Search

PURPOSE We have previously developed and externally validated a prognostic model of overall survival (OS) in men with metastatic, castration-resistant prostate cancer (mCRPC) treated with docetaxel. We sought to externally validate this model in a broader group of men with docetaxel-naïve mCRPC and in specific subgroups (White, Black, Asian patients, different age groups, and specific treatments) and to classify patients into validated two and three prognostic risk groupings on the basis of the model. METHODS Data from 8,083 docetaxel-naïve mCRPC men randomly assigned on seven phase III trials were used to validate the prognostic model of OS. We assessed the predictive performance of the model by computing the time-dependent area under the receiver operating characteristic curve (tAUC) and validated the two-risk (low and high) and three-risk prognostic groups (low, intermediate, and high). RESULTS The tAUC was 0.74 (95% CI, 0.73 to 0.75), and when adjusting for the first-line androgen receptor (AR) inhibitor trial status, the tAUC was 0.75 (95% CI, 0.74 to 0.76). Similar results were observed by the different racial, age, and treatment subgroups. In patients enrolled on first-line AR inhibitor trials, the median OS (months) in the low-, intermediate-, and high-prognostic risk groups were 43.3 (95% CI, 40.7 to 45.8), 27.7 (95% CI, 25.8 to 31.3), and 15.4 (95% CI, 14.0 to 17.9), respectively. Compared with the low-risk prognostic group, the hazard ratios for the high- and intermediate-risk groups were 4.3 (95% CI, 3.6 to 5.1; P < .0001) and 1.9 (95% CI, 1.7 to 2.1; P < .0001). CONCLUSION This prognostic model for OS in docetaxel-naïve men with mCRPC has been validated using data from seven trials and yields similar results overall and across race, age, and different treatment classes. The prognostic risk groups are robust and can be used to identify groups of patients for enrichment designs and for stratification in randomized clinical trials.

Targeting the androgen receptor by depriving testosterone with gonadotropin-releasing hormone agonists or antagonists, or surgical castration, has been the backbone of metastatic prostate cancer treatment. Although most prostate cancers initially respond to androgen deprivation, metastatic castration-resistant prostate cancer evolves into a heterogeneous disease with diverse drivers of progression and mechanisms of therapeutic resistance. Development of castrate resistance phenotype is associated with lethality despite the recent noteworthy strides gained via increase in therapeutic options. Identification of novel therapeutics to further improve survival and achieve durable responses in metastatic castration-resistant prostate cancer is a clinical necessity. In this review, we outline the existing avengers for treatment of metastatic castration-resistant prostate cancer by clinical presentation, placing into context the clinical state of the patient, such as burden of disease and symptoms. Doing so might aid in the ability to optimize the sequence of agents and allow for maximal exposure to life-prolonging therapeutics. Realizing the limitations of the androgen signaling inhibition, we explore the androgen-indifferent prostate cancer: the mutants. Classically, these subtypes have been associated with variant histology, but androgen-indifferent prostate cancer features are now frequently observed in association with heterogeneous morphologies, including double-negative prostate cancers, lacking both androgen receptor and neuroendocrine features, or clinicopathologic criteria, such as the aggressive variant prostate cancer criteria. The framework of new avengers against metastatic castration-resistant prostate cancer based on mechanism, including DNA repair, immune checkpoint inhibition, PTEN/PI3K/AKT pathway, prostate-specific membrane antigen targets, bispecific T-cell engagers, and radionuclide therapies, is summarized in this review.

PURPOSE Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin. PATIENTS AND METHODS This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies. RESULTS Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate. CONCLUSION To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed.

176 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP8/9 & DPP4—triggers inflammasome to alert and prime immune cells, leading to induction of IL-18 & IL-1ß, bridging innate & adaptive immunity. BXCL701 is evaluated in a Phase 2 study in combination with pembrolizumab, in mCRPC patients with SCNC phenotype. SCNC is highly proliferative and aggressive with limited duration of response to platinum-based chemotherapy. Here are reported the results of the Phase 2a after enrollment of 32 patients for the SCNC cohort. The final results will be presented at the Symposium. Methods: Phase 2a patients with any SCNC histopathological features, either de novo or treatment-emergent including mixed SCNC, required to have progression by PCWG3 on ≥1 prior line of cytotoxic chemotherapy (patients who either have refused chemotherapy or are considered unsuitable for chemotherapy also permitted entry with prior approval by sponsor). Patients receive pembrolizumab (200 mg IV q3week) + BXCL701 0.2 mg BID on days 1-7 with step-up to 0.3 mg BID on days 8-14, and 0.3 mg BID on days 1-14 of subsequent cycles. Primary endpoint is Composite Response, either objective response by RECIST 1.1 or PSA50 or CTC count conversion from ≥5/7.5 mL to

