CTCm Score Predicts Outcomes in mCRPC Treated With Bavdegalutamide

Keisuke Otani, MD, PhD

Findings from a single-center analysis presented at the 2025 Genitourinary Cancers Symposium showed that a composite gene expression score (CTCm) derived from pretreatment circulating tumor cells (CTCs) correlated with outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with bavdegalutamide (formerly ARV-110) in the phase 1/2 ARDENT trial (NCT03888612).¹

“A pretreatment CTCm score [of less than] 165 was associated with freedom from radiographic progression at 2 months and time on bavdegalutamide [of longer than] 6 months in this small study of [patients with] mCRPC without androgen receptor [AR] T878/H875 mutations,” Keisuke Otani, MD, PhD, a research fellow in radiation oncology at Massachusetts General Hospital in Boston, Massachusetts, and coauthors wrote in the poster presented during the meeting.

Bavdegalutamide is a first-in-class oral proteolysis targeting chimera (PROTAC) protein degrader that selectively targets the AR. Prior findings from the ARDENT trial illustrated the activity of bavdegalutamide in patients with mCRPC whose disease had progressed after 1 to 2 AR-directed therapies.² Patients with AR wild-type disease exhibited clinical benefit, but the most pronounced activity was seen in those with T878X/H875Y mutations in the AR.

To better understand the patient population who derives the most benefit from bavdegalutamide and potentially identify a biomarker of response investigators evaluated the potential of a CTC RNA biomarker that would enrich for response.¹

The single-center study enrolled patients with progressive mCRPC following more than 1 prior novel hormonal therapy who were enrolled in the ARDENT trial and had consented for prospective collection of pretreatment blood for CTC analysis.

Per the protocol, CTCs were isolated using a negative selection microfluidic CTC enrichment device and evaluated for RNA expression of a panel of prostate cancer genes using a multiplex droplex digital polymerase chain reaction assay. The genes and proteins that were subject to evaluation included AGR2, FAT1, FOLH1, HOXB13, KLK2, KLK3, STEAP2, TMPRSS2, and AR-V7. The CTCm was compared with radiographic response at 2 months, prostate-specific antigen (PSA) response, and duration of time on bavdegalutamide. A cutoff value for CTCm was selected by the receiver operating characteristic curve analysis. The relationship between CTCm and clinical outcomes was evaluated by the 2-sided Fisher’s exact test.

The median age of the patient cohort (n = 20) was 73 years (range, 56-84). Patients were White (90%), Hispanic (5%), or Asian (5%), and had an ECOG performance status of 0 (80%) or 1 (20%). The median PSA level at baseline was 123.1 ng/mL (range, 4.97-1186). Bone and visceral metastases were present in 95% and 20% of patients, respectively. The median number of prior lines of systemic therapy was 5 (range, 3-7). Most patients had received prior chemotherapy (80%) vs not (20%), and 30%, 65%, and 5% of patients had previously received 1, 2, or 3 AR pathway inhibitors, respectively.

All 20 patients who had been treated with bavdegalutamide at doses ranging from 280 mg to 700 mg once daily or 140 mg to 420 mg twice daily consented to pretreatment CTC RNA expression analysis. None of these patients harbored T878/H875 mutations in the AR.

Additional results indicated that 6 patients remained on therapy for at least 6 months with clinical benefit whereas 14 patients discontinued treatment within 6 months. At 2 months, 10 patients had stable radiographic responses, and 7 patients had evidence of progressive disease. Three patients were not evaluable for response. Notably, a pretreatment CTCm score below 165 correlated with stable disease at 2 months (P = .015) and time on therapy for longer than 6 months (P = .014). However, CTCm was not associated with PSA reductions of at least 50% (PSA50; P > .9) or PSA reductions of at least 30% (PSA30; P = .60).

Best PSA50 and PSA30 occurred in 3 and 4 patients, respectively. Notably, the presence of AR-V7 was not associated with radiographic response (P = .15), PSA50 (P > .9), PSA30 (P = .60), or time on therapy for more than 6 months (P = .14).

“Further investigation of the CTCm biomarker is warranted in [patients with] mCRPC treated with bavdegalutamide and potentially other AR PROTACs,” study authors concluded.

Disclosures: Otani had no relationships to disclose.

References

• Otani K, Gao X, Kusaka E, et al. Circulating tumor cell RNA biomarker for bavdegalutamide (ARV-110) in metastatic castration-resistant prostate cancer without AR T878/H875 mutations. J Clin Oncol. 2025;43(suppl 5):235. doi:10.1200/JCO.2025.43.5_suppl.235
• Gao X, Burris III HA, Vuky J, et al. Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(suppl 6):017. doi:10.1200/JCO.2022.40.6_suppl.017