Bryce, Alan H.

Abstract Background: The National Comprehensive Cancer Network (NCCN) recommends the use of tissue-based genetic tests, such as Decipher, Prolaris, and Confirm mdx for localized prostate cancer, to help patients and caregivers make more informed treatment decisions at the time of diagnosis. However, while much enthusiasm currently exists for the burgeoning field of genomic medicine, prostate cancer disparities continue to persist in underserved communities despite the existence of evidence-based treatment guidelines. Methods: A diverse 15-member Community Advisory Board (CAB) representing rural and urban communities in Duval County, Florida were recruited from May to June 2023, to build a community-academic partnership, for the development and implementation of a genetic literacy patient-caregiver educational intervention for localized prostate cancer. The 15-member CAB was divided into groups of 5 for focus group discussions. Qualitative and quantitative data from CAB members were integrated to gain better understanding of the facilitators and barriers for prostate cancer genetic literacy in underserved communities. Results: The thematic analysis reveals several key themes related to prostate cancer, screening, treatment, and genetics. These themes reflect the diverse perspectives and experiences of the CAB members regarding prostate cancer, ranging from personal anecdotes to broader societal issues. Participants expressed thoughts related to fear, lack of knowledge, cultural beliefs, and access to healthcare. The discussion on prostate cancer and tissue based genetic testing highlighted the complexities surrounding prostate cancer and the need for further education, awareness, and access to affordable healthcare for all individuals at risk. Conclusion: CAB members emphasized the importance of improving access to information, promoting education, and addressing cultural barriers to ensure that individuals are informed about available options for prostate cancer diagnosis and treatment. Citation Format: Ewan K. Cobran, Jocelyn Turner, Folakemi Odedina, Alan H. Bryce, Christopher Williams, Jose Rodriguez, Roger Williams, Woodrow Nathan, Thomas Bryant III, LoveVonia Nathan, Laureen Husband. Community advisory board members’ perspectives on genetic literacy and patient-caregiver communication of prognostic genomics for localized prostate cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A042.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions regarding the workup of patients with prostate cancer, risk stratification and management of localized disease, post-treatment monitoring, and treatment of recurrence and advanced disease. The Guidelines sections included in this article focus on the management of metastatic castration-sensitive disease, nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). Androgen deprivation therapy (ADT) with treatment intensification is strongly recommended for patients with metastatic castration-sensitive prostate cancer. For patients with nonmetastatic CRPC, ADT is continued with or without the addition of certain secondary hormone therapies depending on prostate-specific antigen doubling time. In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, the presence or absence of visceral disease, symptoms, and potential side effects.

Abstract Background The efficacy of pembrolizumab monotherapy in metastatic castration-resistant prostate cancer patients when stratified by MSI-H and/or TMB-H is poorly defined. Additionally, outcomes based on sequencing source (i.e., tissue or liquid biopsy) have not been well described. We sought to assess outcomes of pembrolizumab monotherapy in patients with mCRPC and compare efficacy based on MSI-H and/or TMB-H when identified by tissue or liquid biopsy. Methods A retrospective analysis was performed of mCRPC patients treated at Mayo Clinic with pembrolizumab monotherapy between 2018 and 2023. Objective response rates (ORR), median progression-free survival (mPFS), and overall survival (mOS), were determined by RECIST v1.1 criteria. Results Twenty-two patients with mCRPC received pembrolizumab monotherapy for at least 3 cycles for an MSI-H or TMB-H indication. All patients had next generation sequencing (NGS) performed via tissue (n = 11) or liquid (n = 10) biopsy source. The ORR was 50% (27.3% complete response and 22.7% had partial response). The mPFS for TMB 10-14.9 mut/Mb (n = 4), TMB 15-24.9 mut/Mb (n = 6), and TMB ≥ 25 mut/Mb (n = 10) was 2.1, not reached (NR), and NR, respectively (p = 0.0003). The mOS for these same groups was 5.1 months, 20.5 months, and not reached, respectively. Among patients with TMB-H without co-occurring MSI-H or CDK12 (n = 6), none experienced a response and only one patient had stable disease compared to patients with MSI-H (n = 12) for whom the ORR was 75%. Immunotherapy responsive alterations such as ATRX and PTCH1 mutations were frequently noticed among patients who had complete response (CR). Conclusions Our study highlights that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12. This study further demonstrates the utility of liquid biopsy NGS for identifying MSI-H and/or TMB-H disease.

