Background Methyl Methanesulfonate-Sensitivity Protein 22-Like (MMS22L) plays a key role in homology-directed DNA repair, and experimental models have shown that its loss confers sensitivity to Poly (ADP-ribose) polymerase inhibitors (PARPi). A rare germline loss-of-function founder mutation in MMS22L, F722fs (c.2164_2168del), was recently identified as a prostate cancer risk factor among individuals of Ashkenazi Jewish ancestry. The impact of this mutation on the disease course following prostate cancer diagnosis remains unclear. Here, we report the longitudinal outcomes of seven MMS22L F722fs carriers diagnosed with different stages of prostate cancer identified at the Brady Urological Institute at Johns Hopkins University.Methods We investigated the longitudinal outcomes of seven MMS22L F722fs carriers diagnosed with different stages of prostate cancer identified at the Brady Urological Institute.Results With a follow-up time ranging from 5 to 27 years, five of the seven patients who were initially treated with radical prostatectomy remain alive and disease-free, including two patients who had adjuvant and salvage therapies, and one patient who was cured after developing metastatic disease post-surgery. For the remaining two patients with metastatic prostate cancer at diagnosis, one patient responded to ADT for 11 years, and the other died of unknown causes 5 years after diagnosis. None of these patients received PARPi.Conclusions Although limited by its retrospective design and small cohort size, this series suggests the potential for exceptional outcomes in F722fs mutation carriers diagnosed with prostate cancer, despite the aggressive disease features and lack of treatment with PARPi. The findings also suggest that prostate cancer patients with this mutation may respond well to standard systemic treatments.

PURPOSE:Next-generation sequencing (NGS) is recommended for patients with metastatic prostate cancer (PC). Nationwide, testing rates are low. Whether PC disease characteristics and courses differ between those with and without NGS testing is unknown. We identified predictors of testing, explored likely reasons for lack of testing, and compared survival between those with and without testing. METHODS:We retrospectively reviewed patients with metastatic PC initially seen between 2020 and 2022 at Johns Hopkins. Clinical data and reasons for nontesting were abstracted from the electronic medical record. We conducted a logistic regression assessing predictors of NGS testing, adjusting for age, Gleason grade, marital status, and metastatic diagnosis year. We used Cox regression to compare overall survival, defined from the time patients had both a metastatic diagnosis and a visit at our institution until death/last follow-up, between those tested and not tested. We adjusted for age, Gleason grade, initial metastasis (M) stage, comorbidities, and time from metastatic diagnosis to first visit. RESULTS:Of the 435 patients, 257 (59%) had NGS testing. Older patients were less likely to have testing (adjusted odds ratio [aOR], 0.96 [95% CI, 0.94 to 0.98]). Unmarried patients were less likely to have testing (aOR, 0.62 [95% CI, 0.38 to 1.01]). Patients with Gleason Grade Group 5 were more likely to undergo testing than patients with Groups 1-3 (aOR, 1.86 [95% CI, 1.14 to 3.04]). Among those without testing, 139 (78%) had at least one potential reason for lack of testing in the medical record. The most common reason for nontesting was patient/disease factors (37%). CONCLUSION:Older and unmarried men with metastatic PC were less likely to obtain NGS testing, whereas those with high Gleason grade were more likely. Interventions are needed to improve testing rates.

171 Background: Since 2020, guidelines recommend somatic next-generation sequencing (NGS) in patients with metastatic (M1) prostate cancer. Nationwide, genetic testing rates are low with known disparities in access. Whether prostate cancer disease characteristics and courses differ between those with and without testing are unknown. In this study, we determined the NGS testing rate in M1 prostate cancer at a single academic center and assessed social and clinical features by NGS testing status. In those without NGS testing, we reported the most likely reasons for lack of testing. Finally, we compared survival among those with and without testing. Methods: Retrospective chart review of M1 patients with prostate cancer seen as a new visit between 2020-2022 with at least one follow-up. Sociodemographics, comorbidities, prostate cancer clinical features, and vital status were obtained from the electronic medical record (EMR). Reasons for lack of NGS testing were assessed through chart review. A multivariable (MV) logistic regression assessed predictors of NGS testing (covariates: age, Gleason grade group, marital status, M1 diagnosis year). Survival analysis was conducted from the date of first visit with M1 disease to the date of death/last follow-up (covariates: age, Gleason grade group, M stage at initial diagnosis, NCI comorbidity index, days from M1 diagnosis date to first visit date). Results: 258 (59%) of 435 patients had NGS ordered. Patients who were older and not married were less likely to have NGS testing, which remained in MV analysis [age: odds ratio (95% confidence interval) = 0.96 (0.94-0.98); unmarried vs. married/partnered 0.62 (0.38-1.00)]. (Table 1). The most common likely underlying reason for no NGS testing ordered were perceived patient/disease factors (28%), no tissue available (16%), and shared care with another oncologist (18%). There was no clear reason in 22% of patients. Those with testing ordered had worse survival than those without [adjusted hazard ratio (95% confidence interval) = 1.43 (1.03-1.99)]. Conclusions: NGS testing remains underutilized in men with metastatic prostate cancer, particularly among older and unmarried individuals. Those without NGS testing had longer survival, contrary to what is seen in other diseases. Future research is needed to develop and assess interventions to improve NGS testing rates. Multivariable analysis of predictors of ordering next-generation sequencing (NGS) in metastatic (M1) prostate cancer (N=419). Variables Odds Ratio 95% confidence interval p-value Age at M1 diagnosis 0.96 0.94-0.98 <0.01 Gleason score at initial diagnosis 0.07 Group 1-3 1 ref Group 4 1.59 0.84-3.01 Group 5 1.78 1.09-2.91 Gleason score never performed 2.20 1.05-4.59 Marital Status 0.05 Married/partnered 1 ref Not married/partnered 0.62 0.38-1.00 Year of M1 diagnosis 0.07 2019 or earlier 1 ref 2020-2022 0.62 0.36-1.05

