Developing novel targeted anticancer therapies is a major goal of current research. The use of poly(ADP-ribose) polymerase (PARP) inhibitors in patients with homologous recombination-deficient tumours provides one of the best examples of a targeted therapy that has been successfully translated into the clinic. The success of this approach has so far led to the approval of four different PARP inhibitors for the treatment of several types of cancers and a total of seven different compounds are currently under clinical investigation for various indications. Clinical trials have demonstrated promising response rates among patients receiving PARP inhibitors, although the majority will inevitably develop resistance. Preclinical and clinical data have revealed multiple mechanisms of resistance and current efforts are focused on developing strategies to address this challenge. In this Review, we summarize the diverse processes underlying resistance to PARP inhibitors and discuss the potential strategies that might overcome these mechanisms such as combinations with chemotherapies, targeting the acquired vulnerabilities associated with resistance to PARP inhibitors or suppressing genomic instability. Poly(ADP-ribose) polymerase (PARP) inhibitors are approved for patients with several forms of cancer, predominantly those harbouring loss-of-function BRCA1/2 mutations or other homologous recombination defects. Nonetheless, most patients receiving PARP inhibitors will ultimately develop resistance to PARP inhibitors, resulting in disease progression. In this Review, the authors describe the mechanisms of resistance to PARP inhibitors and discuss the potential treatment strategies that might overcome these effects.

Understanding and overcoming resistance to PARP inhibitors in cancer therapy.

The recognition of homologous recombination deficiency (HRD) as a frequent feature of high-grade serous ovarian cancer (HGSOC) has transformed treatment paradigms. Poly(ADP-ribose) polymerase inhibitors (PARPis), developed based on the rationale of synthetic lethality that predicates antitumor efficacy in tumors harboring underlying HRD, now represents an important class of therapy for HGSOC. Recent data have drawn attention to the assessment of homologous recombination DNA repair (HRR) as a prognostic and predictive biomarker in HGSOC, leading to increasing debate on the optimal means of defining and evaluating HRD, both genotypically and phenotypically. At present, clinical-grade assays such as myChoice CDx and FoundationOne CDx are approved companion diagnostics which can identify patients with HRD-positive HGSOC by diagnosing a ‘genomic scar’ reflecting underlying genomic instability. Yet despite the rapid maturation of this field, tumoral HRD status has been recognized to be dynamic over time and with treatment pressure. In practice, this means that restoration of HRR through mechanisms of platinum and PARPi resistance are not adequately represented by genomic scar assays, and contribute toward discordance with clinical PARPi response, or lack-thereof. It is thus critical that HRD testing is optimized to address the controversies of diverse HRD testing methodology, appropriate thresholds for HRD identification, and relevant timepoints for HRD testing, in order to realize the potential for PARPis to maximally benefit patients with HGSOC. Here, we discuss the premise of HRD testing in HGSOC, current methodologies for HRD identification and their performance in the clinic, highlight upcoming strategies, and discuss the challenges faced in moving this field forward.

The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

The current availability of new Poly(ADP-ribose) Polymerase (PARP)-inhibitors for the treatment of ovarian cancer patients independently of the presence of a BRCA pathogenic variant, together with the validation of somatic test for the analysis of BRCA1/2 genes, involves the need to optimise the guidelines for BRCA testing. The AIOM-SIGU-SIBIOC-SIAPEC-IAP Italian Scientific Societies, in this position paper, recommend the implementation of BRCA testing with 2 main objectives: the first is the identification of ovarian cancer patients with higher probability of benefit from specific anticancer treatments (test for response to therapy); the second goal, through BRCA testing in the family members of ovarian cancer patients, is the identification of carriers of pathogenic variant, who have inheredited predisposition to cancer development (test for cancer risk). These individuals with increased risk of cancer, should be encouraged to participate in dedicated high-risk surveillance clinics and specific risk-reducing measures (primary and/or secondary prevention programs).

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Recommendations for the implementation of BRCA testing in ovarian cancer patients and their relatives

Treatment of patients with recurrent epithelial ovarian cancer for whom platinum is still an option

Poly (ADP-ribose) polymerase (PARP) inhibitors have transformed the management of recurrent ovarian cancer in patients with BRCA-mutations and beyond. Olaparib was the first PARP inhibitor to gain approval as maintenance therapy for patients with newly diagnosed, advanced BRCA-mutated ovarian cancer establishing a new standard of care. At the end of 2020, as a result of the SOLO1, PRIMA, and PAOLA-1 phase III trials, we are now in an era where three maintenance PARP inhibitor strategies have FDA and European Medicines Agency approval in the first-line setting. In this review, we provide an overview of the key PARP inhibitor trials that have changed clinical practice, discuss directing therapy according to biomarker status (BRCA and homologous recombination deficiency) and future strategies in ovarian cancer and other gynecological malignancies.

PARP inhibitors in ovarian cancer: An overview of the practice-changing trials

811MO Maintenance olaparib for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): 5-year (y) follow-up (f/u) from SOLO1

Maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients (pts) with advanced ovarian cancer (OC) and a BRCA1/2 mutation (BRCAm): Phase III SOLO1 trial

B-G Kim

Papers

811MO Maintenance olaparib for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): 5-year (y) follow-up (f/u) from SOLO1

Maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients (pts) with advanced ovarian cancer (OC) and a BRCA1/2 mutation (BRCAm): Phase III SOLO1 trial

Increased expression of claudin-1 and claudin-7 during progression of cervical neoplasia

Outcomes of Fertility-Sparing Radical Trachelectomy in Early-Stage Cervical Cancer