145 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease with significant morbidity. Androgen receptor (AR) signaling is a key driver of tumor growth in mCRPC, and AR-targeted therapies are the mainstay for patients (pts) with locally advanced or metastatic disease. Enzalutamide (ENZA) is commonly used, but resistance typically develops within 1–2 years. The glucocorticoid receptor (GR) can substitute for the AR, providing a tumor escape pathway (Arora et al. Cell 2013). In the 22Rv1 CRPC xenograft model, the selective GR modulator exicorilant (EXI) combined with ENZA reduced tumor growth, supporting the hypothesis that dual antagonism of GR + AR may block this escape pathway. Safety and pharmacokinetics from the first study of EXI + ENZA in pts with mCRPC (NCT03437941) were previously presented (Linch et al. ESMO 2022). Here, we report efficacy and pharmacodynamic (PD) results from the same study. Methods: Segment 1 (Seg 1) of this phase 1 study evaluated open-label, fasting, BID dosing of EXI (140 or 180 mg) + ENZA 160 mg QD. Segment 2 (Seg 2) tested QD dosing of EXI with food in a double-blind design: All pts received EXI 240 mg + ENZA and were randomized 3:1 to EXI titration (to 280 mg followed by 320 mg) or to remain on EXI 240 mg + placebo. Efficacy assessments included radiographic response and changes in prostate-specific antigen (PSA) levels. PSA was collected prior to study entry and PSA doubling times were calculated before and during treatment. PD analyses included baseline (BL) tumor GR expression and modulation of GR target genes in whole blood. As not all pts enrolled in Seg 1 were ENZA naïve, efficacy data are reported for Seg 2 only. Data cutoff date: July 7, 2022. Results: 39 pts were enrolled (Seg 1: 14, irrespective of prior ENZA exposure; Seg 2: 25, on a stable ENZA dose with rising PSA, defined as a 25% increase over nadir and absolute value >1 ng/mL). In Seg 2, there were no radiographic responses, 18 pts had a best overall response of stable disease per PCWG3, and 1 pt achieved a PSA response (≥50% PSA reduction from BL). BL tumor GR expression was detectable in all assessed tumors. PD analyses demonstrated EXI modulation of GR target genes, such as CDKN1C. Comparable PD effects were observed across EXI doses (240–320 mg QD). While BL 24-h urinary free cortisol (UFC) for most pts was within the normal range, improvements in PSA doubling times after treatment with EXI + ENZA were predominantly observed in pts with higher BL UFC ( P

Purpose Several studies have reported that among patients with localized prostate cancer, black men have a shorter overall survival (OS) time than white men, but few data exist for men with advanced prostate cancer. The primary goal of this analysis was to compare the OS in black and white men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in phase III clinical trials with docetaxel plus prednisone (DP) or a DP-containing regimen. Methods Individual participant data from 8,820 men with mCRPC randomly assigned in nine phase III trials to DP or a DP-containing regimen were combined. Race was based on self-report. The primary end point was OS. The Cox proportional hazards regression model was used to assess the prognostic importance of race (black v white) adjusted for established risk factors common across the trials (age, prostate-specific antigen, performance status, alkaline phosphatase, hemoglobin, and sites of metastases). Results Of 8,820 men, 7,528 (85%) were white, 500 (6%) were black, 424 (5%) were Asian, and 368 (4%) were of unknown race. Black men were younger and had worse performance status, higher testosterone and prostate-specific antigen, and lower hemoglobin than white men. Despite these differences, the median OS was 21.0 months (95% CI, 19.4 to 22.5 months) versus 21.2 months (95% CI, 20.8 to 21.7 months) in black and white men, respectively. The pooled multivariable hazard ratio of 0.81 (95% CI, 0.72 to 0.91) demonstrates that overall, black men have a statistically significant decreased risk of death compared with white men ( P < .001). Conclusion When adjusted for known prognostic factors, we observed a statistically significant increased OS in black versus white men with mCRPC who were enrolled in these clinical trials. The mechanism for these differences is not known.

