Androgen Signaling Inhibitors Research Articles

Abstract 359: Molecular signatures associated with long-term response to apalutamide (APA) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) in TITAN

Abstract Background: TITAN, a phase 3 placebo (PBO)-controlled study in a broad population of pts with mCSPC (NCT02489318), demonstrated that the addition of APA to androgen deprivation therapy (ADT) significantly improved radiographic progression-free survival (rPFS) (median rPFS in the APA and PBO groups was not reached and was 22.1 months, respectively) and overall survival (OS) compared with PBO + ADT (Chi N Engl J Med 2019). This exploratory analysis investigated molecular signatures of pts with mCSPC who had long-term responses to APA. Methods: Pts (n = 222) in the biomarker cohort of TITAN were characterized as long-term responders (LTR) or early progressors (EP) by separating rPFS into quartiles. The last quartile with longest rPFS (APA, n = 28; PBO, n = 28) represented LTR. The first quartile, with shortest rPFS (APA, n = 17; PBO, n = 21) represented EP. Gene expression profiles of TITAN pts were generated from archival primary prostate tumors; data were summarized based on 110 predefined gene signatures. Mean signature scores between LTR and EP groups were compared within treatment groups using 2 sample t tests to evaluate whether effects were prognostic or specific to APA treatment. Signatures were also evaluated for association with outcome using Cox proportional hazard models in each treatment group. Results: At primary analysis, with median 22.7 months follow-up, median rPFS was, respectively, not reached and 32.9 months in APA and PBO pts in the LTR group, and 10.9 and 3.7 months in APA and PBO pts in the EP group. A higher level of expression (above median) of either polycomb repressor complex 2 activation or the Decipher signature was more frequently associated with EP in both groups. LTR in the APA treatment group, but not those in the PBO group, had lower expression of transcriptional signatures describing myeloid-derived suppressor cells (MDSCs) and cell cycle progression. These results suggest that pts with mCSPC who have relatively lower levels of MDSCs in the tumor, indicative of a less immune-suppressed tumor microenvironment, may have long-term benefit from treatment with APA. Conclusions: Consistent clinical benefit was observed with the addition of APA to ADT in both EP and LTR. Although the data require confirmation in larger studies, these molecular signatures may have utility in selecting pts with mCSPC who may derive the most benefit from APA and other androgen signaling inhibitors. Citation Format: Justin Lucas, Neeraj Agarwal, Felix Feng, Clemente Aguilar-Bonavides, Shibu Thomas, Michael Gormley, Suneel Mundle, Sabine Brookman-May, Sharon A. McCarthy, Anders Bjartell, Hirotsugu Uemura, Simon Chowdhury, Kim N. Chi. Molecular signatures associated with long-term response to apalutamide (APA) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) in TITAN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 359.

Blood Biomarker Landscape in Patients with High-risk Nonmetastatic Castration-Resistant Prostate Cancer Treated with Apalutamide and Androgen-Deprivation Therapy as They Progress to Metastatic Disease.

In the placebo-controlled SPARTAN study, apalutamide added to androgen-deprivation therapy (ADT) improved metastasis-free survival, second progression-free survival (PFS2), and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Mechanisms of resistance to apalutamide in nmCRPC require evaluation. In a subset of patients from SPARTAN, aberrations were assessed at baseline and end of study treatment (EOST) using targeted next-generation sequencing or qRT-PCR. Circulating-tumor DNA (ctDNA) levels were assessed qualitatively. Select aberrations in androgen receptor (AR) and other common PC-driving genes were detected and summarized by the treatment group; genomic aberrations were summarized in ctDNA-positive samples. Association between detection of aberrations in all patients and outcomes was assessed using Cox proportional-hazards models and multivariate analysis. In 247 patients, the overall prevalence of ctDNA, AR aberrations, and TP53 inactivation increased from baseline (40.6%, 13.6%, and 22.2%) to EOST (57.1%, 25.4%, and 35.0%) and was comparable between treatment groups at EOST. In patients who received subsequent androgen signaling inhibition after study treatment, detectable biomarkers at EOST were significantly associated with poor outcomes: ctDNA with PFS2 or OS (HR, 2.01 or 2.17, respectively; P < 0.0001 for both), any AR aberration with PFS2 (1.74; P = 0.024), and TP53 or BRCA2 inactivation with OS (2.06; P = 0.003; or 3.1; P < 0.0001). Apalutamide plus ADT did not increase detectable AR/non-AR aberrations over ADT alone. Detectable ctDNA, AR aberrations, and TP53/BRCA2 inactivation at EOST were associated with poor outcomes in patients treated with first subsequent androgen signaling inhibitor.

