ADCs hold promise for enhancing the therapeutic index of cytotoxics. STEAP1 is overexpressed in mCRPC and is the target of an ADC currently under clinical development. To identify pts most likely to benefit from the ADC, we explored STEAP1 expression as a predictive biomarker in tumor tissue using a CLIA-certified IHC assay, and on circulating tumor cells (CTCs) in blood using the CellSearch and EPIC platforms. Sixty pts with progressive mCRPC received doses ranging from 0.3 to 2.8 mg/kg once every three weeks. Response was defined as a ≥50% decline in PSA from baseline, and time on study for >6 months was consistent with continued clinical benefit. At doses of ≥2 mg/kg, the response rate (RR) was 10/45 (22%, 95% CI 9.9-34.1) and was highest in the STEAP1 IHC 3+ group, as was the fraction of patients who remained on study for >6 months. At ≥2 mg/kg, 20/45 pts (44%, 95% CI 29.5-58.5) had unfavorable CTC counts of ≥5/7.5mL at baseline and were considered evaluable. After treatment, conversions from unfavorable to favorable CTC counts of <5/7.5mL were seen in 11/20 patients (55%, 95% CI 33.2-76.8) and were significantly correlated with PSA declines (Spearman rank r = 0.74). STEAP1 expression in tissues and on CTCs as it related to clinical activity is presented in the following table:

STEAP1 IHC Score and Treatment ResponseSTEAP1 IHC ScorePts Observed/TotalPSA decline by ≥50% from baseline>6 months on treatment(%, 95% CI)(%, 95% CI)(%, 95% CI)1+5/45 (11%, 1.9-20.1)1/5 (20%, -15.1-55.1)0/5 (0%)2+27/454/276/27(60%, 45.7-74.3)(15%, 1.5-28.5)(22%, 6.4-37.6)3+13/455/136/13(29%, 15.7-42.2)(39%, 12.5-65.5)(46%, 18.9-73.1)CTC Analysis and Treatment ResponseCTC endpointTime Point & CTC Conversion vs. baselinePts Observed/TotalPSA decline by ≥50% from baseline>6 months on treatment(%, 95% CI)(%, 95% CI)(%, 95% CI)CTC countsBaseline ≥5/7.5mL20/456/206/20(at ≥2 mg/kg)(44%, 29.5-58.5)(30%, 9.9-50.1)(30%, 9.9-50.1)Baseline <5/7.5mL25/453/257/25(56%, 41.5-70.5)(12%, -0.7-24.7)(28%, 10.4-45.6)CTC conversion11/206/115/11(55%, 33.1-76.8)(55%, 25.6-84.4)(45%, 15.6-74.4)STEAP Expression Status on CTCsBaseline STEAP +ve9/131/91/9(most at <2mg/kg)(69%, 43.9-94.1)(11%, -9.4-31.4)(11%, -9.4-31.4)Baseline STEAP -ve4/13 (31%, 5.9-56.1)0/4 (0%)0/4 (0%)After treatment STEAP +ve4/14 (29%, 5.2-52.8)0/4 (0%)0/4 (0%)After treatment STEAP -ve10/14 (71%, 47.2-94.8)1/10 (10%, -8.6-28.6)1/10 (10%, -8.6-28.6)

An immuno-fluorescence-based assay developed to measure STEAP1 expression levels on CTCs showed readily detectable signal in 18/42 samples (43%, 95% CI 28-58), with a range from 1-56% of STEAP1-positive CTCs per case. After treatment, a decrease in the fraction of patients with STEAP1-positive and an increase in the STEAP1-negative CTCs was observed compared to baseline (see Table). We are prospectively selecting pts with STEAP1 IHC 2+/3+ tumors and assessing STEAP1 levels on CTCs in an ongoing Ph1 expansion study with the goal of developing a companion diagnostic to enrich for mCRPC pts most likely to benefit from treatment with the STEAP1 ADC.

Citation Format: Daniel C. Danila, Howard I. Scher, Edith Szafer-Glusman, Amrita Herkal, Rebecca Suttmann, Martin Fleisher, Nicole A. Schreiber, Kristen Curtis, Houston Gilbert, Daniel Maslyar, Bernard Fine, Ron Firestein, Michael Mamounas, Mark R. Lackner, Omar Kabbarah. Predictive biomarkers of tumor sensitivity to STEAP1 antibody-drug conjugate (ADC) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the 106th …