5056 Background: Ipat + abiraterone (abi) significantly reduced the risk of radiographic disease progression vs placebo (pbo) + abi in pts with mCRPC and PTEN loss tumors by immunohistochemistry (IHC; HR, 0.77; 95% CI: 0.61, 0.98; P=0.034) but not in ITT pts (HR, 0.84; 95% CI: 0.71, 0.99; P=0.043; Sweeney Lancet 2021). A greater risk reduction was seen in pts with PTEN loss by NGS (HR, 0.65; 95% CI: 0.45, 0.95). We describe the efficacy and safety of pbo + abi vs ipat + abi at the second interim analysis (IA) of overall survival (OS) and explore the impact of AKT pathway alterations. Methods: Pts with mCRPC were randomized 1:1 to ipat (400 mg/d) + abi (1000 mg/d) + prednisone (5 mg bid) or pbo + abi + prednisone. Coprimary endpoints were investigator-assessed radiographic progression-free survival by Prostate Cancer Working Group 3 (PCWG3) criteria in pts with PTEN loss tumors by IHC (PTEN loss in ≥50% of tumor cells) and in ITT pts. Secondary endpoints in both populations included OS, objective response rate (ORR) per RECIST 1.1 and PCWG3 and time to pain progression (TPP). Ad hoc analyses assessed pts with PIK3CA/ AKT1/ PTEN alterations by NGS vs wildtype (WT). Results: Median follow-up was 31 mo (cutoff: 2021 Sept 30). In PTEN loss by IHC pts, median OS was 35.8 mo (n=261) with pbo + abi and 36.8 mo (n=260) with ipat + abi (HR: 0.95; 95% CI: 0.74, 1.21; P=0.665); in ITT pts, median OS was 36.7 mo (n=554) with pbo + abi and 40.3 mo (n=547) with ipat + abi (HR: 0.90; 95% CI: 0.76, 1.07). With longer follow-up, the safety profile was consistent with that of the primary analysis. In the full NGS evaluable population (n=743), ipat + abi was associated with better outcomes in pts with PIK3CA/ AKT1/ PTEN alterations (Table). Among pts with PTEN loss tumors by NGS (205 of the evaluable 518 pts), median OS was 29.8 mo (n=102) with pbo + abi and 35.8 mo (n=103) with ipat + abi (unstratified HR: 0.82; 95% CI: 0.56, 1.19). Conclusions: At the second IA, no significant improvement in OS was observed with ipat + abi in pts with PTEN loss by IHC. Exploratory analyses in pts with PIK3CA/ AKT1/ PTEN alterations by NGS suggest that these patients have poorer prognosis but may derive greater benefit from ipat + abi. Clinical trial information: NCT03072238. [Table: see text]

TPS2691 Background: Casitas B-lineage lymphoma proto-oncogene B (CBL-B) is an E3 ubiquitin ligase expressed in multiple immune cell lineages, which in contrast to cell surface immune checkpoints, acts as a regulator of both T and NK cell activation. Inhibition of CBL-B enhances T-cell response, increases response to suboptimal priming, and restores response in exhausted T cells. Thus CBL-B is a promising immune-oncology target and may overcome challenges seen with other T-cell directed therapies. NX-1607 is an oral small molecule inhibitor of CBL-B that has demonstrated anti-tumor activity and long-term survival in murine models as both a single agent and in combination with programmed cell death protein-1 (PD-1) antibodies. Further, NX-1607 elicits dose-dependent increases in cytokine secretion and proliferation in T-cell receptor-stimulated primary human T cells with enhanced tumor antigen-specific T-cell and NK cell anti-tumor responses. Thus, NX-1607 may be effective as a single agent or it may significantly enhance efficacy of other anti-tumor agents. Methods: NX-1607-101 is a first-in-human, multicenter, open-label, Phase 1 dose escalation and expansion trial evaluating NX-1607 in a variety of indications including platinum-resistant epithelial ovarian cancer (EOC), gastric cancer, squamous cell carcinoma of the head and neck (HNSCC), metastatic melanoma, non-small cell lung cancer (NSCLC), metastatic castration-resistant prostate cancer (mCRPC), malignant pleural mesothelioma (MPM), triple-negative breast cancer (TNBC), locally advanced or metastatic urothelial cancer, cervical cancer, microsatellite stable colorectal cancer (MSS CRC), and diffuse large B-cell lymphoma with Richter transformation (DLBCL-RT). The main objective is to establish the safety and tolerability of NX-1607, characterize PK/PD, and determine the recommended Phase 1b dose. NX-1607 will be given orally once daily at doses ranging from 5 to 100 mg in up to 6 dose levels. Dose escalation will proceed using an accelerated modified Fibonacci dose escalation design that transitions to a standard 3 + 3 design based on protocol-specific criteria. Up to 8 expansion cohorts in Phase 1b will be composed of patients with subsets of advanced cancers. Key eligibility criteria include patients with metastatic or unresectable disease that have progressed after prior therapy and for whom standard therapy with proven clinical benefit does not exist, is no longer effective, or is not appropriate. Prior treatment with immune checkpoint inhibitors or CAR-T cells with washout is allowed, but a history of active autoimmune disease is not. Up to 336 patients (60 in Phase 1a, 276 in Phase 1b using a Simon 2-stage design) will be enrolled at approximately 20 sites in the UK and US and treated until disease progression or unacceptable toxicity. Dose escalation is ongoing. Clinical trial information: NCT05107674.

