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Abstract Background Radium (Ra)‐223 is an established treatment option for patients with metastatic castrate‐resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease. Studies have indicated genetic aberrations that regulate DNA damage response (DDR) in prostate cancer can increase susceptibility to treatments such as poly ADP‐ribose polymerase inhibitors and platinum‐based therapies. This study aims to evaluate mCRPC response to Ra‐223 stratified by tumor genomics. Methods This is a retrospective study of mCRPC patients who received Ra‐223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota) and Tulane Cancer Center. Patient demographics, genetic aberrations, treatment responses in terms of alkaline phosphatase (ALP) and prostate‐specific antigen (PSA), and survival were assessed. Primary end points were ALP and PSA response. Secondary end points were progression‐free survival (PFS) and overall survival (OS) from time of first radium treatment. Results One hundred and twenty‐seven mCRPC patients treated with Ra‐223 had germline and/or somatic genetic sequencing. The median age at time of diagnosis and Ra‐223 treatment was 61.0 and 68.6 years, respectively. Seventy‐nine (62.2%) had Gleason score ≥ 8 at time of diagnosis. 50.4% received prior docetaxel, and 12.6% received prior cabazitaxel. Notable alterations include TP53 (51.7%), BRCA 1/2 (15.0%), PTEN (13.4%), ATM (11.7%), TMPRSS2‐ERG (8.2%), RB deletion (3.4%), and CDK12 (1.9%). There was no significant difference in ALP or PSA response among the different genetic aberrations. Patients with a TMPRSS2‐ERG mutation exhibited a trend toward lower OS 15.4 months (95% confidence interval [CI] 10.0−NR) versus 26.8 months (95% CI 20.9−35.1). Patients with an RB deletion had a lower PFS 6.0 months (95% CI 1.28−NR) versus 9.0 months (95% CI 7.3−11.1) and a lower OS 13.9 months (95% CI 5.2−NR) versus 26.5 months (95% CI 19.8−33.8). Conclusions Among mCRPC patients treated with Ra‐223 at Mayo Clinic and Tulane Cancer Center, we did not find any clear negative predictors of biochemical response or survival to treatment. TMPRSS2‐ERG and RB mutations were associated with a worse OS. Prospective studies and larger sample sizes are needed to determine the impact of genetic aberrations in response to Ra‐223.

518 Background: Cisplatin (C) based neoadjuvant chemotherapy (NAC) has been the mainstay treatment for muscle invasive bladder cancer (MIBC). However, the optimal choice of NAC is not well-established. We therefore conducted a network-meta-analysis (NMA) to assess comparative efficacy of different treatment options. Methods: Several electronic databases (MEDLINE, and EMBASE) and conference proceedings were systematically used to identify randomized trials evaluating first-line treatments in neoadjuvant MIBC. Outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and pathologic complete response (pCR). DerSimonian-Laird random-effects meta-analysis was used to compute direct comparisons between NAC and local therapy (LT) only. Fixed effect NMA was conducted within the frequentist framework for mixed treatment comparisons. P-scores were used to assess relative treatment rankings. All statistical analyses were conducted in R (v 4.1.1). Results: This systematic review included 23 trials (25 references) with a total of 5313 patients with 10 unique treatments. Direct comparisons showed significant benefit in PFS (HR: 0.82; 95% CI: 0.71-0.94), and in OS (HR: 0.85; 95% CI: 0.78-0.92) with NAC when compared to LT only. However, the likelihood of achieving an objective response (RR: 1.18; 95% CI: 0.72-1.95: I2: 85%) or CR (RR: 1.51; 95% CI: 0.87-2.61; I2: 79%) was not different between the two arms. Data available in 15 trials contributed to the network for PFS outcome while only eight trials contributed to OS outcome. Mixed treatment comparisons