PARP Inhibitors: Improving Outcomes in Metastatic Prostate Cancer
SAN FRANCISCO — New data from two large clinical trials show that adding a PARP inhibitor to first-line treatment with abiraterone improves radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC).
However, the results from the two trials were slightly different. The PROpel study with olaparib (Lynparza) showed a benefit in all patients, irrespective of mutation status, whereas the MAGNITIDE trial with niraparib (Zejula) showed benefit only in patients with homologous recombination repair (HRR) gene alterations.
The new results, which were presented here at the Genitourinary Cancers Symposium (GUCS) 2022, led to two different conclusions.
Olaparib is already approved for use in patients with mCRPC who have HRR gene alterations. The approval was based on results from the PROfound trial.
Front Cell Dev Biol. 2020 Sep 9;8:564601.
doi: 10.3389/fcell.2020.564601. eCollection 2020.
PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance
The Poly (ADP-ribose) polymerase (PARP) family has many essential functions in cellular processes, including the regulation of transcription, apoptosis and the DNA damage response. PARP1 possesses Poly (ADP-ribose) activity and when activated by DNA damage, adds branched PAR chains to facilitate the recruitment of other repair proteins to promote the repair of DNA single-strand breaks. PARP inhibitors (PARPi) were the first approved cancer drugs that specifically targeted the DNA damage response in BRCA1/2 mutated breast and ovarian cancers. Since then, there has been significant advances in our understanding of the mechanisms behind sensitization of tumors to PARP inhibitors and expansion of the use of PARPi to treat several other cancer types. Here, we review the recent advances in the proposed mechanisms of action of PARPi, biomarkers of the tumor response to PARPi, clinical advances in PARPi therapy, including the potential of combination therapies and mechanisms of tumor resistance.
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