Early Biomarker Data Provide Framework for Precision Medicine-Based Trials in Prostate Cancer

Liquid biopsy with circulating tumor DNA (ctDNA) could help alleviate some of the challenges of tissue biopsy in prostate cancer, and in doing so, lead to a better precision medicine model in the field, according to early evidence from the phase 2 Prostate Cancer Biomarker Enrichment and Treatment Selection (PC-BETS) trial, explained Kim Chi, MD.

In the trial, 250 patients with progressive metastatic castration-resistant prostate cancer (mCRPC) underwent ctDNA screening. A total of 169 patients had 1% or greater ctDNA, and 81 had less than 1% ctDNA. Patients were grouped into 1 of 4 arms, irrespective of biomarker positivity.

Preliminary results from the trial, which were presented at the 2020 ASCO Virtual Scientific Program, showed that 8 patients who were enrolled in the darolutamide (Nubeqa) arm (n = 36) and 1 patient in the adavosertib arm (n = 19) derived clinical benefit.

“There are commercial and research assays out there, and there’s a lot of ongoing research on how we can take ctDNA and apply it to our patients, both for prognostic and predictive purposes,” said Chi. “Our data show the promise of ctDNA to identify actionable alterations in patients.”

In an interview with OncLive, Chi, senior research scientist, Vancouver Prostate Center, chief medical officer and vice president, BC Cancer, medical oncologist, BC Cancer, and professor, Department of Medicine, University of British Columbia, discussed the results of the PC-BETS study and the untapped potential for targeted therapy in prostate cancer.

OncLive: What inspired this research?

Chi: Although we have expanding treatment options for men with CRPC, the disease remains lethal. We also know that there is a long tail on the curve in terms of genomic alterations that could be targeted with novel treatments.

Could you highlight the design of the trial?

We conducted this ongoing phase 2 umbrella study in men with mCRPC who were progressing after next-generation hormone therapy, as well men who were progressing after docetaxel. Patients were enrolled and stratified according to biomarker status. All patients had ctDNA sequencing. Biomarker-positive patients were enrolled by a tumor board using preset criteria to various targeted therapies, and biomarker-negative patients were randomized to any of the open arms.

In the preliminary analysis, we showed that over 250 patients have been screened, and 84 have been enrolled. We see some early activity in the patients who were treated with adavosertib and darolutamide. The safety data was consistent with these agents and what we’ve seen in the past, so there were no safety concerns.

How might these data augment the field of targeted therapy in prostate cancer?

We recently heard about patients with DNA repair alterations benefitting from agents like PARP inhibitors. Our research is expanding [targeted therapy] to a wider group of patients by asking if there are there other alterations that we can target. We need to work on furthering precision medicine for patients with CRPC.

Why has it been so difficult to develop targeted therapies in prostate cancer compared with other malignancies?

The limiting factor has been tissue. Getting archival tissue or fresh biopsies from patients can be a challenge. In the PARP inhibitor studies, the assays often fail to provide a result, be it positive or negative. Biopsies can be challenging for patients, especially for those with prostate cancer who have bone metastases. Also, it’s not uncommon for there not to be enough cells [to biopsy].

With our approach, we started off using ctDNA right at the start. In patients with advanced prostate cancer, especially after progression after 1 or 2 lines of therapy, the majority have abundant ctDNA for analysis.

Could liquid biopsy become as widespread in prostate cancer as it is in lung cancer?

In lung cancer, you’re looking for specific mutations, which can be detected at very low levels of ctDNA. Prostate cancer is a little bit different because we don’t have those point mutations that we’re looking for. We have to adopt a wider view, so we need larger amounts of ctDNA in order to analyze the [sample] appropriately. In prostate cancer, we have these challenges with the tissue. ctDNA liquid biopsies are really going to play a prominent role in the future of prostate cancer, and even for example, with PARP inhibitors, in identifying patients with DNA repair.

Is there anything else about this study that you want to make sure that people know about?

This is an ongoing study. We’re adding additional arms, including an AKT inhibitor, as well as immunotherapy. We will be able to rapidly identify active agents for patients who have actionable alterations.

Reference

Chi KN, Mukherjee S, Saad F, et al. Prostate cancer biomarker enrichment and treatment selection (PC-BETS) study: a Canadian cancer trials group phase II umbrella trial for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(suppl 15):5551. doi:10.1200/JCO.2020.38.15_suppl.5551