showed significantly improved PFS with nintedanib-gemcitabine-cisplatin (NinGC; HR: 0.42; 95% CI: 0.20-0.87) and dose-dense-methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC; HR: 0.61; 95% CI: 0.43-0.88) compared to LT only. Consistent benefit was observed when NinGC (HR: 0.48; 95% CI: 0.24-0.97) and ddMVAC (HR: 0.70; 95% CI: 0.51-0.96) were compared to GC only. However, no significant differences were observed between NinGC (rank 1) and ddMVAC (rank 2) or among other mixed treatment comparisons. Similarly, OS was significantly improved with NinGC (rank 1) relative to MVAC (HR: 0.41; 95% CI: 0.17-0.97), MVC (HR: 0.37; 95% CI: 0.16-0.88), MC (HR: 0.38; 95% CI: 0.16-0.92), AC (HR: 0.36; 95% CI: 0.15-0.91), and GC (HR: 0.39; 95% CI: 0.17-0.90). While similar results were observed with ddMVAC (rank 2) when compared to MVC (HR: 0.63; 95% CI: 0.42-0.94), MC (HR: 0.64; 95% CI: 0.42-0.98), and GC (HR: 0.66; 95% CI: 0.47-0.92), no significant differences were observed with ddMVAC when compared to MVAC (HR: 0.62; 95% CI: 0.38-1.01) and NinGC (HR: 1.70; 95% CI: 0.69-4.19). Conclusions: Current evidence shows improved PFS and OS with the use of neoadjuvant ddMVAC and Nin-GC in patients with MIBC relative to other treatment options.

360 Background: Pembrolizumab has been established as an effective treatment option in adjuvant renal cell carcinoma after the publication of KEYNOTE-564. However, the magnitude of benefit based on different risk categories is not well defined. Methods: We included full-text publications of phase II/III randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors or tyrosine kinase inhibitors (TKIs) in adjuvant renal cell carcinoma after a systematic search. The outcomes of interest included disease free survival (DFS), overall survival (OS), all grade or grade ≥3 treatment related, and all cause adverse events. Mixed treatment comparisons were computed through a fixed-effect multivariate meta-regression within the frequent framework. Relative treatment rankings were assessed using P-scores. We used stratified baseline risks of disease progression from observational data and at 5, 10, 15 years from the Leibovich risk stratification system (based on risk scores ranging from 0 to ≥15). Corresponding intervention risks (CIRs) were then approximated using relative effect estimates (from NMA) and baseline risks. The difference between CIRs and baseline risks were calculated to present absolute risk differences in each baseline category. Results: This NMA included six RCTs with a total of 7525 participants and five unique treatment options. Mixed treatment comparisons showed significant DFS and OS benefit with pembrolizumab (rank 1) when compared against sunitinib (DFS HR 0.74 [0.55-0.99]; OS HR 0.51 [0.27-0.94]). However, there were no significant differences with pembrolizumab compared to pazopanib (DFS HR 0.81 [0.60- 1.09]; OS HR 0.54[0.29-1.01]) and axitinib (DFS HR 0.78 [0.54-1.14]; OS HR 0.52 [0.24-1.16]). The safety profiles were comparable. Absolute benefit of TKIs in adjuvant setting was minimal whereas this benefit increased with higher T and N patients in patients treated with pembrolizumab (Table). Similarly, the treatment benefit increased with higher Leibovich’s risk scores at 5, 10 and 15 years of follow up. Conclusions: The current analysis suggests that a risk adapted approach may be useful when considering adjuvant pembrolizumab in RCC patients.[Table: see text]