TPS210 Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) is a high-affinity prostate-specific membrane antigen (PSMA)-targeted radioligand therapy that delivers β-particle radiation to PSMA-expressing cells and the surrounding microenvironment. Androgen receptor pathway inhibitors (ARPI) may alter PSMA expression and radiosensitivity. PSMAddition will assess the efficacy and safety of 177Lu-PSMA-617 plus standard of care (SOC) versus SOC alone in adults with metastatic hormone-sensitive prostate cancer (mHSPC). Methods: PSMAddition ( NCT04720157 ) is an international, prospective, open-label, randomized, phase 3 trial in adults with mHSPC. Eligible patients are treatment-naïve or minimally treated candidates for hormonal therapy, with PSMA-positive disease (determined by [68Ga]Ga-PSMA-11 PET/CT), Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate major organ function. Patients are excluded if they have rapidly progressing tumors that require chemotherapy. Approximately 1126 patients will be randomized 1:1 to receive 177Lu-PSMA-617 (7.4 GBq i.v. every 6 weeks, ≤6 cycles) plus SOC or SOC alone (control arm). SOC is ARPI and androgen deprivation therapy. Stratification factors are tumor volume (high/low), age (≥70/ < 70 years) and previous/planned prostatectomy or radiation treatment of the primary prostate tumor (yes/no). The primary endpoint is radiographic progression-free survival (rPFS), as assessed by blinded independent centralized review. Upon centrally confirmed radiographic progression, participants in the control arm can cross over to the 177Lu-PSMA-617 arm. The planned sample size provides 95% power to detect a hazard ratio of 0.7 for rPFS after 418 events with an overall one-sided significance level of 0.025. The key secondary endpoint is overall survival. Other secondary endpoints are the proportion of patients with a prostate-specific antigen (PSA) decline of ≥90% from baseline, time to development of metastatic castration-resistant prostate cancer, composite progression-free survival (radiographic, clinical or PSA progression), safety and tolerability, and health-related quality of life. Previously presented at the 2021 European Society for Medical Oncology Congress, FPN 3035, Tagawa S et al. Reused with permission. Clinical trial information: NCT04720157.

126 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP 8/9 & DPP 4—triggers inflammasome to alert and prime immune cells, leading to induction of IL-18 & IL-1ß, bridging innate & adaptive immunity. BXCL701 is evaluated in a phase 1b/2 study in combination with pembrolizumab, in mCRPC patients with SCNC phenotype (and in adenocarcinoma). SCNC is highly proliferative and aggressive and does not express androgen receptor or PSA. Here are reported the interim results of the phase 2a after enrollment of 16 patients for the SCNC cohort. Methods: Phase 2a patients with any SCNC histopathological features, either de novo or treatment-emergent including mixed SCNC, required to have progression by PCWG3 on ≥1 prior line of cytotoxic chemotherapy (patients who either have refused chemotherapy or are considered unsuitable for chemotherapy may be eligible following discussion with the sponsor). Patients received pembrolizumab (200 mg IV q21-days) + BXCL701 0.2 mg BID for a week with step-up to 0.3 mg BID on days 8-14, and 0.3 mg BID on days 1-14 of subsequent cycles. Primary endpoint is Composite Response defined as RECIST 1.1 ± PSA50 ± CTC count conversion. Study uses a Simon 2-stage minimax design with 15 evaluable patients in stage 1 and 13 in stage 2. Baseline markers and changes in relevant immune effector cells also evaluated. Results: As of 9/27/21, 16 patients with SCNC were enrolled (10 evaluable, 6 in active treatment): at the 7/08/21 data extract, 9 of the evaluable patients had prior chemotherapy and a median of 2 prior lines of therapy (range 1-4); 33% have bone only disease. Median follow-up duration is 9 weeks (range 1-27)/ 3 cycles. Although follow-up was short, anti-tumor activity was observed. 3/ 10 evaluable patients showed responses—1 RECIST-defined confirmed PR + 1 unconfirmed PR (both 18 weeks/ 6 cycles) + 1 CTC conversion—amounting to a 30% Composite Response rate, meeting protocol-defined expansion criteria from stage 1 to stage 2. BXCL701 + pembrolizumab demonstrated acceptable tolerability without evidence of increased immune-related AEs compared to historic controls with checkpoint inhibitors. AEs consistent with cytokine activation were observed (hypotension, fever, fatigue). Conclusions: Oral BXCL701 in combination with pembrolizumab demonstrates encouraging anti-tumor activity in very late-line, refractory mCRPC SCNC for which there is currently no standard of care. BXCL701 BID dosing continues to demonstrate an acceptable safety profile. Additional interim phase 2a study results will be presented. Clinical trial information: NCT03910660.