Beyond the Androgen Receptor: The Sequence, the Mutants, and New Avengers in the Treatment of Castrate-Resistant Metastatic Prostate Cancer.

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.

ARC-6: A phase 1b/2, open-label, randomized platform study to evaluate efficacy and safety of etrumadenant (AB928)-based treatment combinations in patients with metastatic castrate-resistant prostate cancer (mCRPC).

5039 Background: Standard-of-care (SOC) chemotherapy may contribute to immunosuppression by elevating intratumoral levels of adenosine, activating the A2a and A2b receptors on immune cells. Extracellular adenosine is primarily produced by the enzyme CD73; in prostate cancer, additional adenosine is also produced by the highly expressed protein, prostatic acid phosphatase (PAP). Etrumadenant (etruma) is an orally bioavailable, small-molecule, selective dual adenosine receptor antagonist and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Adenosine axis inhibition combined with SOC regimens and/or immunotherapy may have a synergistic effect on the induction of sustained antitumor immunity against mCRPC. Initial results from the etruma + zimberelimab (zim; anti–PD-1 mAb) + docetaxel (doc) arm are presented herein. Methods: ARC-6 (NCT04381832) is an ongoing, phase 1b/2, open-label, multicohort platform study to evaluate efficacy and safety of etruma combination therapy. All eligible patients (pts) have mCRPC that has progressed on androgen deprivation therapy and are checkpoint inhibitor-naive; additionally, for this arm, pts must be androgen signaling inhibitor (ASI)-experienced and taxane-naive. Study pts receive 150 mg etruma orally once daily + 360 mg zim IV every 3 weeks + SOC doc (EZD). The primary objectives are to evaluate safety and antitumor activity (prostate-specific antigen [PSA], radiographic, and composite response rates) of EZD. PSA levels are assessed every 3 weeks, and radiographic scans are performed every 12 weeks. PSA response-evaluable pts have baseline (BL) + ≥2 consecutive post-BL PSA assessments; radiographic response-evaluable pts have RECIST measurable or non-measurable disease per BL imaging + ≥1 post-BL radiographic assessment. Results: As of 22Jan2021, 17 pts have received EZD in phase 1b; 14 are PSA response-evaluable and 8 are radiographic response-evaluable. 15 (88%) pts reported treatment emergent adverse events (TEAEs); the most common ( &gt; 30%) were lymphocyte count decreased and neutrophil count decreased (7 pts each; 41%), and hyponatremia and alopecia (6 pts each; 35%). Grade ≥3 treatment-related TEAEs were reported by 9 pts (53%). As of 22Jan2021, 16 pts were continuing treatment; median time on EZD for all pts was 9.9 weeks (0.1–27.4+ weeks). In response-evaluable pts, PSA response rate was 36% (5/14), radiographic response rate was 38% (3/8; 1 CR), and the composite response rate was 43% (6/14). Conclusions: Phase 1b results indicate that EZD treatment in pts with mCRPC had a manageable safety profile and was associated with clinical benefit. Having met phase 2 advancement criteria, randomized pt enrollment to EZD vs. doc is ongoing. Clinical trial information: NCT04381832.