136 Background: Intensification of initial treatment of in patients with metastatic castration-sensitive prostate cancer (mCSPC) with androgen pathway inhibition (API) in addition to docetaxel (DOC) and androgen deprivation therapy (ADT) has shown promise to improve clinical outcomes. Thus, we synthesize the data from modern clinical trials to estimate overall estimates of progression and survival outcomes. Methods: A systematic search of electronic databases (MEDLINE and EMBASE) was conducted to include phase III randomized controlled trials (RCTs) evaluating triplet therapy (API+DOC+ADT) against doublet therapy (DOC+ADT) in mCSPC. Outcomes of interest included overall survival (OS) and radiographic progression-free survival (rPFS). A DerSimonian-Laird random-effects meta-analysis was performed to pool precomputed hazard ratios (HRs) and confidence intervals (CIs) after logarithmic transformation using inverse-variance weighting approach. Cochran’s Q statistical test was used to assess statistically significant heterogeneity not explained by chance, while I2 statistical test was used to quantify the total observed variability, due to between-study heterogeneity. I2 values >50% indicated substantial heterogeneity. A summary of findings table was constructed to translate relative estimates to absolute risks. Results: A total of 1,531 patients in four RCTs with direct comparative data between triplet and doublet therapies, were included in this meta-analysis. PEACE-1 was the only RCT directly assessing this question (AAP+DOC+ADT). ENZA+DOC+ADT was evaluated as a subgroup in two RCTs (ENZAMET; ARCHES), APA+DOC+ADT was evaluated as a subgroup in one (TITAN). To be able to pool studies, the relative efficacy of control arm in ENZAMET (first generation bicalutamide + ADT) was considered equivalent to ADT based on prior literature. A total of 672 rPFS events were observed (34%; 261 events in triplet therapy, 54%; 411 events in doublet therapy). The difference was statistically significant (HR: 0.49; 95% CI: 0.42-0.58; I2: 0%). Similarly, 469 OS events were observed (28%; 217 events in triplet therapy, 33%; 252 events in doublet therapy). The difference was statistically significant (HR: 0.80; 95% CI: 0.67-0.96; I2: 0%). The summary of findings is outlined in the table. Conclusions: The results of this meta-analysis support an improvement in rPFS and OS in favor of triplet therapy over doublet therapy for mCRPC. However, comparative effectiveness of different triplet regimens may be different and needs further exploration.[Table: see text]

134 Background: Recent trials have suggested poly ADP-ribose polymerase inhibitors (PARPi) sensitivity in patients with treatment-refractory metastatic castration-resistant prostate cancer (mCRPC) harboring mutations in DNA damage and response repair genes (DDR). However, the efficacy profile might differ with different genes and is still being explored in multiple studies. Methods: We systematically searched several electronic databases (MEDLINE, EMBASE), and conference proceedings to include abstracts and full-text publications of phase II/III trials evaluating PARPi in treatment-refractory mCRPC with DDR gene alterations. Outcomes of interest included objective response rate (ORR), complete response (CR), prostate specific antigen (PSA) 50% response, circulating tumor cells conversion (CTCc) from ≥ 5 to < 5 cells, composite response (CoR) and risk of progression. Data was pooled using Inverse-variance approach. A DerSimonian and Laird random-effect meta-analysis was conducted to estimate pooled proportion (PP) of events using the Freeman-Tukey transformation in each gene. Clopper-Pearson method was used to estimate the associated 95% confidence intervals (CI). Results: This systematic review and meta-analysis included five unique trials with 648 patients and four PARPi (niraparib, olaparib, rucaparib, talazoparib). Objective response to PARPi was observed in 44.7% of patients with mutations in either BRCA1 or 2 or both (95% CI: 36.0%-53.6%; I2: 0%), 23.5% with ATM (95% CI: 3.91%-51.0%; I2: 65%), 25.0% with CDK12 (95% CI: 8.66%-49.1%), and 45.3% with PALB2 alterations (95% CI: 14.8%-77.5%; I2: 0%). Consistent results were observed for CR outcome. PSA50% response to PARPi was observed in 60.3% of patients with BRCA1/2 mutations (95% CI: 50.3%-70.0%; I2: 