Neeraj Agarwal, MD, Discusses Potential Link Between ctDNA, AR Aberrations, and Survival in mCSPC

The appearance of circulating tumor DNA and androgen receptor aberrations yielded lower overall survival rates for patients with metastatic castration-sensitive prostate cancer during the phase 3 TITAN trial, according to Agarwal, MD.

Based on an exploratory analysis of results from the phase 3 TITAN trial (NCT02489318), which was presented at the 2022 American Society of Clinical Oncology Annual Meeting (ASCO), the presence of circulating tumor DNA (ctDNA) and other androgen receptor (AR) aberrations at baseline appear to be predictive of lower overall survival (OS) rates among patients with metastatic castration sensitive prostate cancer (mCSPC), though more research is necessary to validate this approach in a clinical setting, according to Neeraj Agarwal, MD.1

The TITAN trial was a randomized, double-blind, placebo-controlled study demonstrating the superiority of apalutamide (Erleada) vs placebo, both plus androgen deprivation therapy (ADT), in terms of radiographic progression-free survival (rPFS) and OS among patients with mCSPC. The follow-up multivariate analysis highlighted how the presence of ctDNA and/or AR genomic aberrations or amplifications at baseline and any AR genomic aberrations or PI3K pathway aberrations at the end of study treatment correlated with worse OS in this patient population. Additionally, univariate analyses revealed worse OS in patients treated with subsequent chemotherapy who had PIK3CA aberrations, PI3K pathway aberrations, or TP53 inactivation at the end of study treatment.

According to Agarwal, these findings represent a promising start in identifying biomarkers for mCSPC, but additional data are needed for further stratification of these biomarkers and to make the information more clinically useful.

“Based on [the TITAN] study, the presence of ctDNA or any androgen receptor aberration, mutation, or amplification at baseline seemed to be associated with inferior survival in the context of metastatic castration-sensitive prostate cancer,” Agarwal said. “These data need to be validated before they can be used clinically to identify patients who would be at the highest risk of not responding to the treatment or the highest risk of mortality or death. We have to continue to strive to work on biomarker data which will allow us to risk stratify and personalize medicine in our patients with metastatic castration-sensitive prostate cancer.”

In a recent conversation with CancerNetwork®, Agarwal, professor of medicine, presidential endowed chair of cancer research, and director of both the Genitourinary Oncology (GU) Program and the Center of Investigational Therapeutics at the Huntsman Cancer Institute (HCI) of the University of Utah in Salt Lake City, spoke in detail about findings from the analysis, shared his observations on related studies, and suggested that future research may lead to greater knowledge of these biomarkers for mCSPC.

CancerNetwork®: Can you provide background on the TITAN trial?

Agarwal: TITAN was a phase 3 trial performed in patients with [newly diagnosed] metastatic castration-sensitive prostate cancer that led to approval of a novel androgen receptor [AR] inhibitor, apalutamide, in 2019.2 This trial was a large global phase 3 trial which recruited more than 1000 patients and randomized them to androgen deprivation therapy plus apalutamide versus ADT plus placebo. At the first interim analysis after 22.3 months, both dual primary end points were positive. These included overall survival [OS] as well as radiographic progression-free survival, which [were] significantly improved in patients who received ADT plus apalutamide.

Moving forward, we also saw many other drugs getting approved or trials reporting positive results. These include the ARCHES trial [NCT02677896], which led to approval of enzalutamide [(Xtandi) plus ADT in metastatic hormone-sensitive prostate cancer].3 Then, we saw the data from the ENZAMET trial [NCT02446405].4 Then, we saw data from triplet therapy trials with abiraterone [Zytiga] plus docetaxel chemotherapy.Then at the [2022 Genitourinary Cancers Symposium] we saw the ARASENS trial [NCT02799602] reporting that triplet therapy of darolutamide [Nubeqa] and other novel AR inhibitors plus docetaxel chemotherapy plus ADT [is superior] versus ADT plus docetaxel.5 It is great to have these many trials which are positive. We have seen the standard of care for our patients with metastatic castration-sensitive prostate cancer evolve from single-agent ADT to doublets and triplets. These [new treatments] also pose a new question to us. Is [it better to use] triplet or doublet therapy? Is it possible that some patients really don’t need any intensification therapy? There are some patients who need everything they can get. Most patients may be just fine with doublet therapies. We do not know the answer.

