The tip of the iceberg: predicting PARP inhibitor efficacy in prostate cancer
Authors: Silke Gillessen, Robert G Bristow
Journal: The Lancet Oncology (2019)

In The Lancet Oncology, Joaquin Mateo and colleagues1Mateo J Porta N Bianchini D et al.Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial.Lancet Oncol. 2019; (published online Dec 2)https://doi.org/10.1016/S1470-2045(19)30684-9Summary Full Text Full Text PDF PubMed Scopus (315) Google Scholar report the results of the TOPARP-B trial, in which selected patients with metastatic castration-resistant prostate cancer and DNA damage response (DDR) gene aberrations were found to be responsive to the poly(ADP–ribose) polymerase (PARP) inhibitor, olaparib. Their study adds to the growing body of prospective studies evaluating different PARP inhibitors in patients with metastatic castration-resistant prostate tumours that harbour DNA repair defects. The recently reported phase 3 PROFOUND study showed an improved radiographic progression-free survival for patients with DDR gene aberrations treated with olaparib, compared with a control group treated with physician's choice of therapy.2Hussain M Mateo J Fizazi K et al.PROfound: Phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations.Ann Oncol. 2019; 30: v851-v934Google Scholar These prospective studies are leading to a new era in which metastatic castration-resistant prostate cancer might have predictive, rather than prognostic, molecular markers to guide treatment decisions. Predictive assays are an important and innovative step in the treatment of metastatic prostate cancer. However, before we wholly embrace this approach, we should critically evaluate the outstanding issues, to improve precision in this changing treatment landscape. TOPARP-B was a randomised, phase 2 study that compared 300 mg versus 400 mg twice daily oral olaparib through a pick-the-winner design. 711 patients previously treated with chemotherapy consented to prescreening, of whom 592 underwent targeted next-generation sequencing for DDR aberrations. Therefore, 119 (17%) patients in TOPARP-B could not be molecularly screened because of insufficient tissue or poor tissue quality. In the PROFOUND study, this proportion was reported to be even higher, at around 30%. Thus, the predictive testing for DDR mutations might not be achievable for 20–30% of patients, thereby preventing the use of a potential beneficial treatment because of inadequate tissue sampling and utility. In TOPARP-B, the primary endpoint was confirmed response, defined as a composite of all patients presenting with a radiological response, a decrease in prostate-specific antigen (PSA) of 50% or more, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood), or any combination of the three. This endpoint was in accordance with that used in the previous part of their study, TOPARP-A. However, this composite response cannot be directly compared with other studies that solely use PSA and radiographic responses. The higher olaparib dose of 400 mg twice daily seemed to be more effective than the 300 mg dose and reached the predefined threshold for activity to confirm the putative biomarker data from TOPARP-A, whereas the 300 mg dose did not. However, the trial was not powered to formally compare the two doses, and toxicity also seemed to be increased in the 400 mg cohort. The correct dosing will need to be determined in a series of trials. Interestingly, long-lasting responses were noted in some patients in the 300 mg cohort and in patients of the 400 mg cohort who needed dose reductions. How can we use this trial result to translate questions to the laboratory and improve the results of future trials? In TOPARP-B, some DDR gene aberrations seemed to be more responsive to olaparib than others, which seems to be recapitulated in other trials—eg, patients with BRCA2 mutations are the most frequent and also seem to gain the greatest benefit,3Nombela P Lozano R Aytes A Mateo J Olmos D Castro E BRCA2 and other DDR genes in prostate cancer.Cancers. 