125 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP 8/9 & DPP 4—triggers inflammasome to alert and prime immune cells, leading to induction of IL-18 & IL-1ß, bridging innate & adaptive immunity. BXCL701 is evaluated in a phase 1b/2 study in combination with pembrolizumab, in mCRPC patients with adenocarcinoma phenotype (and in small-cell neuroendocrine carcinoma). Most prostate cancers are classified as adenocarcinomas, characterized by expression of androgen receptor (AR) and PSA. The initial results on the phase 2a adenocarcinoma cohort were reported at ESMO 2021. Here are reported the updated safety and efficacy analyses after enrollment of 40 patients for the adenocarcinoma cohort. Methods: Phase 2a patients with adenocarcinoma required to have progression by PCWG3 on 1 or 2 androgen signaling inhibitor and ≥1 prior line of taxane chemotherapy. Patients received pembrolizumab (200 mg IV q21-days) + BXCL701 0.2 mg BID for a week with step-up to 0.3 mg BID on days 8-14, and 0.3 mg BID on days 1-14 of subsequent cycles. Primary endpoint is Composite Response defined as RECIST 1.1 ± PSA50 ± CTC count conversion. Study uses a Simon 2-stage minimax design with 15 evaluable patients in stage 1 and 13 in stage 2. Baseline markers and changes in relevant immune effector cells also evaluated. Results: As of 9/27/21, 40 adenocarcinoma patients were enrolled (26 evaluable, 12 in active treatment). All had previously received taxane chemotherapy and first and/or second generation Androgen Deprivation Treatments and a median of 5 prior lines of therapy (range 1-11); 44% have bone only disease. Median follow-up duration is 12 weeks (range 1-54)/ 4+ cycles. Although follow-up was short, anti-tumor activity was observed. Composite Response rate was 23% (6/ 26 evaluable patients): 2 RECIST-defined confirmed PR + 1 unconfirmed PR (16%) and 63% disease control rate (defined as PR + SD + non-CR/ non-PD) in 19 patients with measurable disease; 16% PSA50 (3 patients had ̃90% PSA decrease) in 31 patients with ≥1 post-baseline PSA measurement; 25% CTC conversion in 8 CTC evaluable patients. All responders showed decrease in tumor burden, 5/ 6 responders were Micro Satellite Stable. BXCL701 + pembrolizumab demonstrated acceptable tolerability without evidence of increased immune-related AEs compared to historic controls with checkpoint inhibitors. AEs consistent with cytokine activation were observed (hypotension, oedema, fever, fatigue). Conclusions: Oral BXCL701 in combination with pembrolizumab demonstrates encouraging anti-tumor activity in very late-line, refractory mCRPC adenocarcinoma. BXCL701 BID dosing continues to demonstrate an acceptable safety profile. Final phase 2a study results will be presented. Clinical trial information: NCT03910660.