Rate of skeletal-related events (SREs) for abiraterone acetate (AA) versus enzalutamide (ENZ) in prostate cancer: A population-based study using the SEER-Medicare database.

e17038 Background: Skeletal-related events are common in men with prostate cancer, and are associated with significant morbidity and mortality. AA and ENZ are novel androgen signaling inhibitors used in the treatment of metastatic prostate castration-resistant prostate cancer (mCRPC). As directly comparative efficacy data do not exist between AA and ENZ, the differing toxicity profiles inform treatment selection. It is unknown whether SRE rates differ in a real-world population between AA, which is given with corticosteroids, and ENZ, which is associated with imbalance and falls. Methods: The national SEER-Medicare linked database was used to identify men with prostate cancer who received AA or ENZ between 2011-2015; approval during this period was solely for mCRPC. Inclusion criteria included Medicare Part A+B coverage 1 year before and after first receipt of AA/ENZ, without any HMO enrollment. Baseline demographic and comorbidity data were gathered. Diagnosis and procedure claims codes were used to identify SREs, defined as pathologic fracture, surgery to bone, radiation to bone, or spinal cord compression. The time to SRE was defined as time from first receipt of AA/ENZ to the first SRE of any type. A multivariable competing risk regression analysis including death as a competing risk was performed. Results: 5,856 men with prostate cancer who first received AA (N = 4,207) or ENZ (N = 1,649) were identified. The median age at initiation of AA/ENZ was 70 years (range 65-101); 78% were White, 12% Black, 4% Hispanic, 3% Asian, and 4% Other. The median follow-up was 14 months. The overall SRE rate was 13.1% after AA/ENZ start: 574 (13.6%) AA and 194 (11.8%) ENZ, with a cumulative incidence of 11.9% at 2 years. Median overall survival was 16 months (14.4 months for AA and 18.3 months for ENZ). Age, stage at diagnosis, race/ethnicity, baseline comorbidities, and prior history of SRE were balanced between AA vs ENZ, aside from baseline osteoarthritis or rheumatoid arthritis (48.0% AA vs 53.2% ENZ, P &lt; 0.001) and baseline Alzheimer’s dementia (9.2% AA vs 11.1% ENZ, P = 0.03). After controlling for these potential risk factors, receipt of AA versus ENZ was not associated with time to SRE (relative risk ratio [RR] = 0.90, 95% CI 0.77-1.06, P = 0.22). Osteoporosis (RR 1.22, 95% CI 1.01-1.49, P = 0.04), osteoarthritis or rheumatoid arthritis (RR 1.23, 95% CI 1.06-1.43, P &lt; 0.01), and prior history of SRE (RR 1.31, 95% CI 1.07-1.59, P &lt; 0.01) were statistically significant risk factors for SRE. Conclusions: In this real-world population of men with prostate cancer, there was no difference in time to SRE between AA and ENZ. Clinical decision-making on whether to prescribe AA or ENZ should be informed by other potential toxicities as well as cross-resistance with sequencing of these therapies. Analysis of impact of bone protective agent use is underway.

Phase 1b study of AMG 757, a half-life extended bispecific T-cell engager (HLE BiTEimmune-oncology therapy) targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer (NEPC).

