More than 4,000 clinicians, researchers, students, and other stakeholders from around the world who diagnose, treat, and study genitourinary malignancies gathered in San Francisco at the American Society of Clinical Oncology’s annual Genitourinary Cancers Symposium, held between February 14–16.
Conference planners have scheduled more than a third of the three-day event for attendees to focus their attention exclusively on the topic of prostate cancer (PCa). As a result, a day of talks, structured networking events, and more than 300 posters addressed recent findings in prostate cancer treatment and research.
A topic expected to receive considerable coverage is the topic of biomarkers. In PCa, a familiar example is prostate-specific antigen, which is used to screen for signs of the disease and to guide treatment decisions. In the future, one could imagine clinicians using additional biomarkers to determine an appropriate course of treatment.
The case of PARP inhibitors
Genetic biomarkers are particularly relevant to the use of poly ADP-ribose polymerase (PARP) inhibitors. In a retrospective study (Abstract 154), Dr. Catherine Marshall, MD, MPH, and colleagues from Johns Hopkins University School of Medicine investigated the specificity of the PARP inhibitor, Lynparza (olaparib), toward metastatic castration-resistant prostate cancer (mCRPC) patients with mutations in either the breast cancer genes 1 and 2 (BRCA1/2) or ataxia telangiectasia mutated (ATM) genes.
Unlike the DNA repair proteins, BRCA1 and BRCA2, ATM’s role is as a DNA damage sensor. It turns out this functional difference affects how patients respond to Lynparza. The researchers found better endpoints for men with BRCA1/2 mutations than those with ATM mutations. Although more work is needed to support these findings, the results suggest that all genes involved in DNA repair are not equal when it comes to PARP inhibition.
Trial finds four key biomarkers
In preliminary results from a Phase II study (Abstract 142) of a combined therapy with the immune checkpoint inhibitors Yervoy (ipilimumab) and Opdivo (nivolumab) in treating mCRPC patients, Dr. Padmanee Sharma, MD, PhD, and colleagues from MD Anderson Cancer Center pointed out a higher objective response rate (ORR) in a patient population enriched with four biomarkers: program death-ligand 1 (PD-L1), DNA damage repair (DDR), homologous recombination deficiency (HRD), or above-median tumor mutational burden (TMB).
The use of PD-L1 expression as a biomarker is reasonable considering Opdivo blocks PD-L1 from binding PD-1. The other three indicators yield genetic instability, which increases the number of tumour antigens. Checkpoint inhibitors impact the immune system’s ability to recognise those antigens on the cell surface. As a consequence, ORR is higher for patient populations enriched with those biomarkers. These markers can be used to identify patients for whom checkpoint inhibitors are best suited.
The use of biomarkers holds promise for addressing unmet needs in prostate cancer treatment. For example, prostate-specific membrane antigen (PSMA) expression levels could be used as a way to stratify risk at initial diagnosis. In another approach, measuring the number of circulating tumour cells (CTCs) could help in monitoring treatment efficacy.
The use of androgen receptor splice variant-7 (AR-V7) or related pathway genes to predict resistance to antiandrogen therapy could help a clinician eliminate an inappropriate treatment course. Biomarker enthusiasts will notice at this year’s conference that the utility of biomarkers continues to ascend.