How would you sequence PARPi vs pembrolizumab for a patient who has progressed on ARPI to mCRPC that has somatic PALB2 mutation and MSI-H?

MSI-high disease in men with mCRPC is uncommon, accounting for 3-5% of patients overall, and typically results in high TMB. MSI-high disease is usually a result of either germline MMRD (Lynch Syndrome, about 20% of MSI-high cases) or somatic MMRD (typically MSH2 or 6, MLH1, less commonly PMS2). The finding of MSI-high disease, particularly with high TMB, has an immediate clinical impact given the activity of pembrolizumab and other PD-1 inhibitors in this setting and the broad FDA approval of pe...

I completely agree with Dr. @Dr. First Last and would favor pembrolizumab over PARPi. We and others are working on developing/refining the functional signature of HR deficiency which would be extremely important in scenarios like the above.

Bhatlapenumarthi et al., Journal of Clinical Oncology 2024