157 Background: TALAPRO-1 enrolled men with progressive mCRPC with measurable soft-tissue disease and tumor DDRm involved directly or indirectly in homologous recombination repair (HRR) (11 gene panel). These men had received 1–2 taxane chemotherapy and progressed on ≥1 novel hormonal therapy. The primary endpoint was objective response rate ([ORR] per RECIST 1.1; central review). Exploratory ad hoc biomarker analyses assessed germline DDR/HRR (gHRR) alteration landscape and associations with antitumor activity. Methods: Alterations were defined as known/likely pathogenic variants. gHRR alteration (gHRRm) frequency was assessed in the study population evaluable for saliva sequencing (n = 91) using Ambry CustomNext-Cancer (9/11 genes from the tumor panel assessed). Potential associations between gHRRm status and antitumor activity were explored in the HRR-deficient measurable disease population evaluable for gHRRm (n = 70). The potential association of germline vs somatic tumor HRRm and antitumor activity was also assessed in the HRR-deficient measurable disease population (n = 104) using saliva data and somatic-germline-zygosity (SGZ) prediction (when saliva results were unavailable) to annotate tumor alteration origin. This analysis was limited to short variants. Data cutoff was Sept 4, 2020 (primary completion date). Results: Using Ambry saliva results, 19 gHRRm were identified in 18/91 (20%) evaluable patients (pts) ( BRCA2 = 10; ATM = 4; CHEK2 = 4; RAD51C = 1; 1 pt had both ATM and RAD51C). As expected for germline sequencing, all 19 alterations were short variants (12 SNV, 7 InDels). For 17/19 gHRRm, central lab tumor F1CDx records were available: in all 17 cases, identical tumor alterations were found. Of these 17 tumor HRRm, 16 were evaluable for tumor SGZ prediction of origin or zygosity: 15/16 germline, with 1/16 somatic; 9/16 homozygous (incl 7/9 BRCA2), with 7/16 heterozygous (incl 2/9 BRCA2). ORR was 31% (5/16) in men with gHRRm and 26% (14/54) in men without gHRRm ( P = 0.7519, 2-sided Fisher exact test). Based on tumor sequencing results, annotated using saliva results and SGZ predictions, ORR was 25% (10/40) in men with gHRRm and 19% (4/21) in men with only somatic HRRm ( P = 0.7528). Conclusions: Here we report a 20% incidence of gHRRm for this population of men with mCRPC preselected based on tumor HRRm status, which may be impacted by low Ns and assay specific differences in variant calling. In this population, no association with differential antitumor activity was observed with gHRRm status as assessed using germline results alone, or assessed holistically using a combination of tumor and saliva results and SGZ prediction.

TPS215 Background: Standard of care for noncurative adenocarcinoma mCRPC is docetaxel or the next-generation hormonal agents (NHAs) abiraterone and enzalutamide. However, approximately 20% of patients develop t-NE after treatment for adenocarcinoma mCRPC; t-NE is associated with shorter survival, and it has no standard of care beyond combination platinum chemotherapy. The vascular endothelial growth factor (VEGF)/fibroblast growth factor receptor (FGFR) inhibitor lenvatinib inhibits proliferation and angiogenesis in preclinical models of adenocarcinoma prostate cancer. The phase 2 KEYNOTE-199 trial showed some antitumor activity with pembrolizumab monotherapy in docetaxel-pretreated patients with adenocarcinoma mCRPC. VEGF/FGFR inhibition combined with PD-1 inhibition may have enhanced benefit in mCRPC, for adenocarcinoma and possibly as a new treatment option for t-NE. Methods: KEYNOTE-365 (NCT02861573) is a nonrandomized, open-label, multicohort, phase 1b/2 trial designed to evaluate different pembrolizumab combination therapies in several patient populations with mCRPC. Cohort E will enroll patients with confirmed adenocarcinoma of the prostate without small cell histology, per investigator. Cohort F will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review). Each cohort will include patients who previously received docetaxel treatment for mCRPC. Prior treatment with ≤2 NHAs (for hormone-sensitive metastatic prostate cancer [mHSPC] or mCRPC) and 1 other chemotherapy for mCRPC is permitted. Additionally, enrollment in cohort F requires prostate cancer progression within 6 months of starting an NHA (for mHSPC or mCRPC) and within < 6 cycles of docetaxel for mCRPC. Each cohort will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status score of 0 or 1. Both cohorts will receive pembrolizumab 200 mg IV every 3 weeks + oral lenvatinib 20 mg once daily until disease progression, withdrawal of consent, prespecified alanine aminotransaminase or aspartate aminotransaminase level increase, or other discontinuation event. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; ORR and radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and overall survival. These cohorts of KEYNOTE-365 are enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.

