Research round-ups

TOPARP-B analysis ties reversion mutations to PARPi resistance in mCRPC

Serial circulating tumor DNA (ctDNA) analyses in patients with metastatic castration-resistant prostate cancer (mCRPC) from the TOPARP-B trial support a role for reversion mutations in acquired poly (ADP-ribose) polymerase inhibitor (PARPi) resistance.

Both the TOPARP-B trial and the PROfound trial showed that patients with BRCA2 homozygous deletion had the most durable responses to PARPi treatment. A possible mechanism underlying PARPi resistance may be reversion mutations in genes such as BRCA2 and PALB2, which could restore some homologous recombination repair functionality.

This latest research was conducted by George Seed (The Institute of Cancer Research, London, UK) and colleagues and reported in Cancer Cell. It focused on 19 patients from TOPARP-B who had a confirmed response to PARPi and at least three samples available for analysis, and whose tumors had mutations in BRCA2 or PALB2.

By the end of treatment, 79% of tumors had reversion mutations with the potential to restore function protein, comprising 114 frameshift reversions that restored the native reading frame and 34 stop-gain reversions that removed a stop codon, again restoring the functional reading frame.

There were a median of six reversion mutations per patient, and eight patients concluded treatment with multiple co-existing reversions.

Even an apparent complete homozygous deletion did not always remain that way. When the researchers looked in detail at patients with homozygous BRCA2 deletions, they found that one had rare subclonal wild-type tumor cells present prior to the start of treatment “providing a pool of DNA-repair competent cells selected for by subsequent treatment.”

Notably, the emergence of reversion mutations was linked to early tumor progression, with a significant correlation between the detection rate of reversion mutations and poorer radiographic progression-free survival (rPFS) and overall survival (OS).

Median rPFS was 5.59 months for patients with at least one reversion mutation versus 8.81 months for those with none. The corresponding OS durations were 13.9 versus 21.4 months.

However, some patients had disease progression despite few or no detectable reversions, leading the researchers to suggest that “either very small reverted subclones are vitally important in disease progression, or that alternative mechanisms of olaparib resistance other than reversions play an important clinical role.”

The researchers acknowledge several limitations of their study, including the small number of participants and samples and use of a targeted sequencing panel, which restricted the scope of the analysis.

Understanding resistance mechanisms is crucial for developing next-generation therapeutic strategies and improving patient outcomes.

This research underscores the complexity of PARPi resistance in mCRPC and the potential of ctDNA for real-time monitoring of patients. Continuous research and development of new therapeutic approaches are essential to overcome resistance and enhance patient care.