Pan-cancer assessment of BRCA1/2 genomic alterations (GAs) by comprehensive genomic profiling (CGP) of tissue and circulating tumor DNA (ctDNA)

Agarwal, Neeraj; Sokol, E.S.; Lara, Primo N.; Ross, Jeffrey S.; Miller, VA; Welsh, Allison W.; Gregg, Jeff P.; Frampton, Garrett M.; Ali, Simak; Chung, Jon

doi:10.1093/annonc/mdy269.049

Cited by 2 publications

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“…Indeed, the phase I trials of olaparib, niraparib, and talozaparib have already documented responses beyond the two now approved indications. A recent study analysed the prevalence of BRCA1/2 alterations across tumour types beyond ovarian and breast cancer, in prostate, skin (non-melanoma), endometrial, pancreatic, and biliary duct cancers the prevalence was 5% [42]. Of those, clinical trials have been reported primarily for prostate and pancreatic cancer.…”

Section: Expanding the Indications For Parpi To Other Tumour Types Wimentioning

confidence: 99%

A decade of clinical development of PARP inhibitors in perspective

Mateo

Lord

Serra³

et al. 2019

Annals of Oncology

492

428

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Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce tumour-specific vulnerabilities that can be exploited therapeutically. In 2009, a first-in-man clinical trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib clinically validated the synthetic lethal interaction between inhibition of PARP1, a key sensor of DNA damage, and BRCA1/ BRCA2 deficiency. In this review, we summarize a decade of PARP inhibitor clinical development, a work that has resulted in the registration of several PARP inhibitors in breast (olaparib and talazoparib) and ovarian cancer (olaparib, niraparib and rucaparib, either alone or following platinum chemotherapy as maintenance therapy). Over the past 10 years, our knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and we summarise this work here. We also discuss opportunities for expanding the precision medicine approach with PARP inhibitors, identifying a wider population who could benefit from this drug class. This includes developing and validating better predictive biomarkers for patient stratification, mainly based on homologous recombination defects beyond BRCA1/BRCA2 mutations, identifying DNA repair deficient tumours in other cancer types such as prostate or pancreatic cancer, or by designing combination therapies with PARP inhibitors.

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