2019; 11: 352Crossref Scopus (52) Google Scholar but in TOPARP-B, the results for BRCA1 and BRCA2 are presented together. In addition, not all DDR-deficient tumours, including selected BRCA1/2 mutated tumours, responded to PARP inhibition. This lack of response could be related to the need for specific germline versus somatic base pair mutations, or additional secondary gene hits within the monoallelic or biallelic DDR-inactivated tumours, to show maximum PARP inhibitor efficacy. The tumour microenvironment or immune response might also be heterogenous and differentially altered by PARP inhibition in patients.4Chabanon RM Muirhead G Krastev DB et al.PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.J Clin Invest. 2019; 129: 1211-1228Crossref PubMed Scopus (158) Google Scholar, 5Bhandari V Hoey C Liu LY et al.Molecular landmarks of tumor hypoxia across cancer types.Nat Genet. 2019; 51: 308-318Crossref PubMed Scopus (286) Google Scholar Mutation-specific assays could be replaced by future assays that look for functional differences in DNA damage repair, such as genomic alterations in homologous recombination or DNA repair foci assays.6Gulhan DC Lee JJ Melloni GEM Cortés-Ciriano I Park PJ Detecting the mutational signature of homologous recombination deficiency in clinical samples.Nat Genet. 2019; 51: 912-919Crossref PubMed Scopus (122) Google Scholar, 7Meijer TG Verkaik NS Sieuwerts AM et al.Functional ex vivo assay reveals homologous recombination deficiency in breast cancer beyond BRCA gene defects.Clin Cancer Res. 2018; 24: 6277-6287Crossref PubMed Scopus (37) Google Scholar Functional assays could uncover additional patients who respond to PARP inhibition, and start to provide an explanation for the intriguing observation that radiographic progression-free survival is improved by PARP inhibition in patients with metastatic castration-resistant prostate cancer who lack DDR mutations.8Clarke N Wiechno P Alekseev B et al.Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial.Lancet Oncol. 2018; 19: 975-986Summary Full Text Full Text PDF PubMed Scopus (218) Google Scholar Other reasons for differential response include inherent or acquired resistance mechanisms to PARP inhibition, including expression of multidrug-resistant genes and inhibition of the TP53-binding protein 1 and shieldin protein complexes that reactivate homologous recombination or alter intracellular drug concentrations.9Gogola E Rottenberg S Jonkers J Resistance to PARP inhibitors: lessons from preclinical models of BRCA-associated cancer.Annu Rev Cancer Biol. 2019; 3: 235-254Crossref Scopus (35) Google Scholar To continue progress in this field, we need to examine in more detail the characteristics of patients who show a profound, durable response, to further tailor the approach to treatment. When approved alongside a predictive assay, clinicians will have a new drug with a novel mechanism of action in their armamentarium to treat men with prostate cancer. But we still need to learn on the basis of biology how to make best use of it, ideally by finding the right drug combinations for each individual patient and maximising the opportunities for its use. In this regard, TOPARP-B also provides a rationale to study PARP inhibition in patients presenting with potentially aggressive, DDR-defective prostate cancers in hormone-naive settings.10Taylor RA Fraser M Livingstone J et al.Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories.Nat Commun. 2017; 813671Crossref PubMed Scopus (138) Google Scholar SG reports being on advisory boards or independent data monitoring committees (compensated) for AAA International, Active Biotech, Astellas, Bayer, Bristol-Myers Squibb, Clovis, Curevac, Dendreon, Ferring, Innocrin, Janssen, MaxiVAX, Menarini Silicon Biosystems, Millennium, Orion, Roche, Sanofi, and Tolero; advisory boards (uncompensated) for Aranda, Astellas, Bayer, ESSA Pharmaceuticals, Nectar, ProteoMediX, and Sanofi; speakers bureaus (compensated) for Janssen and Novartis; and speakers bureaus (uncompensated) for Amgen, Astellas, Janssen, and Sanofi. She was also a co-inventor on a patent application (WO 2009138392 A1) for a method for biomarker discovery. RGB reports being on advisory boards or independent data monitoring committees (compensated) for AstraZeneca, Onxeo, and Celgene; and an advisory board (uncompensated) for Cancer Research UK Therapeutic Discovery Laboratories. He also reports research grants from AstraZeneca and GenomeDx Biosciences. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trialOlaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice. Full-Text PDF Open Access