David C. Smith

PURPOSE: There are few established prognostic biomarkers in metastatic hormone-sensitive prostate cancer (mHSPC). Disease volume and timing of metastases are prognostic and predictive factors but may be inadequate due to heterogeneity. Circulating tumor DNA (ctDNA) provides both circulating volume (tumor fraction [TF]) and genomic data. There are limited data on ctDNA in mHSPC. METHODS: This was a multicenter, prospective study of ctDNA testing in mHSPC. Presented here are the results before androgen-deprivation therapy initiation. The primary objective was to evaluate the association between TF and overall survival (OS) and time to mCRPC (TTCRPC). Secondary analyses included evaluating outcomes in subgroups of interest and key genomic subtypes. RESULTS: Between 2018 and 2024, 85 patients were enrolled, of whom 72 (25% Black) had evaluable baseline ctDNA samples and are included herein. Baseline TF was positive in 46 patients (64%). Compared with patients with negative ctDNA TF, most patients with positive ctDNA TF had de novo (87% v 39%, P < .001) and high-volume disease (80% v 46%, P = .01). At a median follow-up of 20.8 months, median OS was not reached (NR) with those with negative ctDNA TF and 33 months with positive ctDNA TF (hazard ratio [HR], 3.33 [95% CI, 1.1 to 9.9]; P = .03). However, a negative TF at baseline was associated with an undetectable 7-month prostate-specific antigen, a validated OS surrogate. Median TTCRPC was NR versus 13 months (HR, 3.43 [95% CI, 1.5 to 7.9]; P = .004). ctDNA TF was also potentially prognostic in high-volume disease and those who received doublet therapy. CONCLUSION: In this diverse cohort, a positive ctDNA TF at baseline was associated with worse outcomes in mHSPC and may potentially complement current further risk stratification tools.

PURPOSE: Preclinical studies suggest the combination of the poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) inhibitor olaparib and the ataxia telangiectasia–mutated and Rad3-related (ATR) inhibitor ceralasertib has synergistic antitumor activity in homologous recombination proficient (HRP) and homologous recombination repair gene mutation (HRRm) patients. This study aims to determine the efficacy of olaparib plus ceralasertib in metastatic castration-resistant prostate cancer (mCRPC) with and without HRRm. PATIENTS AND METHODS: Thirty-five HRP and 12 HRRm PARP inhibitor–naïve patients with mCRPC progressing on ≥1 line of therapy or previous androgen receptor pathway inhibitor were enrolled. Patients received olaparib (300 mg twice daily) and ceralasertib (160 mg once daily, days 1-7) in 28-day cycles. HRRm was defined as biallelic inactivation of BRCA2 or BRCA1 , monoallelic inactivation of ATM , or germline inactivation of any of these genes. The primary end point was disease response rate (dRR; confirmed prostate-specific antigen decline ≥50% and/or complete/partial radiographic response by RECIST v1.1) in HRP patients. Secondary end points included dRR in HRRm patients, progression-free survival (PFS), and safety/toxicity. Two-stage designs were used. RESULTS: Four of 35 (11%; 95% CI, 3.2 to 26.7) HRP and four of 12 HRRm patients responded. Median PFS was 8.2 months (95% CI, 5.3 to not reached) for HRP patients. Thirty-six percent of patients had ≥grade 3 toxicity, most commonly from anemia. Limitations include small, single-arm, nonrandomized trial design. CONCLUSION: Combining ceralasertib with olaparib had limited activity in patients with HRP mCRPC. HRRm response rate was not greater than previous single-agent PARP inhibitor clinical trials.

Falchook et al: Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies - Supplemental Methods, Results, Tables, and Figures

Supplementary Table 2 from Characterization of Bone Metastases from Rapid Autopsies of Prostate Cancer Patients

Supplementary Table 1 from Characterization of Bone Metastases from Rapid Autopsies of Prostate Cancer Patients

Supplementary Figure and Table Legends from Characterization of Bone Metastases from Rapid Autopsies of Prostate Cancer Patients

Supplementary Table 2 from Characterization of Bone Metastases from Rapid Autopsies of Prostate Cancer Patients