There are no biomarkers, unfortunately, being used in the clinic in the context of patients with metastatic castration-sensitive prostate cancer. This is very unfortunate. Given how big of a burden metastatic prostate cancer is—metastatic prostate cancer is the second most common cause of cancer-related deaths in American and Western men—not having biomarkers to prognosticate, to help with decision making, is just unfortunate. I know there are several teams of stellar investigators working across the planet to find biomarkers, but we still do not have anything for clinical use. In this [TITAN] abstract presented at 2022 ASCO, we attempted to look at biomarkers which could correlate with poor survival in our patients with metastatic castration-sensitive prostate cancer who were enrolled in the TITAN study.

What did the biomarker data reveal in the TITAN trial?

In the 2022 ASCO Annual Meeting, we presented the biomarker data from the TITAN study. The presence of circulating tumor DNA at baseline in patients who enrolled in the TITAN study was a bad sign. Circulating tumor DNA was detected in 36% of patients who were available for biomarker studies. The [percentage of patients with detectable] ctDNA increased from baseline to end of treatment, from 36% to 75%, which was statistically significant [P <.001]. Presence of AR alterations, whether they were mutations or amplifications, also statistically increased from baseline at 27% and 24% respectively, to approximately 65% by the end of the treatment [P <.001]. These biomarkers were also associated with inferior survival. If you look at the univariate analysis, presence of ctDNA or any AR aberration at baseline or at the end of treatment was associated with significantly shorter overall survival. Even aberrations in the PI3K pathway were also associated with inferior survival. If we look at the multivariate analysis, presence of ctDNA and any AR genomic aberration at baseline were associated with inferior overall survival. PI3K pathway aberrations at the end of treatment were also associated with inferior survival in these patients. What are the implications of these data? Of course, they need to be validated in other trials. However, it is a good start for us to look for these biomarkers in large phase 3 trials. Hopefully one day, we will be able to use baseline ctDNA data or androgen receptor aberration or amplification data in stratifying our treatment decision making. Are these patients going to need more aggressive therapy? Maybe, but those data need to be validated.

Are there going to be any other planned analyses for the TITAN trial?

Multiple analyses are underway. We all have a common goal of trying to get as much biomarker data as possible from any phase 3 trial. Phase 3 trials which have already been conducted give us a golden opportunity to have a deep dive into the tissue and liquid biopsy data which have been collected during the conduct of those trials and to use the advancements in translation and laboratory-based research to glean more information from those biomarker data and see how those correlate with survival. As long as we continue to do that, I have no doubt that in the very near future—the next 2 or 3 years—we’ll be using biomarkers to risk stratify our patients and in our treatment decision making. Hopefully that will optimize the risk-benefit ratio, minimize cost, and maximize overall survival and quality of life.


  1. Agarwal N, Lucas J, Aguilar-Bonavides C, et al. Genomic aberrations associated with overall survival (OS) in metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) or placebo (PBO) plus androgen deprivation therapy (ADT) in TITAN. J Clin Oncol. 2022;40(suppl 16):5066. doi:10.1200/JCO.2022.40.16_suppl.5066
  2. FDA approves apalutamide for metastatic castration-sensitive prostate cancer. News release. FDA. Published September 18. 2022. Accessed October 18. 2022.
  3. FDA approves enzalutamide for metastatic castration-sensitive prostate cancer. News release. FDA. Published December 17, 2019. Accessed October 18. 2022.
  4. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835
  5. Smith MR, Hussain M, Saad F, et al. Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial. J Clin Oncol. 2022;40(suppl 6):13. doi:10.1200/JCO.2022.40.6_suppl.013