57%), 5.54% (95% CI: 0.01-16.6; I2: 0%) with ATM, and 70.1% (95% CI: 35.6%-96.6%; I2: 0%) with PALB2 mutations while no PSA 50% response was observed in patients with CDK12 mutations (PP: 0.00%; 95% CI: 0%-16.84%). Moreover, CTCc was observed in 68.3% of patients with BRCA1/2 mutations (95% CI: 45.0%-87.8%; I2: 77), 34.2% (95% CI: 11.2-61.3%; I2: 45%) with ATM, 41.7% (95% CI: 15.2%-72.3%) with CDK12, and 48.5% (95% CI: 6.39%-92.9%; I2: 49%) with PALB2. CoR was observed in 76.5% patients with BRCA1/2 mutations (95% CI: 65.4%-86.1%; I2: 22%), 30.4% (95% CI: 16.0%-46.9%) with ATM, 25% (95% CI: 8.66%-49.1%) with CDK12, and 63.9% (95% CI: 31.0%-91.8%; I2: 0%) with PALB2 mutations. Similarly, the risk of progression was 50.9% in patients with BRCA1/2 mutations (95% CI: 37.7%-63.9%), 70.9% (95% CI: 60.0%-80.40%; I2: 0%) with ATM, and 75% (95% CI: 19.4-99.3%) with PALB2. Conclusions: Current evidence is sparse regarding efficacy by specific genes. Limited data favors the use of PARPi in mCRPC patients harboring mutations in BRCA1/2 and PALB2 genes.

132 Background: Treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) is rapidly evolving. Recent updates of relevant trials and presentation of PEACE-1 results warranted mixed treatment comparisons to inform the choice of treatment in mCSPC. Methods: MEDLINE and EMBASE, along with conference proceedings were searched using a systematic search strategy to identify relevant abstracts and full-text publications of phase II/III randomized controlled trials (RCTs) assessing first-line treatment options in mCSPC. Outcomes of interest included overall survival (OS), radiographic progression-free survival (rPFS), and grade ≥3 adverse events (AEs). Direct comparisons were made using DerSimonian-Laird random-effects meta-analysis. Fixed-effect frequentist NMA was conducted to compute network estimates using a multivariate meta-regression approach. Relative treatment rankings were assessed in congruency with direct estimates using P-scores. Secondary NMAs were conducted in several substrata (young, and old; Gleason score < 8 and ≥8; performance status 0 and 1-2, low and high volume of disease). Results: This NMA included nine trials (23 references) with nine unique treatments. rPFS was improved with abiraterone acetate and prednisone-docetaxel-androgen deprivation therapy combination (AAP-D-ADT; rank 1) when compared against most treatment options including AAP-ADT (HR: 0.58, 95% CI: 0.44-0.76; rank 5), apalutamide (APA)-ADT (HR: 0.63, 95% CI: 0.46-0.87; rank 4), TAK-ADT (HR: 0.55, 95% CI: 0.36-0.84; rank 6), and enzalutamide(E)-AAP-ADT (HR: 0.70, 95% CI: 0.51-0.97; rank 3), however no significant differences were observed between AAP-D-ADT, and E+ADT (rank 2). Improved OS was observed with AAP-D-ADT (HR: 0.75, 95% CI: 0.59-0.95; rank 2), E-AAP-ADT (HR: 0.68; 95% CI: 0.48-0.97; rank 1), and AAP-ADT (HR: 0.82, 95% CI: 0.70-0.96; rank 3) compared to D+ADT (rank 6). However, most of the mixed treatment comparisons were statistically insignificant in terms of OS. Similarly, in patients with high volume of disease, AAP+D+ADT (rank 1) was observed to significantly improve rPFS compared to AAP-ADT, APA-ADT, E-ADT, and D-ADT; however, no significant differences were observed among treatment comparisons with regards to OS improvement. E+ADT (rank 1) improved rPFS compared to other treatment in low volume disease but was not different for OS. No significant differences were observed among different treatment options when compared across prespecified subgroups. Moreover, AAP+D+ADT was ranked as the least safe with significantly increased risk of grade 3 AEs relative to other treatments. Conclusions: Current NMA suggests that triplet therapy options were ranked as most likely to improve rPFS and OS at the cost of increased toxicity. Doublet combinations may still be preferred for older patients with low volume of disease.