Table S2 shows Association of HDIVC Treatment with PSA Response Adjusting for Prior Docetaxel Exposure

Table S9 shows FACT-P Total Scores: Baseline, Cycles 4, 6, and 8

Table S3 shows Adverse Events Included in the Co-Primary Endpoint: All Occurrences

Table S13 shows Comparison of F2-Isoprostanes at Baseline between Treatment and Control Arms

Table S15 shows Comparison of F2-Isoprostanes Control and Intervention Changes (post - pre) Immediately after Cycle 6

Table S11 shows FACT-P Change (on Study Minus Baseline) Scores

Trial Protocol shows the details of the study

167 Background: Addition of docetaxel (D) to ADT has demonstrated improved overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC). In this post hoc OS analysis of the CHAARTED trial (NCT00309985), we report 10-year OS and cause of death (COD) by baseline clinical factors, PSA nadir at 6 months in mHSPC patients treated with ADT +/- D. Methods: An updated survival sweep was conducted in July 2024. Patients were prospectively identified by the state of metastatic disease (metachronous/prior local therapy vs. synchronous/no prior local therapy) and low volume (LV) vs. high volume (HV; visceral and/or ≥4 bone metastases with one lesion beyond the vertebral bodies or pelvis) disease. OS defined as time from 6 mos post randomization to death was calculated using the Kaplan-Meier method and compared between PSA nadir (<0.2 vs. ≥0.2) groups using the log rank test. Results: A total of 334 patients achieved PSA nadir of <0.2 at any timepoint with a median time to PSA nadir of 4.8 months. At 6 months, PSA nadir <0.2 was seen in 204 (26.8%) patients. Patients with PSA nadir <0.2 had significantly better median OS in both ADT + D (100.3 vs. 45.4 mos; P<0.0001; Table) and ADT (116.8 vs. 31.8 mos; P<0.0001) arms. This prognostic impact was significant across prespecified prognostic subgroups. Of the 101 patients who achieved a PSA of < 0.2 at 6 mos, the COD was ‘prostate cancer’ in 58.4% (n=59), ‘other’ in 14.9% with 26.7% being unknown. Of the unknown/missing (n=27), 10 patients died without a record of having progression. In the PSA nadir ≥0.2 group, the reported COD was ‘prostate cancer’ in 78.2% with 6.5% being ‘other' and 15.4% being unknown/missing. Conclusions: Compared with patients with PSA ≥0.2, PSA nadir of <0.2 at 6 months was associated with less prostate cancer deaths and more than doubling of the median OS with approximately 50% of patients alive at 8 years across treatment and all prespecified prognostic groups except de novo high volume treated with ADT alone. Clinical trial information: NCT00309985 . Outcomes by PSA nadir at 6 months in overall population and pre-specified subgroups. ADT+ D ADT # Death/N Median OS (95% CI; months) p-value # Death/N Median OS (95% CI; months) p-value Overall 6-month PSA <0.2 66/127 100.3 (70.4, NA) <0.0001 35/77 116.8 (87.3, 141.5) <0.0001 6-month PSA ≥0.2 203/256 45.4 (39.2, 51.6) 246/301 31.8 (26.3, 38.1) Denovo HV6-month PSA <0.2 20/39 93.5 (45.9, NA) 0.0001 7/11 74.7 (37.4, NA) 0.007 6-month PSA ≥0.2 135/166 39.5 (32.8, 48.5) 162/183 26.4 (23.5, 32.0) Metach HV6-month PSA <0.2 12/23 105.7 (61.4, NA) 0.0009 8/15 87.3 (47.4, NA) 0.0002 6-month PSA ≥0.2 22/25 43.2 (23.5, 66.0) 25/26 22.1 (13.9, 39.4) Metach LV6-month PSA <0.2 18/34 101.5 (58.6, NA) 0.04 11/38 123.4 (123.4,141.5) 0.003 6-month PSA ≥0.2 17/21 63.6 (49.7, 99.3) 14/26 48.9 (25.6, NA)

