible only in a limited patient subset.
  4. Future Research Directions: These results highlight the crucial need for ongoing development of novel biomarkers and combination therapies to enhance treatment efficacy and patient selection for ICIs in mCRPC.
  5. Conclusion: Our study underscores the complexity of mCRPC treatment and the challenges of predicting ICI response. While nivolumab demonstrates potential in a small subset of patients, DRDs alone are insufficient for predicting therapeutic benefit. Future research should focus on robust biomarker identification and innovative therapeutic combinations to improve patient outcomes.

Written by: Pedro Isaacsson, MD, PhD, Coordenador Núcleo de Tumores Genitourinários, Hospital Moinhos de Vento, Scientific Steering Committee, LACOG GU, Adjunct Assistant Professor, Johns Hopkins University, Baltimore, MD

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