TPS5100 Background: NEPC is an aggressive cancer with poor prognosis. No standard treatment approach for NEPC exists and it remains an unmet need. NEPC is usually treatment-emergent, characterized by histological transformation from adenocarcinoma to a high-grade neuroendocrine tumor (NET), and may develop in 15%–20% of patients (pts) treated with standard prostate adenocarcinoma therapies, including novel hormonal therapies. The inhibitory Notch ligand, Delta-like ligand 3 (DLL3), is highly expressed on the surface of cancer cells, including NEPC cells, making it an attractive and a promising therapeutic target. AMG 757 is an HLE BiTE immuno-oncology therapy designed to redirect cytotoxic T cells to tumor cells by binding DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. AMG 757 showed in vitro activity in DLL3-expressing NETs, including NEPC. Preliminary results of an on-going first-in-human study suggest AMG 757 is safe and effective in pts with small cell lung cancer (NCT03319940), which prompted its study in NEPC. Methods: NCT04702737 is an open-label, phase 1b study evaluating AMG 757 infusion in pts with metastatic de novo or treatment-emergent NEPC, consisting of dose exploration and then dose expansion. Key eligibility criteria include adults (≥18 y) with NEPC whose disease progressed/recurred after ≥1 treatment course including a platinum-based regimen for de novo NEPC or an androgen signaling inhibitor, measurable disease per modified RECIST 1.1 per Prostate Cancer Working Group 3 modifications, ECOG performance status ≤2, life expectancy &gt; 3 mo, adequate organ function, and no untreated/symptomatic brain metastases. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757. Secondary objectives are to evaluate antitumor activity (ie, objective response, duration of response, progression-free survival, overall response) and characterize pharmacokinetics. The starting dose for dose exploration will be based on the dose deemed safe and tolerable in the ongoing trial of AMG 757 in SCLC. The study is open to enrollment. Clinical trial information: NCT04702737.

Immunogenic priming with 177Lu-PSMA-617 plus pembrolizumab in metastatic castration resistant prostate cancer (mCRPC): A phase 1b study.

5053 Background: Immune checkpoint inhibitors have limited single agent activity in microsatellite-stable mCRPC. 177Lu-PSMA-617 (Lu) is a PSMA-targeting radioligand therapy that has demonstrated promising anti-tumor activity. We sought to determine whether a single dose of Lu can induce an immunogenic priming effect to improve outcomes of men with mCRPC subsequently treated with pembrolizumab (P). Methods: We undertook a phase 1b, single arm trial enrolling chemotherapy-naïve mCRPC patients (pts) with progression (PD) on at least one prior androgen signaling inhibitor (NCT03805594). Pts were required to have ≥ 3 PSMA-avid lesions on 68Ga-PSMA-11 PET and measurable disease by RECIST 1.1 criteria. No genomic selection was undertaken. Pts were enrolled sequentially on one of three schedules: A) Single dose of Lu (7.4 GBq) followed by initiation of P (200 mg IV q 3 weeks) 28 days later; B) Lu x 1 dose given concomitantly with first P administration; C) Lu x 1 dose given on C2D1 following initiation of P on C1D1. Pts were treated with P until confirmed radiographic or clinical PD. The primary endpoint was safety; key secondary endpoints included PSA response, objective response rate by RECIST 1.1 criteria (ORR), median duration of response (DOR), and radiographic progression-free survival (rPFS). Results: 18 pts were enrolled, 6 per schedule. The median age was 64 (range 51 – 80) and 44% of pts had visceral metastases. The median baseline number of PSMA-avid metastatic lesions was 20 (range 6 – 50+). Six pts (33%) had progressed on prior abiraterone, 4 (22%) on enzalutamide, and 8 (44%) on both. There were no dose-limiting toxicities and one Grade ≥ 3 treatment-related adverse event (AE) (inflammatory arthritis, schedule B). There were no grade ≥ 3 hematologic AEs. The ORR was 8/18 (44%) and median DOR has not been reached (range 1.9+ – 15.9+ months). Four pts (2 on schedule A, 1 on schedule B, 1 on schedule C) with durable partial responses remain on study treatment for 5.4+, 8.9+, 9.2+, and 17.8+ months, respectively. The median rPFS was 6.5 months (95% CI: 2.5 – 9.8). PSA30, PSA50, and PSA90 response rates were 44%, 28%, and 17%, respectively. Fourteen pts (78%), including all durable responders, had somatic genomic data available. One (7%) harbored a DNA repair mutation ( BRCA1, non-responder), none were MSI-high, and all carried low tumor mutational burden (≤ 5 mutations/MB). Single cell sequencing of the immune microenvironment from paired metastatic tumor biopsies is underway. Conclusions: 177Lu-PSMA-617 as a priming dose followed by pembrolizumab was well tolerated and leads to durable responses in a subset of mCRPC without high mutational burden or microsatellite instability, suggesting a possible immunogenic priming effect of radioligand therapy. Further evaluation of the combination is ongoing in a phase 2 study. Clinical trial information: NCT03805594.

