Page 21 - Flipbook

PARPi early clinical trials: Interpretation and hypotheses

• Safety, tolerability of multiple PARPi (olaparib, niraparib, rucaparib, talazoparib)

• Hematological toxicity dose limiting; agents have similar antitumor activity

• Talazoparib is most potent PARP ‘trapper’ on DNA; trapping causes DNA double strand breaks

• Antitumor activity in gBRCA tumors including mCRPC

• Some patients have durable responses

• Antitumor activity in sporadic cancers including mCRPC

• Ovarian, breast, prostate, pancreas

• Association of platinum sensitivity with PARPi sensitivity in ovarian ca

• Incomplete cross-resistance: carboplatin can work after PARPi, and vice versa in BRCA ovarian

• Previous mCRPC studies with satraplatin reported a 25% PSA response rate

• We therefore hypothesized that a proportion of mCRPC had DNA repair defects

Fong et al, NEJM 2009; Fong et al, JCO 2010; Ang et al, CCR 2013; Sandhu et al, Lancet Oncology 2013;
de Bono et al Cancer Discovery 2017; Sternberg et al, JCO 2009