OA: “Back to a false normality”: new intriguing mechanisms of resistance to PARP inhibitors

open access:
“Back to a false normality”: new intriguing mechanisms of resistance to PARP inhibitors
 
 Table 1: Phase II and III clinical trials investigated PARP inhibitors in breast and ovarian cancer.

 Abstract

Several evidences have shown that BRCA mutations increased tumor-cells sensitivity to PARP inhibitors by synthetic lethality leading to an accelerated development of several compounds targeting the PARP enzymes system as anticancer agents for clinical setting. Most of such compounds have been investigated in ovarian and breast cancer, showing promising efficacy in BRCA-mutated patients. Recently clinical studies of PARP-inhibitors have been extended across different tumor types harboring BRCA-mutations, including also “BRCA-like” sporadic tumors with homologous recombination deficiency (HRD). This review summarizes the biological background underlying PARP-inhibition, reporting the results of the most relevant clinical trials carried out in patients treated with PARP inhibitors alone or in combination with chemotherapy. Molecular mechanisms responsible for the occurrence of both primary and acquired resistance have been elucidated, in order to support the development of new treatment strategies.

 PARPi have been developed and tested in clinical trials to treat patients carrying BRCA1/2 mutations. These genetic alterations have been detected in about 17% of patients with ovarian cancer, mainly high grade serous adenocarcinoma.

Clinical development of PARP inhibitors

To date there are about ten molecules, including olaparib, veliparib, rucaparib, niraparib, among those in more advanced stages of experimental development. The majority of such studies have been focused on solid tumors harboring germ-line BRCA1-2 mutations, mainly ovarian and breast, but also prostate or pancreatic cancers. However the use of PARP inhibitors as single agent was extended also to “BRCA-like” sporadic tumors with suspected homologous recombination (HR) genes defects, including high grade serous ovarian cancer (HGSOC) and triple negative breast cancer (TNBC). Furthermore the peculiar mechanisms of action of such compounds has led to evaluate potential combinations with both DNA damaging cytotoxic agents, including chemotherapy and radiotherapy, and targeted agents able to induce HR dysfunctions, such as CDK1, PI3K, PTEN and HSP90 inhibitors or anti-angiogenic drugs.

