Sartor, Oliver

Abstract Purpose: This multicenter, single-arm, phase II trial evaluated the safety and efficacy of cabazitaxel and carboplatin followed by abiraterone, plus androgen deprivation therapy (ADT), in patients with high-volume metastatic castration-sensitive prostate cancer (mCSPC). Patients and Methods: Eligible patients had high-volume mCSPC and ≤3 months of prior ADT. Patients received six 21-day cycles of cabazitaxel (20 mg/m2) and carboplatin (AUC 4) with continuous ADT, followed by maintenance abiraterone (1,000 mg daily) and prednisone (5 mg daily). The primary endpoint was the proportion of patients free of prostate-specific antigen (PSA) or radiographic progression at 12 months. Secondary endpoints included complete PSA response (≤0.2 ng/mL), objective response, progression-free survival (PFS), and safety. Overall survival (OS) was also reported. Results: Sixty-one participants were enrolled at eight sites. The median age was 64 years, median baseline PSA was 6.6 ng/mL (0.07–745.7 ng/mL), 73.3% had Gleason grade group 5, 69.5% had 10 or more metastases, and 19.6% had a homologous recombination repair (HRR) mutation. PSA PFS at 12 months was 84.6% [95% confidence interval (CI), 72.5%–91.7%], and OS at 12 months was 94.8% (84.7%–98.3%). Complete PSA response was 66.7%, and complete objective response was 30.7%. Contrary to our hypothesis, relative to HRR wild-type patients, HRR-mutated patients (19.6%) had numerically fewer complete PSA responses (33.3% vs. 70.3%) and inferior PFS (HR, 2.43; 95% CI, 0.93–6.39). Common side effects of this quadruplet regimen included fatigue, nausea, and diarrhea. Conclusions: Cabazitaxel and carboplatin followed by abiraterone, together with ADT, were feasible, safe, and efficacious in patients with high-volume mCSPC and warrant further study in larger randomized trials.

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

BACKGROUND Predictive biomarkers to guide chemotherapy decisions for metastatic castration–resistant prostate cancer (mCRPC) are lacking. Preclinical studies indicate that circulating tumor cell (CTC) studies of chromosomal instability (CTC-CIN) can predict taxane resistance. METHODS The CARD trial randomized individuals with mCRPC progressing within a year of treatment with an androgen receptor pathway inhibitor (ARPI; enzalutamide or abiraterone acetate plus prednisolone/prednisone) to cabazitaxel or the alternative ARPI. As a preplanned biomarker analysis, CTCs were isolated from blood samples obtained at baseline, cycle 2, and the end of treatment. Associations between baseline CTC and CTC-CIN counts with imaging-based progression-free survival (ibPFS), overall survival (OS), time to prostate-specific antigen (PSA) progression, RECIST 1.1 objective response rate (ORR), and PSA 50 response rate were assessed. RESULTS High baseline CTC-CIN counts significantly associated with worse OS after adjustment for confounding variables (median OS, 15.3 vs. 8.9 months; univariate HR, 2.16; 95% CI, 1.52–3.06; P < 0.001; multivariate HR, 1.56; 95% CI, 1.01–2.43; P = 0.047). Detectable CTC-CIN counts at baseline may predict a lack of ibPFS and OS benefit when comparing cabazitaxel with ARPI. CONCLUSION This preplanned analysis of biomarker data from the CARD trial confirms that CTC-CIN counts are a clinically useful prognostic and predictive biomarker of taxane resistance in mCRPC. Detectable CTC-CIN at baseline defines a patient subpopulation with unmet clinical needs in which alternative therapeutics should be tested. TRIAL REGISTRATION ClinicalTrials.gov number NCT02485691. FUNDING Funded by Sanofi and Epic Sciences.

