The discovery that BRCA1/2-deficient tumour cells are highly sensitive to poly-ADP ribose polymerase (PARP) inhibitors (PARPi) established the foundation of synthetic lethality in metastatic castration-resistant prostate cancer (mCRPC). The TOPARP-A trial confirmed clinical benefit, with PARPi activity largely restricted to patients with homologous recombination repair (HRR) gene alterations, especially BRCA2. However, efficacy varies with other HRR genes due to differing levels of homologous recombination deficiency (HRD). Current selection for PARPi therapy relies on identifying pathogenic alterations in HRR genes through germline or tumour DNA testing. Functional HRD assays and genomic signatures have shown promise in other cancers but remain unreliable in mCRPC. Furthermore, individual HRR gene mutations are rare, limiting conclusions from single trials. Meta-analyses like Naqvi et al’s are essential to clarify gene-specific responses. PARPi efficacy also depends on their ability to trap PARP on damaged DNA. Preclinical data suggested that androgen receptor (AR) inhibition suppresses HRR gene expression, potentially sensitising even HRR-proficient tumours to PARPi. This led to combination trials (MAGNITUDE, PROpel, TALAPRO-2) of PARPi with AR pathway inhibitors (ARPIs), which showed variable benefit depending on HRR mutation status and trial design. Testing challenges persist; results between tissue and ctDNA assays are common, particularly with low ctDNA levels. Misclassification may impact treatment decisions. Regulatory bodies differ in their interpretations: the EMA has approved broader use of combinations, while the FDA has restricted approvals to patients with BRCA1/2 alterations. Subgroup analyses suggest BRCA2-altered tumours benefit most, while evidence remains unclear for non-BRCA HRR genes. Whether combination therapy is superior to sequential monotherapy is yet unresolved. In this uncertain landscape, regularly updated living meta-analyses, such as the one by Naqvi et al., are critical for informing future treatment guidelines and regulatory decisions.
PARP inhibitors and prostate cancer
Reviewed by Asif H Ansari
PARP inhibitors and prostate cancer: the struggle to separate the grain from the chaff.