Seed-mediated RNA interference of androgen signaling and survival networks induces cell death in prostate cancer cells

Resistance to anti-androgen therapy in prostate cancer (PCa) is often driven by genetic and epigenetic aberrations in the androgen receptor (AR) and coregulators that maintain androgen signaling activity. We show that specific small RNAs downregulate expression of multiple essential and androgen receptor-coregulatory genes, leading to potent androgen signaling inhibition and PCa cell death. Expression of different short hairpin/small interfering RNAs (sh-/siRNAs) designed to target TMEFF2 preferentially reduce viability of PCa but not benign cells, and growth of murine xenografts. Surprisingly, this effect is independent of TMEFF2 expression. Transcriptomic and sh/siRNA seed sequence studies indicate that expression of these toxic shRNAs lead to downregulation of androgen receptor-coregulatory and essential genes through mRNA 3′ UTR sequence complementarity to the seed sequence of the toxic shRNAs. These findings reveal a form of the “death induced by survival gene elimination” mechanism in PCa cells that mainly targets AR signaling, and that we have termed androgen network death induced by survival gene elimination (AN-DISE). Our data suggest that AN-DISE may be a novel therapeutic strategy for PCa.

95871 Mortality in Castration-Resistant Prostate Cancer Patients with Pre-existing Cardiovascular Comorbidities Receiving Oral Androgen Signaling Inhibitors

ABSTRACT IMPACT: Limited research has been conducted on the survival of men with castration-resistance prostate cancer (CRPC) with a pre-existing history of cardiovascular disease, receiving oral androgen signaling inhibitors. This study highlights all-cause and prostate cancer-specific mortality for elderly patients with CRPC with pre-existing history of cardiovascular disease. OBJECTIVES/GOALS: Inadequate knowledge is known about the survival of men with castration-resistance prostate cancer (CRPC) with pre-existing history of cardiovascular disease (CVD), receiving oral androgen signaling inhibitors (OASI). We compared all-cause and prostate cancer-specific mortality for elderly patients with CRPC with pre-existing history of CVD. METHODS/STUDY POPULATION: An active comparator, new user design, was used to identify 2,608 men older than age 65 years with CRPC using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database from 2011 to 2015. Patients were grouped into two analytical cohorts by CVD history. Within each analytical cohort patients were divided into two arms based on their new-user status (OASI vs. chemotherapy). All demographics and clinical characteristics were adjusted by inverse probability treatment weights (IPTWs). Unadjusted and IPTW-adjusted time-dependent Cox models, and Fine and Gray’s models were conducted to evaluate associations between OASI and all-cause and prostate cancer-specific mortality. RESULTS/ANTICIPATED RESULTS: Nearly 64.5% of patients had pre-existing CVD. We observed a lower all-cause mortality in the pre-existing CVD cohort compared to the no pre-existing CVD cohort (IPTW-adjusted hazard ratio [AHR], 0.59; 95% Confidence Interval [CI], 0.54 to 0.64; IPTW-AHR, 0.68; 95% CI, 0.59 to 0.78, respectively). Similarly, the prostate cancer specific-mortality was showed to be lower in the pre-existing CVD cohort compared to the no pre-existing CVD cohort when comparing OASI versus chemotherapy by the IPTW-adjusted time-dependent Fine and Gray’s models (IPTW-AHR, 0.60; 95% CI, 0.55 to 0.66; IPTW-AHR, 0.68; 95% CI, 0.59 to 0.80, respectively). DISCUSSION/SIGNIFICANCE OF FINDINGS: OASI showed a significant protective effect against all-cause and prostate cancer-specific mortality compared with chemotherapy; however, were less protective among patients without pre-existing CVD. Further studies are needed to investigate OASI in patients with and without pre-existing CVD.