TPS211 Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) is a high-affinity prostate-specific membrane antigen (PSMA)-targeted radioligand therapy that delivers β-particle radiation to PSMA-expressing cells and their surrounding microenvironment. In the phase 3 VISION trial, 177Lu-PSMA-617 significantly prolonged radiographic progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with ≥1 androgen receptor pathway inhibitor (ARPI) and 1–2 taxanes. PSMAfore is investigating the effect on rPFS in taxane-naïve patients with mCRPC treated with either 177Lu-PSMA-617 or a change in ARPI. Methods: PSMAfore (NCT04689828) is a multicenter, open-label, randomized phase 3 trial in adults with progressive mCRPC and confirmed PSMA expression by [68Ga]Ga-PSMA-11 PET/CT. Eligible patients are taxane-naïve in the metastatic setting and have: received one prior ARPI and are candidates for a change in ARPI; an Eastern Cooperative Oncology Group performance status of 0 or 1; a castrate level of serum/plasma testosterone ( < 50 ng/dL or < 1.7 nmol/L); and recovered to grade ≤2 from toxicities related to prior therapies. Approximately 450 patients will be randomized 1:1 to receive 177Lu-PSMA-617 (7.4 GBq i.v. every 6 weeks for 6 cycles) or a change in ARPI to either abiraterone or enzalutamide. Best supportive care is allowed in both arms. Stratification factors are prior ARPI use in castration-resistant vs hormone-sensitive prostate cancer settings and pain symptomatology (score 0–3 vs 4–10 on the worst pain intensity item of the Brief Pain Inventory–Short Form). The primary endpoint is rPFS according to PCWG3-modified RECIST v1.1 criteria. Participants with blinded independent centrally confirmed radiographic progression in the ARPI arm can crossover to the 177Lu-PSMA-617 arm. The planned sample size provides 95% power to detect a hazard ratio of 0.56 for rPFS after 156 events with an overall one-sided significance level of 0.025. The key secondary endpoint is OS; other secondary endpoints include safety and tolerability of 177Lu-PSMA-617 and health-related quality of life. Previously presented at the 2021 European Society for Medical Oncology Congress, FPN 942, Morris M et al. Reused with permission. Clinical trial information: NCT04689828.

118 Background: Abi + p is a standard of care for mCRPC. Cohort D of the phase 1b/2 KEYNOTE-365 study (NCT02861573) was used to evaluate safety and efficacy of the PD-1 inhibitor pembro + abi and p in patients (pts) who had not received chemotherapy for mCRPC. Methods: Chemotherapy-naive pts who had not previously used next-generation hormonal agents (NHAs) for mCRPC or were intolerant to enzalutamide or for whom enzalutamide was ineffective for mCRPC, whose disease progressed ≤6 months before screening, and who had ECOG PS score 0/1 were eligible. Enrolled pts received pembro 200 mg IV Q3W + abi 1000 mg PO QD and p 5 mg PO BID. Primary end points were PSA response rate (PSA decrease ≥50% from baseline), confirmed ORR per RECIST v1.1 by blinded independent central review, and safety. Secondary end points included rPFS per PCWG3-modified RECIST v1.1, DCR (CR + PR + SD or non-CR/non-PD ≥6 mo), DOR, OS, time to symptomatic skeletal-related event, radiographic bone progression, and radiographic soft tissue progression. Results: Of 103 treated pts, 35.9% had RECIST-measurable disease and 26.2% had previously received enzalutamide. Median (range) time from enrollment to data cutoff was 17.6 (9.7-27.0) months. Confirmed PSA response rate in all 103 pts was 56.3%. Overall, 78.6% of pts had a reduction in PSA level from baseline (confirmed and unconfirmed). For 37 pts with RECIST-measurable disease, ORR was 16.2% (1 CR; 5 PRs) overall, 7.7% for those who previously received enzalutamide (n = 13) and 21.7% for those who had not previously received NHAs (n = 23). Two pts with RECIST-nonmeasurable disease had a CR. DOR was not reached (NR; range, 2.1+ to 19.4+ mo); 4 pts had a response ≥12 months. DCR was 44.7% overall, 11.1% in pts who previously received enzalutamide (n = 27), and 57.3% in pts who had not previously used NHAs (n = 75). Additional analyses are listed in the table. Treatment-related AEs (TRAEs) were experienced by 90.3% of pts; 36.9% experienced grade 3-5 TRAEs. Overall, 18.4% of pts had a grade 3/4 ALT laboratory elevation and 12.6% had a grade 3/4 AST elevation. Five pts died of AEs; 1 was treatment-related (myasthenic syndrome). Conclusions: Pembro + abi and p showed antitumor activity in chemotherapy-naive pts with mCRPC. Safety was generally consistent with individual profiles of each agent, although there was an increased incidence of grade 3/4 ALT/AST laboratory elevations than reported for the individual treatments. Clinical trial information: NCT02861573. [Table: see text]

