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Advanced prostate cancer with ATM loss: PARP and ATR inhibitors

  • Antje Neeb,
  • Nicol├ís Herranz,
  • Sara Arce-Gallego,
  • Susana Miranda,
  • Lorenzo Buroni,
  • Wei Yuan,
  • Alejandro Athie,
  • Teresa Casals,
  • Juliet Carmichael,
  • Daniel Nava Rodrigues,
  • Bora Gurel,
  • Pasquale Rescigno,
  • Jan Rekowski,
  • Jon Welti,
  • Ruth Riisnaes,
  • Veronica Gil,
  • Jian Ning,
  • Verena Wagner,
  • Irene Casanova-Salas,
  • Sarai Cordoba,
  • Natalia Castro,
  • Maria Dolores Fenor de la Maza,
  • George Seed,
  • Khobe Chandran,
  • Ana Ferreira,
  • Ines Figueiredo,
  • Claudia Bertan,
  • Diletta Bianchini,
  • Caterina Aversa,
  • Alec Paschalis,
  • Macarena Gonzalez,
  • Rafael Morales-Barrera,
  • Cristina Suarez,
  • Joan Carles,
  • Amanda Swain,
  • Adam Sharp,
  • Jesus Gil,
  • Violeta Serra,
  • Christopher Lord,
  • Suzanne Carreira,
  • Joaquin Mateo,
  • Johann S. de Bono

Publication: European Urology, November 2020

Background

Deleterious ATM alterations are found in prostate cancer (PC) and associate with a higher grade; PARP inhibition has antitumour activity against this subset, but only some ATM loss PCs respond.

Objective

To characterise ATM-deficient lethal PC and to study synthetic lethal therapeutic strategies for this subset.

Design, setting, and participants

We studied advanced PC biopsies using validated immunohistochemical (IHC) and next-generation sequencing (NGS) assays.

Outcome measurements and statistical analysis

In vitro cell line models modified using CRISPR-Cas9 to impair ATM function were generated and used in drug-sensitivity and functional assays, with validation in a patient-derived model.

Results and limitations

Overall, we detected ATM IHC loss in 68/631 (11%) PC patients with synchronous and metachronous intrapatient heterogeneity; 45/61 (74%) of ATM loss tumours had ATM mutations or deletions by NGS. ATM IHC loss was not associated with worse outcome from advanced disease, but ATM loss was associated with increased genomic instability (the number of subchromosomal regions with allelic imbalance extending to the telomere, p = 0.005; large-scale transition, p = 0.05). In vitro, ATM loss PC models were sensitive to ATR inhibition, but had variable sensitivity to PARP.

Commentary by Prof. Igor Tsaur

A short while ago, olaparib was approved by the European Medical Agency (EMA) for the treatment of patients with metastasized castration-resistant prostate cancer (mCRPC) and germline and/or somatic BRCA1/2-mutations based on the results of the PROfound trial. In general, it has been speculated that deleterious aberrations in DNA Damage Response (DDR) genes, particularly in those critical for homologous recombination repair (HRR), may predict response to poly(ADP-ribose) polymerase (PARP) inhibition.

In the PROfound trial, the cohort of males defined as harbouring at least one mutation in BRCA1/2 as well as ATM genes exhibited benefit in radiographic progression-free survival (PFS). Importantly, genomic subgroup analysis revealed that only men with BRCA1/2 mutations experienced advantage from a treatment with olaparib, while those with ATM mutations did not. Obviously, PARP inhibition completely suppresses HRR in BRCA-deficient patients, but not in ATM-deficient patients with mCRPC. Consequently, further molecular targets playing a critical role in HRR maintenance need to be assessed for therapeutic purposes in the context of PARP inhibition and ATM-defects.

Neeb et al. present a translational research study on possible treatment options for ATM-deficient mCRPC. The prevalence of ATM loss in immunohistochemistry (IHC; defined by H Score 0) was 11% in the study cohort of 653 men while targeted next-generation sequencing (NGS) data about 61 patients with ATM loss were available. 65 % of the ATM-deficient biopsies had ATM mutations or deletions by NGS, as compared to the 10% of the ATM-proficient biopsies that had ATM gene alterations by IHC. As compared to ATM proficiency by IHC, ATM loss was associated with increased genomic instability, however the overall survival from diagnosis or from CRPC as well as from time of diagnosis to CRPC were similar. Cell culture and xenograft models demonstrated that combining PARP with inhibitors of ATR in the context of ATM defects represents a promising treatment strategy by a powerful blocking of HRR.

One essential finding is that NGS does not capture all ATM loss due to post-transcriptional or epigenetic modifications or due to the inability of clinically implemented NGS assays to detect complex genomic rearrangements. Conversely, IHC may detect late truncated proteins with underlying mutations. Overall, predictive value of both approaches needs to be tested in clinical trials. Furthermore, research on refining the definition of a predictively relevant IHC threshold of the ATM protein expression is warranted. Finally, since PARP inhibitors do not completely stall HRR in ATM-deficient CRPC, combining them with other drugs targeting crucial molecular machinery of HRR maintenance is one possible way to provide precise medicine for males with this subset of mCRPC.