PURPOSE A multi-cancer detection test using a targeted methylation assay and machine learning classifiers was validated and optimized for screening in prospective, case-controlled Circulating Cell-free Genome Atlas (ClinicalTrials.gov identifier: NCT02889978 ) substudy 3. Here, we report test performance in a subgroup of participants with symptoms suspicious for cancer to assess the test's ability to potentially facilitate efficient diagnostic evaluation in symptomatic individuals. METHODS We evaluated test performance (sensitivity, specificity, and accuracy of cancer signal origin [CSO] prediction accuracy) in participants with clinically presenting cancers (CPCs) and noncancer with underlying medical conditions and among two subgroups (65 years and older and GI cancers). Overall survival (OS) of participants who had a cancer signal detected/not detected was compared with SEER-based expected survival. RESULTS A total of 2,036 cancer and 1,472 noncancer participants were included. Specificity was high in all noncancer participants (99.5% [95% CI, 98.4 to 99.8]). In participants with CPCs, the overall sensitivity was 64.3% (95% CI, 62.2 to 66.4) and the overall accuracy of CSO prediction in true positives was 90.3%. For GI cancers, the overall sensitivity was 84.1% (95% CI, 80.6 to 87.1). In participants 65 years and older, test performance was similar to that of all participants. Individuals with cancers not detected had a significantly better OS than that expected from SEER ( P < .01). CONCLUSION This test detected a cancer signal with high specificity and CSO prediction accuracy and moderate sensitivity in symptomatic individuals, with especially high performance in participants with GI cancers. The survival analysis implied that the cancers not detected were less clinically aggressive than cancers detected by the test, providing prognostic insights to physicians. This multi-cancer detection test could facilitate efficient workup and stratify cancer risk in symptomatic individuals.

6559 Background: Recent findings that Black and Hispanic patients were significantly underrepresented in industry-sponsored prostate cancer trials warrant a detailed investigation across cancer types to assess the association between funding source and enrollment disparities. Methods: Phase II/III clinical trials in prostate, breast, colorectal, and lung cancers reporting age, gender, race/ethnicity, and reporting NIH or industry as the funding source were considered eligible for inclusion. For age, and gender analysis, all trials were considered eligible. For race/ethnicity analysis, trials recruiting from the United States (US) were considered eligible. Enrollment-incidence ratios (EIR) comparing trial proportion from age/gender or racial/ethnic subgroups against global cancer incidence in the corresponding group (from Global Burden of Disease) or US-population-based incidence in the corresponding racial/ethnic subgroup (from SEER 22), were computed. Trial-level EIRs were pooled using a random-effects model and subsequently stratified by funding source. A univariate meta-regression was conducted to assess the temporal changes in EIR by each funding category. Results: Of 42,390 studies initially identified, 2234 trials (1989-2021) met the eligibility criteria. Regarding age, 361 (16%) trials reported age categories by 65 years threshold. Of 698 trials recruiting from the US, 498 (71%) reported race, and 198 (28%) reported ethnicity. Regarding representation, older adults were under-represented (EIR: 0.66; 95% CI: 0.62-0.70) in the industry but not in NIH-sponsored clinical trials (0.79; 0.62-1.00). Regarding gender, no significant disparity was observed regarding the enrollment of men and women in colorectal and lung cancer clinical trials. In terms of race, there was a greater under-representation of Black patients in industry sponsored trials (0.29; 0.26-0.32) as compared to NIH-sponsored clinical trials (0.65; 0.57-0.74) [Pint <0.01]. Asian patients were significantly overrepresented in industry sponsored trials (3.17; 2.69-3.74) but not in NIH sponsored clinical trials (1.43; 0.85-2.41) [Pint <0.01]. Hispanic patients were significantly under-represented in both, industry (0.27; 0.22-0.34) and NIH-sponsored clinical trials (0.35; 0.22-0.55) [Pint 0.32]. Secondary analyses including trials recruiting exclusively from the US, and analyses by specific cancer types showed consistent results. Recruitment of older adults, men, and Black patients is decreasing over time. Conclusions: There is a consistent under-representation of older adults in industry-sponsored, and of Black and Hispanic patients in both industry-sponsored and NIH-sponsored clinical trials. The under-representation of Black patients is likely to be greater in industry-sponsored trials, which has worsened over the last three decades.