Abstract Background: Chromosomal instability (CIN) is frequent in patients with metastatic castration-resistant prostate cancer (mCRPC) and determines taxane resistance. A circulating tumor cell (CTC) assay which morphologically identifies CTCs with CIN (CTC-CIN) from a single tube of whole blood could predict clinical outcomes in this population. We tested this hypothesis as a pre-planned, secondary outcome of the CARD trial, where patients with mCRPC progressing within a year of treatment with an androgen receptor pathway inhibitor (ARPI; enzalutamide or abiraterone acetate + prednisolone/prednisone) were randomized to treatment with cabazitaxel or the alternative ARPI. Methods: CTCs were isolated from blood samples obtained at baseline; cycle two, and end of treatment. The associations of baseline CTC and counts with imaging-based progression free survival (ibPFS), overall survival (OS), time to prostate-specific antigen (PSA) progression, RECIST 1.1 objective response rate (ORR), and PSA50 response rate (PRR) were assessed. Results: Of 255 patients randomized, CTC counts were acquired from 237 patients at screening, 213 patients at C2D1, and 166 patients at EOT. High baseline CTC counts were significantly associated with worse OS (median OS, 14.9 vs 9.8 months; univariate HR, 1.81; 95% CI, 1.30 - 2.51; p &lt; 0.001). High baseline CTC-CIN counts were significantly associated with worse OS after adjustment for confounding variables (median OS, 15.3 vs 8.9 months; univariate HR, 2.16; 95% CI, 1.52 - 3.06; p &lt; 0.001; multivariate HR, 1.56; 95% CI, 1.01 - 2.43; p = 0.047). Low CTC-CIN at baseline predicted ibPFS, ORR, and PRR benefit with cabazitaxel; conversely, high at baseline predicted no different ibPFS or OS outcomes with cabazitaxel or a second ARPI. Conclusions: This preplanned biomarker analysis of CARD confirmed that CTC-CIN counts are prognostic for OS and may be predictive of cabazitaxel benefit. (Funded by Sanofi and Epic Sciences; CARD ClinicalTrials.gov number, NCT02485691.) Citation Format: Ossian Longoria, Jan Rekowski, Santosh Gupta, Nick Beije, Klaus Pantel, Eleni Efstathiou, Cora Sternberg, Daniel Castellano, Karim Fizazi, Bertrand Tombal, Adam Sharp, Oliver Sartor, Sandrine Mace, Christine Geffriaud-Ricouard, Richard Wenstrup, Ronald de Wit, Johann de Bono. Morphological evaluation of chromosomal instability in circulating tumor cells and prediction of taxane resistance in metastatic prostate cancer: a prespecified sub-analysis of the CARD trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1145

PURPOSE Long-term androgen deprivation therapy (ADT) improves survival in men with high-risk localized prostate cancer (PCa) receiving radiotherapy (RT). Predictive biomarkers are needed to guide ADT duration. METHODS A multimodal artificial intelligence (MMAI)–derived predictive biomarker was trained for long-term (LT) versus short-term (ST) ADT using pretreatment digital prostate biopsy images and clinical data (age, prostate-specific antigen, Gleason, and T stage) from six NRG Oncology phase III randomized radiotherapy trials. The novel MMAI-derived biomarker was developed to predict the differential benefit of LT-ADT on the primary end point, distant metastasis (DM). MMAI predictive utility was validated on a seventh randomized trial, RTOG 9202 (N = 1,192), which randomly assigned men to RT + ST-ADT (4 months) versus RT + LT-ADT (28 months). Fine-Gray and cumulative incidence analyses for DM, and secondarily, death with DM, were performed. Deaths without DM were treated as competing risks. RESULTS In the validation cohort (median follow-up, 17.2 years), LT-ADT significantly improved DM from 26% to 17% (subdistribution hazard ratio [sHR], 0.64 [95% CI, 0.50 to 0.82], P < .001). A significant biomarker-treatment predictive interaction was observed ( P = .04) for DM, whereby MMAI biomarker–positive men (n = 785, 66%) had reduced DM with LT-ADT versus ST-ADT (sHR, 0.55 [95% CI, 0.41 to 0.73], P < .001), whereas no treatment benefit was observed for MMAI biomarker–negative men (n = 407; sHR, 1.06 [95% CI, 0.61 to 1.84], P = .84). The estimated 15-year DM risk difference between RT + LT-ADT and RT + ST-ADT was 14% in MMAI biomarker–positive men and 0% in MMAI biomarker–negative men. The MMAI biomarker was also prognostic for DM, irrespective of treatment (sHR, 2.35 [95% CI, 1.72 to 3.19], P < .001). CONCLUSION To our knowledge, the MMAI model is the first validated predictive biomarker to guide ADT duration with RT in localized/locally advanced PCa. Approximately one third of men with high-risk PCa could safely be spared the additional 24 months of ADT and the associated morbidity.