TPS204 Background: Treatment options are limited for patients with mCRPC that progresses after treatment with next-generation hormonal agents (NHAs)—such as enzalutamide and abiraterone acetate—or docetaxel. Approximately 20% of patients with adenocarcinoma mCRPC that progresses on androgen deprivation therapy develop t-NE mCRPC, which is associated with shortened overall survival (OS). The PD-1 inhibitor pembrolizumab showed antitumor activity as monotherapy in docetaxel-pretreated patients with adenocarcinoma mCRPC in the phase 2 KEYNOTE-199 trial. The T-cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor vibostolimab showed antitumor activity when combined with pembrolizumab in pretreated patients with several tumor types in a phase 1 dose-escalation study. Combining PD-1 and TIGIT inhibition might have enhanced benefit in mCRPC, potentially both adenocarcinoma and t-NE. Methods: KEYNOTE-365 (NCT02861573) is a nonrandomized, open-label, multicohort, phase 1b/2 trial designed to evaluate the efficacy and safety of several pembrolizumab combination therapies in patients with mCRPC. Patients enrolled in cohort G will have confirmed adenocarcinoma of the prostate without small cell histology, per the investigator. Cohort H will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review). Each cohort will include patients who previously received docetaxel treatment for mCRPC. Prior treatment with ≤2 NHAs (for hormone-sensitive metastatic prostate cancer [mHSPC] or mCRPC) and 1 other chemotherapy for mCRPC is permitted. Enrollment in cohort H requires prostate cancer progression within 6 months of starting an NHA (for mHSPC or mCRPC) and within < 6 cycles of docetaxel for mCRPC. Each cohort will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status score 0 or 1. Both cohorts will receive MK-7684A, a coformulation of pembrolizumab 200 mg and vibostolimab 200 mg, IV every 3 weeks. Treatment will continue until disease progression, withdrawal of consent, or other discontinuation event. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; ORR and radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and OS. These cohorts of KEYNOTE-365 are enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.

TPS218 Background: In previously treated adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC), approximately 20% of patients develop t-NE PC, which is aggressive with short overall survival (OS). t-NE PC treatment includes platinum-containing chemotherapy because of t-NE’s histologic, biologic, and clinical similarity to small cell/NE lung cancer. In the open-label, multicohort, phase 1b/2 KEYNOTE-365 study (NCT02861573), pembrolizumab, when combined with several agents for treatment of adenocarcinoma mCRPC, showed clinical activity and acceptable safety. To identify new treatment options for t-NE mCRPC, cohort I will help to evaluate platinum-containing chemotherapy alone or combined with pembrolizumab for patients with t-NE. Methods: Cohort I of the KEYNOTE-365 study will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review) and prior docetaxel treatment for mCRPC. Prior treatment with ≤2 next-generation hormonal agents (NHAs) for metastatic hormone-sensitive prostate cancer (mHSPC) or mCRPC and 1 other chemotherapy for mCRPC is permitted. Additionally, enrollment in cohort I requires previous prostate cancer progression within 6 months of starting an NHA (mHSPC or mCRPC) and within < 6 cycles of docetaxel for mCRPC. Each arm will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1. Eligible patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg IV on day 1 of each cycle every 3 weeks + carboplatin AUC of 5 IV on day 1 + etoposide 100 mg/m2 IV on days 1, 2, and 3 of each 21-day cycle for 4 cycles (arm 1) or the same chemotherapy regimen without pembrolizumab (arm 2). Pembrolizumab treatment will continue for up to 2 years until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will be stratified by ECOG PS score (0 vs 1). Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; duration of response (DOR) and disease control rate (DCR) per RECIST v1.1 by BICR; ORR, DOR, DCR, and radiographic progression-free survival per Prostate Cancer Working Group 3–modified RECIST v1.1 by BICR; and OS. End points will be summarized for each arm without formal hypothesis testing. This cohort of KEYNOTE-365 is enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.