Abstract IA18: Sensitivity and resistance biomarkers to PARP inhibitors in Mcrpc
Authors: Mateo Joaquin 
Published: February 2019

Abstract
A better understanding of the molecular underpinnings of prostate cancer renders the opportunity for more precise patient care by individualizing therapeutic strategies according to predictive biomarkers of benefit. Until now, clinical management of patients with prostate cancer, either localized or metastatic, has not yet incorporated precision medicine strategies. To pursue this, a new classification of the disease needs to be based on molecular features that are clinically relevant. Several studies have now confirmed genomic defects in the DNA damage response pathways (DDR), and primarily in the homologous recombination mediated repair pathway (HR), as a cornerstone of prostate cancer biology. This is particularly relevant in patients with metastatic castration-resistant prostate cancer (mCRPC). Among this population with lethal disease, around 20-25% of cases present genomic loss (by pathogenic mutations or by homozygous deletion) of at least one gene involved in HR, and in half of this cases the mutation is inherited, which makes these findings also relevant for patients’ relatives, considering how some of this events are linked to increased risk of prostate and others cancers. The HR gene most commonly lost in advanced prostate cancer is BRCA2 (8-12% in different series), followed by ATM (4-6%), CDK12 (3-5%), BRCA1, and PALB2 (&lt;3% each). Clinical trials have previously shown the synthetic lethal interaction between BRCA2 loss and pharmacologic PARP [poly(ADP-ribose) polymerase] inhibition in other tumor types, and preclinical studies suggested loss of other HR sensors and effectors also could render sensitivity to PARP inhibition.
PARP-1 and 2 are key proteins in DNA single-strand break repair and a therapeutic target using a family of drugs (PARP inhibitors) already approved for the treatment of ovarian cancer associated to HR defects, primarily BRCA2 mutations. We completed a first stage of a phase II adaptive clinical trial evaluating the antitumor activity of the PARP inhibitor olaparib in mCRPC (TOPARP), as well as investigating predictive biomarkers associated with response to PARP inhibition. In a cohort of 49 evaluable patients who previously to docetaxel (49/49) and abiraterone and/or enzalutamide (48/49), 16 (32%) achieved a response to olaparib, using the trial preplanned definition of response (radiologic response by RECIST and/or 50% PSA fall and/or CTC conversion from &gt;5 to &lt;5 CTC/7.5 mL blood, confirmed in a second reading 4 weeks apart). Responses occurred primarily among patients with HR gene alterations in whole-exome sequencing studies of fresh metastatic biopsies. All 7 patients with somatic or germline BRCA2 defects achieved a response, in some cases prolonged for over a year. Responses among patients with ATM, BRCA1, or PALB2 defects were also observed. This study has led to a validation stage currently ongoing in the UK, where mCRPC patients are prospectively screened for HR gene pathogenic mutations or homozygous deletions aiming to treat 88 patients with such biomarkers with olaparib to better determine the antitumor effect of PARP inhibition among this molecularly defined subset of prostate cancer. Several phase II and phase III studies of different PARP inhibitors have been launched or are planned. These studies are targeting patients with mutations in a limited gene list, primarily ATM, BRCA2, BRCA1, and PALB2. However, we still need to better understand the optimal predictive biomarker suite for PARP inhibitors in prostate cancer; the target population may be broader than patients with pathogenic mutations in these genes; moreover, clinical data suggest that not all patients with mutations in these limited gene lists respond to PARP inhibition, and when they do, duration of respond may also differ dramatically among patients.
On one hand, it is possible that different genes have a different weight in determining HR proficiency, and hence, synthetic lethality with PARP inhibition. It is possible that loss of some genes may be partially or totally compensated for by other proteins, whereas loss of some other genes may be more catastrophic for the tumor cell. On the other hand, it is also feasible that the presence of secondary biologic events in prostate cancer, such as AR aberrations, TP53/Rb1 loss, or others, may modulate the impact of HR defects. Analytical validation and clinical qualification of functional assays as predictive biomarkers of PARP inhibitor sensitivity would help towards integrating complex genomic, transcriptome, and epigenetics data with regards to defining the optimal predictive biomarkers for treatment stratification.
The complex interaction between androgen receptor (AR) signaling and DDR may be relevant for PARP inhibition stratification. Preclinical studies suggest that blocking AR may render the cell sensitive to PARP inhibition; however, the impact of these findings on therapeutic strategies in the clinic is still not clear and further studies in localized and advanced disease are needed. Previously, a synthetic lethal interaction for PARP inhibition with PTEN loss or with the presence of ERG rearrangements in prostate cancer has been postulated from preclinical studies; to date, these data have not translated into clinical data supporting that these are optimal biomarkers to stratify patients for PARP inhibitors. It is possible these data are, however, very relevant to designing rational combination trials.
Lastly, HR gene mutations are also relevant towards secondary resistance mechanisms to PARP inhibitors, which further supports their relevance in determining sensitivity. In a follow-up study we identified how in patients with germline or somatic BRCA2 and PALB2 mutations responding to olaparib, secondary genomic events (basically small fragment deletions) emerged in the region of the original mutation, reverting the gene reading frame to normal. These events occur in a polyclonal manner and may be restoring HR function. These have now been confirmed by other studies in prostate, breast, and ovarian cancer.
Citation Format: Joaquin Mateo. Sensitivity and resistance biomarkers to PARP inhibitors in Mcrpc [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA18.