An Overview of PARP Inhibitors for the Treatment of Breast Cancer

Abstract

Loss-of-function mutations in BRCA1 and BRCA2 are detected in at least 5% of unselected patients with breast cancer (BC). These BC susceptibility genes encode proteins critical for DNA homologous recombination repair (HRR). This review provides an update on oral poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of BC. Olaparib and talazoparib are PARP inhibitors approved as monotherapies for deleterious/suspected deleterious germline BRCA-mutated, HER2-negative BC. Olaparib is approved in the USA for metastatic BC and in Europe for locally advanced/metastatic BC. Talazoparib is approved for locally advanced/metastatic BC in the USA and Europe. In phase 3 trials, olaparib and talazoparib monotherapies demonstrated significant progression-free survival benefits compared with chemotherapy. Common toxicities were effectively managed by supportive treatment and dose interruptions/reductions. Veliparib combined with platinum-based chemotherapy has also shown promise for locally advanced/metastatic BC in a phase 3 trial. Differences in efficacy and safety across PARP inhibitors (olaparib, talazoparib, veliparib, niraparib, rucaparib) may relate to differences in potency of PARP trapping on DNA and cytotoxic specificity. PARP inhibitors are being investigated in early BC, in novel combinations, and in patients without germline BRCA mutations, including those with somatic BRCA mutations and other HRR gene mutations. Ongoing phase 2/3 studies include PARP inhibitors combined with immune checkpoint inhibitors for the treatment of triple-negative BC. Wider access to testing for BRCA and other mutations, and to genetic counseling, are required to identify patients who could benefit from PARP inhibitor therapy. The advent of PARP inhibitors has potential benefits for BC treatment beyond the locally advanced/metastatic setting.

Fig. 1

DNA damage response pathways ( modified from O’Connor MJ [54])

Fig. 2

The role of PARP in base excision repair of single-strand breaks in DNA. LigIII DNA ligase 3, NAD⁺ nicotinamide adenine dinucleotide, PARP poly(ADP-ribose) polymerase, pol b, DNA polymerase beta, XRCC1, X-ray repair cross-complementing protein 1

Fig. 3

Synthetic lethality by PARP inhibitors in HRR-deficient cancer cells (modified from O’Connor [54]). HRR homologous recombination repair, PARP poly(ADP-ribose) polymerase

Fig. 4

Possible treatment pathways for germline BRCA-mutated, HER2-negative breast cancer and proposed positions of germline BRCA mutation testing (author opinion, based on treatment guidelines and licensed indications [, , , , , , –92]). ^aRed star denotes potential positions of gBRCA mutation testing in the treatment pathways. ^bThe PD-L1 inhibitor atezolizumab plus albumin-bound paclitaxel. For patients with visceral crisis (organ dysfunction) and PD-L1+, first-line treatment could be CT or PARPi. For patients with visceral crisis (organ dysfunction) and PD-L1-, first-line CT may be appropriate. ^cDouble-headed arrows show that therapies can be provided in either sequence. ^dOlaparib and talazoparib are PARPi monotherapies approved for deleterious/suspected deleterious gBRCA-mutated, HER2-negative BC. Olaparib is approved in the USA for gBRCA-mutated metastatic BC and in Europe for gBRCA-mutated locally advanced/metastatic BC; talazoparib is approved for gBRCA-mutated locally advanced/metastatic BC in the USA and Europe. ^eIn Europe, the PI3K inhibitor alpelisib plus fulvestrant is approved for use after disease progression following ET as monotherapy. In the USA, alpelisib plus fulvestrant is approved for use after disease progression on or after an ET-based regimen. ^fAlt. Tx includes everolimus plus ET. Return arrows show that patients can receive more than one line of Alt. Tx. Alt. Tx alternative treatment to PARPi or CT, BC breast cancer, CDK4/6i cyclin-dependent kinase 4 and 6 inhibitor, CT chemotherapy, ET endocrine therapy, gBRCAm germline BRCA mutation, HER2 human epidermal growth factor receptor 2, HR+ hormone receptor-positive, IOT immuno-oncology therapy, L line, PARPi PARP poly(ADP-ribose) polymerase inhibitor, PD-L1 programmed cell death ligand 1, PI3Ki phosphoinositide 3-kinase inhibitor, TNBC triple-negative breast cancer