Abstract Purpose: Two randomized clinical trials (STOMP and ORIOLE) demonstrated that stereotactic ablative radiotherapy (SABR) can prolong androgen-deprivation therapy–free survival or progression-free survival (PFS) in patients with metachronous oligometastatic castration-sensitive prostate cancer (omCSPC). Although most patients with omCSPC have a more modest delay in progression, a small subset achieves a durable response following SABR. We investigated the prognostic and predictive value of circulating prostate-specific membrane antigen-positive (PSMA+) extracellular vesicles (EV) and PSA in a biomarker correlative study using blood samples from three independent patient cohorts. Experimental Design: Plasma samples from 46 patients with omCSPC on the ORIOLE trial and 127 patients with omCSPC on the STOMP trial protocol treated with SABR were included in the study. Pre-SABR PSMA+EV levels (EV/mL) were measured by nanoscale flow cytometry. Kaplan–Meier curves and logistic regression models were used to determine the association of PSMA+EV and PSA levels with clinical outcomes. Results: In the pooled cohorts, the median biochemical PFS were 26.1 and 15.0 months (P = 0.005), and the median radiographic PFS were 36.0 and 25.0 months (P = 0.003) for PSMA+EV-low and -high groups, respectively. The combination of pre-SABR low levels of both PSMA+EV and PSA was associated with a lower risk of radiographic progression (HR, 0.34, 95% confidence interval, 0.18–0.58; P = 0.0002). In the ORIOLE cohort, which included both an SABR arm and an observation arm, low PSMA+EV was predictive of benefit from SABR (P = 0.012). Conclusions: PSMA+EV is a novel prognostic and predictive biomarker of radiographically occult tumor burden in omCSPC. PSMA+EV may inform clinical decisions about identifying patients who will achieve a durable benefit from consolidative SABR alone.

Abstract Purpose: Around 10% to 15% of prostate cancers harbor recurrent aberrations in the Forkhead Box A1 gene, FOXA1, whereby the alteration type and the effect on the forkhead (FKH) domain affect protein function. We developed a FOXA1 classification system to inform clinical management. Experimental Design: A total of 5,014 prostate cancer samples were examined using whole-exome and -transcriptome sequencing from the Caris Life Sciences database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain. These were in the first part of the FKH domain [class 1A: amino acids (AA) 168–246], within the Wing2 region of FKH (class 1B: AA 247–269), or outside FKH (class 1C: AA 1–167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1–269 and class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims. Results: FOXA1 alterations did not influence survival when considered in aggregate but had distinct prognostic effects when stratified by class. In primary prostate samples, class 1A alterations were associated with overall improved survival (HR, 0.57; P = 0.03); a similar trend was seen in metastatic biopsies with class 1B (HR, 0.84; P = 0.09). Conversely, in primary specimens, class 1C exhibited worse survival upon second-generation androgen receptor signaling inhibitor treatment (HR, 1.93; P &lt; 0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR, 2.05; P &lt; 0.001) and worse outcomes to first-line androgen-deprivation therapies (HR, 2.5; P &lt; 0.001). Class 3A alterations indicated improved survival (HR, 0.70; P = 0.01), whereas class 3B alterations portended poor outcomes (HR, 1.50; P &lt; 0.001). Amplifications (class 4) indicated poor outcomes in metastatic samples (HR, 1.48; P = 0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European Americans, African Americans had increased class 1C alterations, whereas Asian/Pacific Islander patients had increased class 1B alterations. Conclusions: FOXA1 alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision-making for patients with prostate cancer and uncovers important racial differences.

Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer have expanded over the past decade, particularly related to precision therapies and management. GGT has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic prostate cancer, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Here, we present data supporting the notion that clinicians should offer all patients with prostate cancer the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.