26 Background: The underrepresentation of minority populations in clinical trials negatively impacts cancer and widens inequities. We aimed to quantify the enrollment disparities in prostate cancer (PC) clinical trials over the last three decades. Methods: MEDLINE and Embase were searched to identify primary reports of prostate cancer RCTs (1989-2020). Data for trial characteristics, the proportion of trials reporting race, ethnicity and age, and the proportion of patients by race, ethnicity and age enrolled in trials were summarized using descriptive statistics. Enrollment incidence ratios (EIR), which compare trial enrollment against global estimates of incidence in age-related subgroups (acquired from the Global Burden of Disease database) and U.S. population-based estimates of racial/ethnic subgroups (acquired from the SEER 18 incidence database) were calculated. Individual trial EIRs were pooled using random-effects meta-analyses to account for the substantial heterogeneity between trials. Multivariable meta-regression was used to explore associations between key trial characteristics and EIR. Annual percentage changes (APC) over the last three decades in enrollment disparities were analyzed using the Joinpoint Regression Analysis. Results: 281 trials from 1989 to 2020 with 99,588 patients were included in this analysis. 107 trials reported race (38%), of which only 25 trials (9%) reported data on all 5 U.S. racial categories (Black, White, Asian, Pacific Islander and Native American. 255 (91%) trials reported mean or median but only 71 trials (25%) specifically reported the enrollment proportion of older adults (age > 65 years). Clinical outcomes by race and age were reported in 9 (8%) and 37 (14%) trials, respectively. Results from meta-analyses showed that Black patients (summary EIR: 0.42 [95% CI: 0.35 - 0.51]), Hispanics (summary EIR: 0.50 [95% CI: 0.37 - 0.68]) and older adults (summary EIR: 0.95 [95% CI: 0.91 - 0.99]) were underrepresented in trials relative to their population estimates. Significantly fewer Black participants (EIR for Black patients = 0.42, EIR for White patients = 0.99; p < 0.0001), Hispanic participants (EIR for Hispanics = 0.50, EIR for non-Hispanics = 1.00; p = 0.001) and older adults (EIR for older adults = 0.95, EIR for younger adults = 1.06; p = 0.037) were enrolled. Representation of Black patients decreased significantly from 1989-2019 (APC: -4.25), while Hispanic representation increased significantly from 2000-2020 (APC: 5.89). Meta-regression showed Black patients were particularly underrepresented in larger-size trials (p < 0.0001). Conclusions: Black representation in PC clinical trials is less than 50% of their expected share based on cancer incidence and it has consistently decreased over last three decades, contributing to the disparities experienced by the population.

6549 Background: Representation and outcomes of women, older adults, and racial minorities in ICI trials has not been previously described. Methods: MEDLINE and Embase were searched to identify ICI RCTs. Data for trial characteristics, proportion of trials reporting race, age and sex as well as the proportion of patients by race, age and sex enrolled in ICI trials was collected. Descriptive statistics were reported for trials reporting minority representation and proportion of included patients by race, age and sex. Disparities in representation were calculated using enrollment incidence disparity (EID) and enrollment incidence ratios (EIR) by comparing trial enrollment against U.S. population-based estimates acquired from the SEER 18 incidence database. The relationship of EID to key trial characteristics were compared using standard parametric and non-parametric statistical tests. Trends in EIR were analyzed using the Joinpoint Regression Analysis software. Results: 108 ICI trials from 2009 to 2020 with 48,360 patients were included in this analysis. All RCTs reported sex (101/101). 