Transcriptional mediators of treatment resistance in lethal prostate cancer

Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell–intrinsic epithelial–mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4–6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.

Mechanisms and markers of resistance to androgen signaling inhibitors in patients with metastatic castration-resistant prostate cancer

Next-generation androgen signaling inhibitors such as abiraterone and enzalutamide are widely used for the treatment of metastatic castration-resistant prostate cancer. Unfortunately, baseline and acquired resistance to these treatments is commonly observed. In the last few years, significant effort has been devoted to uncover the molecular mechanisms and predictive markers of resistance. These analyses identified various DNA (single nucleotide variations, amplifications) and RNA variants (e.g., the splice variant AR-V7) of androgen receptor in association with resistance to abiraterone and enzalutamide therapies. Additionally, androgen receptor independent resistance mechanisms were also described. Some of these alterations can be detected in tumor tissues and/or in liquid biopsies of prostate cancer patients and therefore may serve as predictive biomarkers. According to the diversity of potential resistance mechanisms, it appears that a combination of markers representing various resistance mechanisms may provide better performance as single markers. In the present review, we summarize the most important androgen receptor dependent and independent resistance mechanisms and pay attention to methodological details. Recent data has highlighted that some of the resistance mechanisms to next-generation antiandrogen agents are associated with a better response to other therapies, we give an overview on currently ongoing clinical studies evaluating this promising aspect.

Adiposity and response to androgen signaling inhibition (ASI) in men with metastatic castration-resistant prostate cancer (mCRPC).

72 Background: Improved understanding of how host factors influence the efficacy and toxicity of ASI could improve outcomes. Adiposity increases the risk for recurrence and lethal disease in men with localized prostate cancer. Few studies have evaluated the influence of adiposity in metastatic prostate cancer, and in these studies, adiposity was associated with improved outcomes, a potential “obesity paradox”. Herein, we assess whether adiposity is associated with response to maximal ASI in mCRPC and assess how individual body composition measurements interact to influence outcomes. Methods: Men with mCRPC uniformly treated on a prospective clinical trial with abiraterone acetate plus apalutamide were included in this post-hoc analysis (NCT02703623). Responders were defined as those with a decrease in PSA of &gt; 50% after 8 weeks of therapy. Body composition was assessed at the level of L3 on baseline CT scan at trial registration using Slice-O-Matic version 5.0. Body composition indices were normalized for height (m2). Non-parametric Kruskal-Wallis test was used to evaluate associations between continuous baseline measures. A multivariable CART model was used to determine if baseline measures could divide patients into distinct risk groups. Results: In 186 men with mCRPC, responders to maximal ASI (n = 128) had higher subcutaneous adiposity (SATi, 79.3 vs. 67.6, p = 0.02), visceral adiposity (VATi, 76.4 vs. 61.5, p = 0.03), and body mass index (BMI, 30.3 vs. 29.2, p = 0.04). There was a strong correlation between BMI and SAT (r = 0.81). In exploratory multivariable modeling, BMI and VATi had the strongest associations with response to ASI. Specifically, men with a BMI ≥ 26.73 had a higher response rate (75% vs. 46%). For men with a BMI &lt; 26.73, a VATi ≥ 24.7 enriched for response to therapy (86% vs. 26%). Conclusions: Elevated subcutaneous and visceral adiposity is associated with improved response to maximal ASI in men with mCRPC. In hypothesis-generating models, visceral adiposity had the strongest association with response to ASI in men with lower BMI. Further studies need to assess how and when adiposity becomes favorable for outcomes in advanced prostate cancer.

BXCL701, first-in-class oral activator of systemic innate immunity pathway, combined with pembrolizumab (Keytruda) in men with metastatic castration-resistant prostate cancer (mCRPC).

