Dr. Cookson began by highlighting that prostate cancer is a highly heterogeneous disease with treatment decisions, historically, driven by clinicopathologic features and the trajectory of PSA trends. However, evolving research in biomarkers and precision medicine offers the potential for targeted treatment and may also predict outcomes.
He then provided a definition of a biomarker, as a characteristic that is objectively measured and evaluated as an indicator of normal biologic or pathogenic process, or pharmacologic responses to intervention. Within this, we can consider prognostic biomarkers, which provide information about a patient’s outcome independent of therapy, and predictive biomarkers, which provide information about the efficacy of an intervention.
Looking at the use of biomarkers, we can assess either germline (inherited) or somatic (acquired) mutations in a cancer patient and their tumors.
In prostate cancer, there are many relatively commonly mutated genes. Many of these relate to the DNA damage and repair response including ATM, BRCA1, BRCA2, CHECK2, and others. Further tumor suppressor genes such as TP53 and PALB2 may also be present. Most of these do not cause cancer but interact with other genes and the environment to increase cancer risk. Thus, when mutated, prostate cancer tends to be more aggressive. Notably, mutations in HOXB13 is associated with clearly defined inherited prostate cancer of early-onset.
Given the frequency of genes related to DNA damage repair (DDR), Dr. Cookson then discussed this pathway in more detail, emphasizing that downregulation or dysfunction in the DDR pathway is associated with genomic instability which can lead to progression from the normal through precancerous to cancerous disease states. Such pathway alterations are common in prostate cancer.
Dr. Cookson then focused on the example of BRCA1 and BRCA2 mutations in prostate cancer. These genes function as DNA damage response genes. Mutations are associated with an increased lifetime prevalence of prostate cancer (with a greater effect among those with BRCA2 mutations), as well as increased aggressivity (particularly among those with BRCA2 mutations). Given the association with prostate, as well as many other hereditary cancers, there is an increased role for directed screening as well as targeted systemic therapies in patients with known mutations in BRCA1 and BRCA2.
Germline mutations are present in approximately 12% of patients with metastatic prostate cancer, and a much smaller proportion of those with localized disease. BRCA2 represents the most common of these. In addition to germline mutations, there are other actionable somatic mutations such that 23% of patients with metastatic castration-resistant prostate cancer (mCRPC) have DNA repair pathway alterations and 90% of those patients have actionable molecular alterations.
Currently, assays are typically intended to detect either somatic or germline mutations, thus it is important to understand the strengths and limitations of testing platforms prior to their use. Further, differing panels including a differing repertoire of genes for which alterations are examined.
In terms of somatic testing, a tissue biopsy is a traditional approach, though emerging data suggests a good correlation of liquid biopsy examining circulating tumor cells (CTCs) and circulating tumor cell DNA (ctDNA).
Based on guidelines, Dr. Cookson highlighted that all patients with metastatic prostate cancer, those with intraductal or ductal histology, those with early-onset prostate cancer in multiple family members, those with high risk localized prostate cancer and family history suggestive of an inherited syndrome, and those in whom tumor sequencing suggests mutation in a hereditary cancer gene should undergo germline testing. This needs to be performed in the context of shared decision making with informed consent and, ideally, with the support of a genetic counselor.
Dr. Cookson then transitioned to discussing PARP inhibitors, systemic therapy that is targeted at the tumor-related defects associated with DNA damage repair pathways. In patients with BRCA1 or BRCA2 mutations, the use of PARP inhibitors can cause synthetic lethality due to the induction of double-stranded breaks which cannot be repaired due to the BRCA-deficiency. He then reviewed trial data for the two approved PARP inhibitors, olaparib and rucaparib.
As has been previously presented, published, and reported in UroToday, the phase III PROfound trial compared olaparib and androgen-axis inhibitor switch in patients with mCRPC who had progressed on one androgen-axis inhibitor. In a biomarker-based cohort stratification, the benefit of olaparib was seen among patients with mutations in BRCA1, BRCA2, or ATM.
In terms of rucaparib, available data to date come from the phase II TRITON2 study examining rucaparib in a single-arm fashion among men with mCRPC who had progressed on 1-2 lines of androgen-axis inhibition and 1 line of taxane-based chemotherapy who had deleterious mutations in DDR-related genes. Again, the predominance of patients had BRCA-related alterations and the majority of these patients derived significant PSA-based response rates. The ongoing phase III trial will examine rucaparib in a similar design to PROfound though no prior chemotherapy is allowed.
These data have resulted in guideline recommendations suggesting that PARP inhibitors should be offered to appropriate patients with deleterious mutations in these genes. Many ongoing trials will continue to define the role of PARP inhibitors, particularly in combination therapy and early in the disease space.
Presented by: Michael S. Cookson, MD, MMHC, is Professor and Chairman of the Department of Urology and holds the Donald D. Albers Endowed Chair in Urology at the University of Oklahoma Health Sciences Center in Oklahoma City
Written by: Christopher J.D. Wallis, MD, PhD, FRCSC Contact: @WallisCJD on Twitter during the 18th Meeting of the EAU Section of Oncological Urology (ESOU21), January 29-31, 2021