Genotoxic therapies have a long history in a variety of cancers, and recent interest in the poly(ADP-ribose) polymerase (PARP) enzymes as an avenue to command synthetic lethality has led to successes in advanced prostate cancer.  Thus far two PARP inhibitors (PARPi) are approved for metastatic castration resistant prostate cancer (mCRPC) in men harboring alterations in genes that are critical to homologous recombination (HR).  The agents are rucaparib and olaparib, supported by the TRITON2 and PROfound studies, respectively.1,2 Herein authors de Bono et al. deploy talazoparib, a potent inhibitor of PARP catalytic activity, in a heavily pretreated mCRPC population.  Notably, this open-label phase 2 trial (TALAPRO-1) was conducted in men who had previously received one or two taxane chemotherapies and progressed on at least on ARSI.3  Selection required the presence of a genomic alteration in one of a group of genes, irrespective of germline or somatic origin, or zygosity.  Among those 1425 men screened, 1297 did not have a qualifying HRR gene alteration, meaning approximately only 9% of screened subjects had evidence of deficient homologous recombination (by the author’s chosen definition), lower than some previously reported rates of up ~20%.  Safety was assessed across 127 subjects who received at least one dose and antitumor activity among 104 with measurable disease.