124 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP), primarily DPP8 and DPP9, triggers inflammasome mediated pyroptosis in macrophages, leading to induction of IL-18 and IL-1ß, bridging between innate and adaptive immunity. PD-L1 expression correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor growth inhibition was observed with BXCL701 plus checkpoint inhibition. In a prior clinical study, single-agent BXCL701 resulted in objective responses in patients with Stage IV melanoma (unpublished). Methods: Eligible patients included in Phase 1b portion of this multicenter study, had progressing mCRPC (PCWG3), ≥1 prior systemic therapy, ≤2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anticancer therapy. In Phase 2 portion, patients with adenocarcinoma must have received 1 or 2 2nd generation androgen signaling inhibitors; patients with SCNC/t-NEPC must have received ≥1 prior line of chemotherapy. Patients received fixed-dose pembrolizumab (200 mg IV q21-days) with BXCL701 on days 1-14 at recommended Phase 2 dose (RP2D)/schedule. Primary endpoint is Composite Response (RECIST 1.1, PSA, CTC). Change in relevant immune effector cells was also evaluated. Results: In Phase 1b portion 13 patients were treated with BXCL701 in 3 cohorts: 0.4 mg qd (n = 3); 0.6 mg qd (n = 3) and 0.6 mg split dose (n=7). 7 patients had adenocarcinoma, 6 had small cell/neuroendocrine prostate cancer phenotype. Prior treatment included androgen deprivation therapy (n = 10), 2nd-generation androgen signaling inhibitors (n = 9), chemotherapy (n = 11), radiation therapy (n = 11). On-target adverse events (AEs) consistent with cytokine activation were seen at highest dose levels. In 0.6 mg qd cohort, all patients had events consistent with cytokine release syndrome: 3/3 had hypotension, including 1 grade 3 syncope—dose-limiting toxicity (DLT)—and 2 patients each had dizziness and lower extremity edema. Splitting 0.6 mg dose improved tolerability while maintaining total daily dose (TDD) previously associated with objective response; 3/7 patients had fatigue, and 1 patient each had low grade hypotension, dyspnea, chills, myalgia. Preliminary anti-tumor activity was seen with 1 patient achieving a PSA response and 4 patients with RECIST1.1 stable disease. Consistent dose and time dependent increases in serum IL-18 levels were observed. Conclusions: BXCL701 0.3 mg BID (0.6mg TDD) administered on days 1-14 was identified as RP2D when administered with pembrolizumab 200 mg every 21 days. Splitting TDD was associated with improved tolerability as evidenced by no reported DLTs and lower rates of other AEs of interest e.g. hypotension and peripheral edema. Preliminary data from Phase 2 portion will be presented. Clinical trial information: NCT03910660.

Molecular determinants associated with long-term response to apalutamide (APA) in nonmetastatic castration-resistant prostate cancer (nmCRPC).

8 Background: SPARTAN, a phase 3 placebo (PBO)-controlled study in patients (pts) with nmCRPC, showed that APA plus androgen deprivation therapy (ADT) significantly improves metastasis-free survival compared with PBO + ADT. This exploratory analysis investigated potential biological signatures of pts with long-term responses to APA and PBO. Methods: The biomarker cohort of SPARTAN was characterized as long-term responders (LTR) or early progressors (EP) based on time to metastasis, and separated into quartiles for APA and PBO groups. Pts progressing in the first quartile (APA, 21; PBO, 17), with shortest time to metastatic event, were classified as EP, those progressing in the last quartile (APA, 39; PBO, 20) as LTR. Gene expression profiles were generated from 233 archival primary prostate tumors. Predefined gene signatures indicative of cancer biology were compared between LTR and EP groups within the APA and PBO arms using 2 sample t tests. Signatures associated with LTR and EP were identified using p values of less than 0.05. Results: Median time to metastatic progression was 40.5 months in APA pts and 22 months in PBO pts in the LTR group and 7.3 and 3.6 months in APA and PBO pts, respectively, in the EP group. Signatures categorized into 3 general mechanistic classes (immune regulation, proliferation, and hormone dependence) associated with LTR on APA included increased T cell activity reflected by T cell activation ( p = 0.0045), stimulation ( p = 0.0642), cytokine response ( p = 0.0489), and interferon production (gamma response p = 0.0227 ), and decreased T cell exclusion ( p = 0.0652), low proliferative capacity ( p = 0.0435), and increased hormonal dependence ( p = 0.0485). High risk (DECIPHER p = 0.0406, metastatic potential p = 0.0077), hormone nonresponsive (basal p = 0.0115; androgen receptor activity-low, p = 0.0437), and neuroendocrine-like tumors ( p = 0.0125) were associated with early progression on treatment with PBO. Conclusions: Although the data require confirmation in larger studies, these molecular determinants may have utility in selecting pts with nmCRPC who may derive the most benefit from APA and other androgen signaling inhibitors. Clinical trial information: NCT01946204.