78 trials reported race (72%), of which only 41 trials (38%) reported data on all 5 U.S. racial categories (Black, White, Asian, Pacific Islander and Native American). Participation of Black patients was reported in 66 trials (61%), White participants in 78 trials (72%), Asians in 69 trials (64%), Native Americans and Pacific Islanders in 41 trials (38%), and Hispanics in 24 trials (22%). Age categories were inconsistently defined, and 80 trials (74%) reported the proportion of patient by age categories. Subgroup analyses of clinical outcomes by race, age and sex were reported in 17 (22%), 62 (79%) and 57 (73%) trials respectively. Women (trial proportion [TP]: 32%; EIR: 0.77), patients aged ≥ 65 years (TP: 42%; EIR: 0.74), Black participants (TP: 1.8%; EIR: 0.17) and Hispanic participants (TP: 5.9%; EIR: 0.67) were largely underrepresented, and Asians were overrepresented (TP: 15.9%; EIR: 2.64). Black patients were underrepresented across all cancer types. Similarly, women, older adults ( > 65 years of age) and Hispanic patients were consistently underrepresented across cancer types with few exceptions. Representation of older adults increased significantly from 2010-2020 (APC: 2.72), while representation of Black patients decreased significantly from 2009-2020 (APC: -23.37). Black patients were found to be significantly underrepresented in phase III trials (p = 0.0005), trials with OS as the primary endpoint (p = 0.004), and PD1 inhibitor trials (p = 0.002). Hispanics were significantly underrepresented in PD1 inhibitor trials (p = 0.003). Conclusions: There is both suboptimal reporting about participation and underrepresentation of women, racial minorities (particularly Black patients) and older adults in ICI trials as compared to their cancer incidence.

4541 Background: Radical cystectomy (RC) is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC), but many patients are unfit for surgery or elect bladder preservation. This trial was designed to evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This single arm phase II registration trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year aimed to enroll 135 (70 CIS and 65 non-CIS) eligible patients with histologically proven BCG-unresponsive high risk NMIBC who were unfit for or declined RC. Here we report the 18 month results for all eligible patients who received at least one protocol treatment. The co-primary endpoints were pathological complete response (CR) rate at 6 months in patients with CIS (reported at ASCO 2020), and event-free survival (EFS) in all patients at 18 months using Kaplan-Meier methods (KM), conditional on a positive CIS response rate. A sample size of 135 evaluable patients provided 93% statistical power for detecting a 30% 18-month EFS rate versus 20% using a one-sided alpha = 0.05. EFS in the subset with Ta/T1 disease and duration of response in CIS patients were secondary endpoints. Results: 172 patients were enrolled, 166 received at least one dose of atezolizumab and are included in the safety analysis, and, of those, 128 were eligible and included in the efficacy analysis. As previously reported, 20 (27%) out of 74 patients with CIS attained a pathologic CR at 6 months. The KM estimate of 12 month (actual 11.9 mo) duration of response after 6 month CR for CIS patients was 54% (95% CI 30%, 78%) and the median duration of response was 16.5 months. The KM EFS rate at 18 months in 74 patients with CIS was 17% (90% CI 9%, 25%). The 18 month KM EFS rate in the overall population of 128 patients with Ta, T1 and CIS was 29% (90% CI 22%, 36%). The 18 month actuarial EFS rate in 54 patients with Ta/T1 disease was 45% (90% CI 34, 57%). Any possibly or probably treatment-related adverse event (TRAE) was observed in 142 out of 166 (86%) patients who received any atezolizumab regardless of eligibilty. The most frequent TRAEs were fatigue 72 (43%), diarrhea 34 (20%), and anemia 38 (23%). Grade 3-5 TRAEs occurred in 28 (17%) patients, including rash in 4 (2%), hyponatremia in 4 (2%), hypertension in 3 (2%) and elevated liver function tests in 3 (2%). There were two treatment-related deaths (sepsis and respiratory failure due to myasthenia gravis). Conclusions: The observed response of atezolizumab at 6 and 18 months in patients with BCG-unresponsive CIS suggests that this could be a valuable treatment to address a critical unmet need in this patient population. The 18 month EFS in patients with Ta/T1 disease suggests activity in this patient subset. This trial provided no new safety concerns. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, CA180863 and in part by Genentech. Clinical trial information: NCT02844816.

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.