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Cambridge Neoadjuvant Cancer of the Prostate (CANCAP03): A Window Study into the Effects of Olaparib ± Degarelix in
Harveer Dev1, Mark Linch2, Krishna Narahari3
1Early Cancer Institute, University of Cambridge, Cambridge, United Kingdom.
Purpose:
The purpose was to investigate combined PARP and androgen inhibition in primary prostate cancer and understand the biological mechanisms underlying clinical efficacy, especially in the absence of mutations in homologous recombination (HR) repair pathways.
Patients And Methods:
The primary objective was to measure PARP inhibition, and the secondary objectives were to assess safety and feasibility. Participants received olaparib for 2 weeks before prostatectomy and were randomly assigned or not assigned (1:1) to degarelix. We analyzed diagnostic biopsy and radical prostatectomy samples for PARylated protein expression using IHC. Exploratory analyses included tumor gene sequencing, mutation analysis, and RNA sequencing (RNA-seq) using both bulk and single-cell RNA-seq performed on pretreatment and posttreatment tissues.
Results:
PARylated protein expression was significantly reduced in both cohorts, with no drug-related delays in radical prostatectomy. The gene set enrichment analysis identified distinct treatment response signatures related to olaparib in both cohorts and showed downregulation of androgen response genes after olaparib + degarelix treatment.Transcript profiling revealed an upregulation of the p53 hallmark, which was more pronounced with the combination treatment. Canonical cell-cycle progression hallmarks, including E2F targets and the G2-M checkpoint, were suppressed across all cases, correlating with a HR-deficient transcriptional signature. Single-nuclear RNA-seq indicated a greater increase in inflammatory response pathway activity within tumor epithelia after combination treatment.
Conclusions:
Transcriptomic analysis identified common hallmark alterations reflecting the combined impact of PARP inhibitor and androgen blockade on cell-cycle progression. We observed a shared phenotypic response to combination therapy across prostate cancers without known HR repair gene alterations. This suggests alternative mechanisms rather than antiandrogen-induced HR deficiency.
Insights
Combined PARP and androgen inhibition effectively reduced PARylated protein in prostate cancer. This combination therapy suppressed cell-cycle progression and altered gene expression, offering insights into treatment mechanisms beyond HR repair deficiencies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate cancer treatment often involves androgen blockade.
- Poly (ADP-ribose) polymerase (PARP) inhibitors are emerging as a therapeutic strategy.
- Investigating combined therapies is crucial for understanding treatment resistance.
Purpose of the Study:
- To investigate the efficacy of combined PARP and androgen inhibition in primary prostate cancer.
- To elucidate the biological mechanisms of this combination therapy, particularly in tumors lacking homologous recombination (HR) repair mutations.
- To assess PARP inhibition, safety, and feasibility of the treatment regimen.
Main Methods:
- Patients received olaparib (PARP inhibitor) followed by radical prostatectomy.
- Random assignment to degarelix (androgen inhibitor) or no assignment.
- Analysis of PARylated protein expression via immunohistochemistry (IHC).
- Exploratory analyses included gene sequencing and bulk/single-cell RNA sequencing (RNA-seq).
Main Results:
- Significant reduction in PARylated protein expression observed in both treatment cohorts.
- No drug-related delays in prostatectomy.
- Distinct treatment response signatures identified, including downregulation of androgen response genes with combination therapy.
- Upregulation of p53 hallmark and suppression of cell-cycle progression hallmarks observed, correlating with HR deficiency signature.
- Combination therapy increased inflammatory response pathway activity in tumor epithelia.
Conclusions:
- Combined PARP inhibition and androgen blockade impact cell-cycle progression and gene expression in prostate cancer.
- A shared phenotypic response to combination therapy occurs in prostate cancers without known HR repair gene alterations.
- Alternative mechanisms, not solely antiandrogen-induced HR deficiency, may underlie the observed responses.
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