5077 Background: In the phase 3 PRESTO study, intensified androgen deprivation therapy (ADT) with apalutamide (Apa) with or without abiraterone acetate plus prednisone (AAP), administered for a finite treatment period of 52 weeks, prolonged prostate-specific antigen progression-free survival (PSA PFS) in pts with high-risk biochemically relapsed prostate cancer (BRPC). We evaluated the association between PSA nadir within 3 months of treatment initiation with subsequent PSA PFS in this study. Methods: PRESTO is a randomized phase 3, open-label trial in pts with BRPC following radical prostatectomy (RP) and PSA doubling time (PSADT) ≤ 9 months, without distant metastases on conventional imaging (NCT03009981). Pts were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + Apa, or ADT + Apa + AAP, stratified by PSADT (< 3 vs 3–9 months), with post-treatment follow-up. The association between PSA nadir within the first three months on treatment with subsequent PSA PFS was analyzed in a post hoc fashion. Results: 504 pts were randomized to ADT alone (N = 167), ADT + Apa (N = 168) or ADT + Apa + AAP (N = 169). 463 pts were evaluable for PSA nadir at 3 months. Across the three treatment arms, a PSA nadir of less than 0.1, between 0.1 – 0.2, and ≥ 0.2 ng/mL within the first three months of treatment was observed in 86.3%, 4.4%, and 9.3% of patients, respectively. A PSA nadir of < 0.2 ng/mL was reached within 3 months of treatment initiation in 79.8%, 96.9%, and 95.0% of pts randomized to the ADT, ADT + Apa, and ADT + Apa + AAP arms, respectively. The association between time to PSA nadir and subsequent PSA PFS was -0.30 (standard error = 0.03, Kendall’s tau modified for bivariate censoring), and median time to PSA nadir was 2.0 months (interquartile range 1.12 – 4.76 months). Failure to reach a PSA nadir < 0.2 ng/mL within the first three months of treatment was associated with a significantly shorter PSA PFS compared to pts with a PSA nadir ≤ 0.1 ng/mL (median PSA PFS of 13.9 vs. 22.8 months from 3 months post-treatment initiation; hazard ratio = 5.60, 95% CI: 3.58 – 8.75, p < 0.0001). There was also a significant difference in PSA PFS in those with a three-month PSA nadir between 0.1 – 0.2 vs ≤ 0.1 ng/mL (median PSA PFS 17.4 vs 22.8 months, HR = 2.63, 95:CI: 1.49 – 4.63, p = 0.0008). Conclusions: Using a landmark analysis at 3 months, a failure to reach PSA nadir less than 0.1 ng/mL within three months following initiation of ADT in BRPC is associated with shorter time to subsequent progression following treatment discontinuation. Follow-up is ongoing to integrate genomic profiling of primary prostate cancer tissues and whole blood RNA in pts with suboptimal PSA nadir to identify potential markers of relative androgen pathway inhibitor resistance. Clinical trial information: NCT03009981 .

5074 Background: Analysis of phase 3 studies of patients (pts) with mHSPC in the era of ADT, including in combination with docetaxel and/or androgen receptor axis targeted therapies have established PSA-7mo as a key prognostic marker. Our objective was to evaluate the association between PSA-3mo, PSA 7-mo and OS measured in the phase 3 S1216 trial in mHSPC comparing ADT + orteronel (treatment arm) vs ADT + bicalutamide (control arm) [NCT01809691]. Methods: Pts enrolled in the S1216 trial with available PSA-3mo & PSA-7mo were included in this analysis. PSA responses were defined as complete response (CR) if PSA ≤ 0.2 ng/mL, partial response (PR) for PSA >0.2 and ≤ 4ng/mL, and no response (NR) as PSA >4 ng/mL at month 3 or 7. Landmark OS was measured and Cox regression model applied adjusting for stratification (performance status, extent of disease, early vs late start of treatment, treatment arm). Results: 1251 pts were alive and evaluable for PSA-3mo and 1231 pts were evaluable at 7 mo, out of a total of 1279 pts. The median age was 67 (range: 43-92), 10% of patients were black, 96% had a Zubrod performance status of 0-1. Median PSA at baseline was 29 ng/ml (range: 2-6710). Of pts on treatment vs.control arm, PSA-3mo CR, PR, and NR occurred in 52% vs 35%; 31% vs 42%, and 17% vs 23%, respectively. Of pts on treatment vs control arm, PSA-7mo CR, PR, and NR occurred in 61% vs 46%, 20% vs 26%, and 19% vs 29%, respectively. CR or PR at either timepoint led to significantly better outcomes than those with NR. No interaction between treatment arm and PSA response was observed in terms of OS. Conclusions: PSA-3mo and PSA-7mo are strong prognostic markers for pts with mHSPC. More pts on ADT with orteronel achieved CR at 3 and 7 mo. In addition to its use in counseling patients in the clinic, PSA-3mo and PSA-7mo may be used as parameters for designing future trials in pts with mHSPC, utilizing the next generation of intensification or de-intensification treatment regimens. Clinical trial information: NCT01809691 . [Table: see text]