Table S6 shows AEs with Attribution Possible, Probable or Definite to Docetaxel listed by types and grades

150 Background: Current guidelines recommend NGS testing for all patients with metastatic prostate cancer, and yet this remains underutilized. In addition, there is uncertainty on when patients should undergo NGS testing. This study aims to determine the timing and characteristics of patients undergoing NGS testing at a single academic institution. Methods: Patients with metastatic prostate cancer diagnosed between January 2020 and January 2024 who underwent NGS testing were identified. We recorded patient and disease characteristics at time of diagnosis and time of metastatic disease. We used a time-varying cox hazard model to investigate the associations of disease factors (M stage, Gleason grade, castration resistant prostate cancer), social characteristics (race, smoking history, area deprivation index (ADI)) of the participants and the timing of NGS testing. Additionally, we analyzed median overall survival from date of metastatic disease comparing those with early (pre castration resistant prostate cancer (CRPC)) NGS testing versus late NGS (after CRPC) testing. Results: 205 patients were included. Median age at testing was 70 years [range 50-94]. 68% of participants identified as White, 26% as Black and 84% were non-Hispanic (15% unknown). At diagnosis, 56% had metastatic disease, 57% had Gleason grade group 5, 35% had T3/4 disease. 74% had ECOG 0-1 at time of metastasis. The most common source of tissue for testing was the prostate (67%) followed by blood (13%). 44% of patients developed CRPC by the last follow up date. Median time from metastatic disease to NGS testing was 2.92 months in Black patients, 2.25 in White and 1.54 in those of other races. Of the deceased (n = 66), 6.06% had testing within 3 months of death and 24.24% within 6 months of death. In multivariable time-varying analyses, higher Gleason group (HR range: 5.41-7.27, p < 0.03) and metastasis at diagnosis (12.42 [6.22, 24.78], p < 0.001) were significantly associated with increased hazard of NGS testing and thus implies a higher likelihood of earlier testing. Age at diagnosis (1.05 [1.02,1.08], p < 0.001) was also significant with each additional year increasing the hazard of NGS testing by 5%. For overall survival, the median time for early testing patients was 58.7 months versus 27.2 months for late testing patients ( p < 0.001). The relationship between NGS testing and ADI is undergoing analysis and will be shared at the meeting. Conclusions: Older age, Gleason grade group, and metastasis at diagnosis were associated with earlier NGS testing among men with metastatic prostate cancer. Nearly a quarter of men who died had testing within the last 6 months of life. As targeted therapies move earlier into treatment of metastatic prostate cancer, facilitating additional tissue acquisition and understanding of use and limitations of liquid biopsies are needed to facilitate earlier NGS testing in metastatic prostate cancer.

Table S4 shows Adverse Events Included in the Co-primary Endpoint: Worst Grade by Patient

Background Clonal hematopoiesis (CH) may be inferred from clinical next-generation sequencing (NGS) of tumor tissue. The clinical significance of inferred CH when detected as part of routine tumor sequencing is not well established and it is unknown whether or not CH is associated with other somatic mutations in tumors of men with prostate cancer. Methods We performed a retrospective review of clinical-grade NGS results from primary prostate tissue at a single institution. NGS reports were reviewed for the presence of pathogenic mutations in a panel of 27 genes commonly known to be mutated in CH. Overall survival from time of diagnosis and association with somatic alterations were interrogated. Results A total of 396 patients were included, with a median follow-up of 7.8 years (range 0.2-21.4 years). Approximately 12% of patients had inferred CH detected (n = 46) with ASXL1, TET2, and DNMT3A being the most commonly affected genes. In univariate analysis, those with inferred CH had an 81% increased risk of death compared to those without inferred CH (hazard ratio 1.8, 95% CI 1.1, 3.1, P = .03). This was attenuated after controlling for age at diagnosis and race (HR 1.1, 95% CI 0.6, 2.0, P = .77). Those with inferred CH were more likely to have pathogenic somatic mutations in PIK3CA (15% vs 4%), CTNNB1 (13% vs 2%) and BRCA1 (4% vs 0.3%). Conclusion Inferred CH is commonly detected on tumor-tissue NGS testing but does not clearly have a negative prognostic impact after adjusting for age. It may also be associated with the identification of other somatic driver mutations.

Table S8 shows Prevalence of adverse events

Table S7 shows Serious Adverse Events (N = 11 patients), by Type and Grade. Attributions Assigned Docetaxel versus HDIVC or Placebo

Figure S2 shows Plasma ascorbic acid concentrations

Table S5 shows AEs with Attribution Possible, Probable or Definite to Treatment (HDVIC or Placebo) listed by types and grades

Table S16 shows Comparison of F2-Isoprostanes Control and Intervention Changes 60 minutes after Cycle 4