Ovarian cancer

Fong et al have has first demonstrated the activity of single agent PARP inhibitor olaparib in BRCA-deficient advanced ovarian, breast and prostate cancers [43], with greater activity observed in platinum sensitive ovarian cancer patients [44]. Response rates of 30% have been reported in a subsequent phase II studies conducted in refractory advanced BRCA-mutant ovarian cancer [45], suggesting BRCA1-2 mutations as potential predictive biomarkers for clinical use. However another phase II study including both BRCA mutant and wild type patients with breast cancer and HGSOC showed encouraging activity also in the cohort of wild type, platinum-sensitive HGSOC patients [46], likely due to the acquired defects of HR genes responsible for “BRCA-like phenotype”, which conferred the same sensitivity to both platinum-chemotherapy and PARP inhibition. All such findings have led to the design of a randomized phase III, placebo controlled trial, of olaparib as single agent maintenance therapy in patients with recurrent HGSOC who responded to prior platinum-based chemotherapy, showing a significant improvement of 3.6 months progression free survival (PFS) in the overall population (HR: 0.35, p < 0·001), with the greatest increment of 6.9 months PFS (HR 0.18, p < 0.0001) occurring in the subgroup of patients with BRCA mutations [47]. The updated analysis of the study 19 has recently shown a significant overall survival benefit limited to the BRCA mutant patients (34.9 vs 30.2 months; HR: 0.62, p = 0.025), which was not extended to the wild type population (HR 0.83, p = 0.37). As expected adverse events like fatigue, anemia, nausea and vomiting were significantly higher with olaparib than placebo [48]. On the basis of such positive results olaparib was the first PARP-inhibitor receiving the approval by the European Medical Agency (EMA) at doses of 400 mg twice daily as maintenance therapy for platinum-sensitive patients with advanced HGSOC, fallopian tube, or primary peritoneal cancer, harboring BRCA-mutations. A companion diagnostic test has been also approved by FDA to identify mutations in BRCA1/2 genes using DNA obtained from a blood sample. Along with olaparib, several other PARP inhibitors, including veliparib, rucaparib and niraparib have shown encouraging activity and acceptable safety profile in early phase I-II studies. In particular the phase II randomized ARIAL 2 study of rucaparib has shown an objective response rate (ORR) of 80% and median PFS of 12.8 months in BRCA-mutant platinum sensitive patients with recurrent ovarian cancer and ORR 39% with and median PFS of 7.2 months in BRCA wild type patients with a BRCA-like signature, compared to ORR of 13% and median PFS of 5 months in biomarker negative patients. Rucaparib was associated with a manageable safety profile, including nausea, asthenia/fatigue and ALT/AST elevations among the most common treatment-related AEs [49, 50]. These impressive results led to the recent Breakthrough Therapy designation status of rucaparib by the FDA for the treatment of ovarian cancer, while the ARIEL3 randomized study is currently recruiting patients. Veliparib has recently shown a significant activity and tolerable safety profile as single agent in a phase II single arm trial including ovarian cancer patients carrying a germline BRCA1-2 mutation who progressed to prior chemotherapy regimens, reporting ORR of 35% and 20% in platinum-sensitive and platinum-resistant patients, respectively [51]. A phase 3 trial is currently ongoing in order to further elucidate the potential of this drug in such setting. Niraparib 300 mg/day has shown a good safety profile and a promising activity with ORR 40% in pre-treated ovarian cancer patients with BRCA 1-2 mutations [52]. The phase III randomized ENGOT-OV16/NOVA trial investigated the PARP inhibitor niraparib as single agent maintenance therapy in patients with recurrent, platinum sensitive HGSOC, stratified by BRCA-mutation status. The study has met its primary end-point showing a significant PFS improvement both in BRCA-mutant (HR: 0.27; p < 0.001) and in BRCA-wild type (HR: 0.45; p < 0.0001) populations. A further analysis of BRCA-wild type patients identified the subgroup of HRD-positive patients who receive more benefit (HR: 0.38; p < 0.001) compared to HRD-negative patients (HR: 0.58; p < 0.0226) [53]. The large benefit observed in the overall population included in the NOVA study could led to a fast approval of niraparib in the treatment of platinum sensitive recurrent ovarian cancer, regardless of BRCA-status. An alternative approach has been investigated by another phase II randomized trial comparing olaparib plus chemotherapy (paclitaxel and carboplatin), followed by olaparib single agent maintenance versus chemotherapy alone in platinum-sensitive recurrent HGSOC patients. The results of such trial showed that combining olaparib 200 mg twice daily for 10 days of each cycle with lower dose of carboplatin (AUC 4) plus paclitaxel, followed by olaparib 400 mg twice daily as maintenance treatment is an effective and tolerable option leading to a significant 2.6-month PFS advantage (HR 0.51, p = 0.0012), with the greatest clinical benefit in BRCA-mutated patients (HR: 0.21, p = 0.0015) [54]. The addition of veliparib to cyclophosphamide didn’t improve RR and PFS in patients with recurrent HGSOC [55], while another phase II randomized study comparing veliparib plus temozolomide vs PLD in the same setting of patients has just completed recruitment (NCT01113957, https://clinicaltrials.gov/ ). A very promising strategy emerged from the phase II randomized trial by Liu et al. which showed a further PFS benefit from adding the anti-angiogenic agent cediranib to olaparib for platinum-sensitive, recurrent, HGSOC, fallopian tube, or primary peritoneal cancer (median PFS 17.7 vs 9 months; (HR: 0.42; p = 0·005) [56], warranting investigation in a phase III ongoing trial. Similarly a phase I-II study is currently comparing tolerability and efficacy of niraparib alone versus niraparib-bevacizumab combination versus sequential bevacizumab and niraparib in platinum sensitive relapsed ovarian cancer [57], while the PAOLA1 trial is currently investigating first-line chemotherapy with bevacizumab plus olaparib or placebo as maintenance treatment. Finally the combination of olaparib and PD-L1 checkpoint inhibitor Durvalumab has shown promising durable long-term responses and a tolerable safety profile in pre-treated ovarian cancer and triple negative breast cancer (TNBC) patients [58].....

 Finally PARPi and PD1/PDL1 checkpoint inhibitors combinations have recently shown durable responses, emerging as another promising strategy to expand the treatment arsenal against cancer.

New findings on acquired resistance

Since the advent of PARP inhibitors for cancer treatment, there are growing evidences showing that not all patients with BRCAness genes alterations report the same treatment responses. Commonly to other targeted treatments the majority of tumors will develop acquired resistance within 1 year of therapy, leading to the disease progression and the subsequent discontinuation of cancer treatment [73]. It’s likely that the different emerging mechanisms of resistance may depend from the original BRCAness gene alterated, ultimately leading to different patterns of treatment response observed in clinical setting [98].

Considering the recent introduction of PARP inhibitors for clinical use, there is currently very limited understanding about the molecular mechanisms underlying the occurrence of acquired resistance to this family of drugs.....