5071 Background: Best treatment of mCSPC involves doublet therapy (ADT + novel hormonal agent) or triplet therapy (ADT + novel hormone + docetaxel); however, opportunity remains for further improvement. Studies show that homologous recombination repair (HRR) gene mutations are enriched in metastatic prostate cancer, and may portend resistance to docetaxel. CASCARA tested quadruplet therapy (ADT + cabazitaxel/carboplatin + abiraterone) in high-volume mCSPC, aiming to enhance PSA responses and decrease progression at 1 year. Methods: This phase 2 study enrolled 61 mCSPC patients with high-volume disease who received ADT plus cabazitaxel (20 mg/m2 q21d x 6) and carboplatin (AUC=4 q21d x 6) followed by abiraterone (1000 mg, plus prednisone 5 mg). Primary endpoint was freedom from PSA/radiographic progression at 1 year. Other endpoints included PSA50 response, freedom from PSA progression, and safety. Archival biopsies were retrospectively evaluated for HRR ( BRCA1/2, ATM, CHEK2, CDK12, BRIP1, RAD51B) mutations at a CLIA-certified lab. A sample size of 61 was determined using a Simon two-stage design (stage 1: 32 men, stage 2: 29 men) with a null hypothesis of a 1-year PSA/radiographic progression-free rate of 0.80 against a one-sided alternative of 0.92. Results: From 11/2019 to 06/2022, 61 men enrolled at 7 sites. Median age was 64 (range, 45–76) years; 21% were African American. Median baseline PSA was 8.9 (range, 0.1–1021) ng/mL. 44% of men had ECOG=1. 91% had Gleason sum 8–10. Prevalence of DNA alterations (50 evaluable pts) was 18% for HRR mutations, 38% for TP53 muts, 22% for ERG fusions, 10% for SPOP muts. Freedom from PSA/radiographic progression at 1 year was 77% (95% CI, 63–87%), and freedom from PSA progression at 1 year was 81% (95% CI, 67–90%). The PSA50 rate response was 97%. PSA ≤0.2 ng/mL at month-7, a surrogate for survival in other mCSPC studies, was 61%; PSA ≤4 ng/mL at month-7 was 82%. Outcomes according to mutation status are shown. AEs included 7% grade (Gr)-3/4 myelosuppression, 8% Gr-3/4 infections, 10% Gr-3 GI disorders, and 3% Gr-3 fatigue. There were 4 treatment-related discontinuations. Conclusions: Quadruplet therapy with ADT + cabazitaxel/carboplatin + abiraterone was well tolerated. At 1 year, 77% of pts were progression-free. PSA ≤0.2 ng/mL at month-7 was 61%, exceeding the historical month-7 PSA ≤0.2 ng/mL rate of 45% in CHAARTED–docetaxel arm. Further exploration of this quadruplet strategy in randomized phase III studies is warranted. Clinical trial information: NCT03934840 . [Table: see text]

2561 Background: Some cancers, including breast, ovarian, pancreatic, and prostate cancers, are traditionally considered “cold” tumors, less likely to trigger an immune response and/or respond to immune checkpoint inhibitors (ICIs). However, some patients with these cancer types may benefit from ICIs. Here we investigate if a high blood tumor mutational burden (bTMB-H) may predict benefit to ICIs in such tumor types. Methods: We retrospectively queried the Guardant Health database for patients with advanced breast (n = 8531), ovarian (n = 1106), upper GI/pancreatic (n = 5110), and prostate (n = 7153) cancer who had ctDNA next-generation sequencing (Guardant360, Redwood City, CA) as part of routine clinical care from 2020-2022. Mutation profiles were evaluated for patients with bTMB-H (based on previously reported 80th percentiles for each tumor type, breast ≥15.31mut/Mb, ovarian ≥14.98mut/Mb, pancreatic ≥11.36mut/Mb, prostate ≥13.4mut/Mb) vs those with bTMB below this threshold (bTMB-L). A subset of cases were analyzed in a multi-institutional clinical cohort with a bTMB of ≥10mut/Mb (n = 35). Results: bTMB-H was observed in 9.5% of patients with breast cancer, 5.1% ovarian, 2.0% pancreatic, and 4.4% prostate. Genes more often mutated in patients with pTMB-H vs pTMB-L in each cancer type included TP53 and PIK3CA in breast cancer; TP53 and CHEK2 in ovarian; ATM and CHEK2 in pancreatic; TP53 and AR in prostate (all p values < 0.01). Patients in the clinical cohort (n = 35) had a median age of 74 (range: 40-85) 29/35 White / 4/35 Black, 27 prostate, 1 breast, 3 upper GI. Patients underwent first ctDNA analysis after a median of 3 (range 0-11) lines of therapy. The median bTMB detected was 16.59 mut/Mb (range: 10.02-152.85); six patients (6/35) were MSI-H. Twenty-three patients received ICI after a median of 6 (range: 0-8) lines of therapy, either alone (9, 39%) or in combination with hormonal therapy (5, 22%), chemotherapy (3, 13%) or targeted therapy (6, 26%). The median time to progression on ICI was 5.0 (95% CI, 3.6-6.4) months and median duration of response was 19.8 months (12.1-20.2). The ORR for evaluable patients was 13% and 74% of patients had progressed on therapy at time of data cut-off. Conclusions: "Cold” tumors represent a meaningful portion of patients with advanced cancer in which ICIs are not typically leveraged, and ctDNA was a feasible tool for identifying patients with bTMB-H who achieved durable responses from ICI-based therapy. The efficacy in this clinical cohort of traditionally “cold” tumors approaches other pan-cancer cohorts that include more traditionally immunoresponsive tumor types; further research is warranted to explore predictive value of bTMB, including potential tumor-specific thresholds, for optimizing patient selection for ICIs.

5088 Background: Previous evidence suggests that there may be no additional benefit of triplet therapy in low volume disease based on limited data. Therefore, we investigated the efficacy of triplet therapy as compared to docetaxel (D) and androgen pathway inhibitor (API) doublets by volume of disease using the most up to date results from the ARASENS trial. Methods: Phase III randomized controlled trials (RCTs) assessing treatment intensification with API, and/or D in patients with mCSPC were included. Precomputed hazard ratios (HR) with 95% confidence intervals (CI) for OS were pooled using an inverse-variance approach. A DerSimonian-Laird random-effects meta-analysis was conducted to assess the efficacy of triplet therapy compared to D doublet therapy. P-value of interaction was computed to assess difference between high (HV) and low volume (LV) disease subgroups (Pint <0.1 - statistical significance). Additionally mixed treatment comparisons were computed using network meta-analysis (NMA) to assess the comparative effectiveness of triplet therapy compared to API doublets by volume of disease. Results: Pairwise meta-analysis included a total of 3 RCTs (ARASENS, PEACE-1, ENZAMET) with 2518 patients (HV: 1820; LV: 698) as shown. In patients with HV disease, 385 (43%) and 484 (53%) deaths were observed with triplet therapy, and D doublet, respectively. Triplet therapy significantly improved OS as compared to D doublet in HV (HR: 0.73; 95% CI: 0.64-0.84). In patients with LV disease, 73 (20%) and 94 (28%) deaths were observed with triplet therapy, and D doublet, respectively. Triplet therapy significantly improved OS as compared to D doublet in LV (HR: 0.71; 95% CI: 0.52-0.97). There was no statistically significant interaction by volume of disease for triplet therapy vs. D doublet (Pint: 0.86). NMA including 10 clinical trials and over 11500 patients updated as of 13th Feb 2023 showed that in HV mCSPC, triplet therapy was ranked as potentially the most efficacious treatment option and may improve OS compared to API doublet therapy (HR: 0.83; 95% CI: 0.66-1.03). In LV mCSPC, API doublet therapy was ranked as potentially the most efficacious treatment followed by triplet therapy. There was no significant difference between triplet therapy and API doublet therapy (HR: 1.12; 95% CI: 0.74-1.12). Conclusions: These results underscore that triplet therapy may be preferred in mCSPC patients with HV disease whereas API doublet therapy may be preferred in LV disease. [Table: see text]