Final results of a phase I/II prospective dose escalation trial evaluating safety and efficacy of combination 177Lu PSMA 617 and NOX66 in men with end-stage metastatic castration-resistant prostate cancer (LuPIN trial).

103 Background: 177LuPSMA – 617 is a promising therapy for metastatic castrate-resistant prostate cancer (mCRPC). However, treatment resistance occurs frequently and synergistic combination therapy may improve outcomes. We combined 177LuPSMA – 617 with idronoxil (NOX66), an inhibitor of external NADH oxidase type 2 with radio-sensitizing properties. We present the final safety and efficacy results. Methods: Men with progressive mCRPC after androgen signalling inhibition (ASI) and taxane chemotherapy were enrolled. Key inclusion criteria were: PSMA PET/CT intensity SUV max &gt; 15 with no discordant disease on FDG PET/CT, haemoglobin &gt; 100g/L, platelets &gt; 100x109/L and eGFR &gt; 40mls/min. Enrolled patients received up to six doses of 177 Lu-PSMA 617 (7.5Gbq) day 1 every 6 weeks in combination with NOX66 days 1-10 each cycle. Cohort 1 (n = 8) received 400mg NOX66. Following safety reviews the doses were escalated in cohorts 2 (n = 24) and 3 (n = 24) to 800mg and 1200mg of NOX66, respectively. Blood samples were prospectively collected for androgen receptor splice variant 7 (ARV7) expression. PSMA and FDG PET/CT were performed at study entry and on progression. The primary outcomes were safety and tolerability; the secondary outcomes evaluated were efficacy, pain scores, and quality of life. Results: Of the 56 men enrolled, all had received prior treatment with ASI and docetaxel, and 95% (53/56) had prior cabazitaxel. 96% (54/56) patients received ≥2 cycles and 46% (26/56) completed six cycles of treatment. Adverse events are summarized in the table below. PSA responses were as follows: 86% (48/56) had any PSA reduction and 61% (34/56) had &gt; 50% PSA reduction. 84% (47/56) have had PSA progression to date with median follow up 18.9 months (95% CI 11.9-25.8). Median PSA PFS was 7.5 months (95% CI 6.0-9.0). 55% (31/56) have died and median overall survival was 19.7 months (95% CI 10.7-28.7). 34/56 men had baseline pain scores ≥3, of whom 53% (18/34) had significant reduction in pain indicators. There was no correlation between quantitative PET results and either PSA &gt; 50% response, PSA PFS or OS. Conclusions: The combination of 177 Lu-PSMA 617 + NOX66 appears safe and efficacious in men with heavily pre-treated mCRPC. Exploratory analysis of ARV7 expression and quantitative PET imaging markers of treatment response and resistance is in progress. Clinical trial information: ACTRN12618001073291. [Table: see text]

Health-related quality-of-life (HRQoL) analysis from a randomized phase II trial of androgen signaling inhibitors with or without androgen deprivation therapy (ADT) for castration-sensitive prostate cancer: LACOG 0415.

64 Background: LACOG0415 is a 3-arm randomized trial evaluating ADT with abiraterone acetate plus prednisone (ADT+AAP), apalutamide alone (APA) or apalutamide with AAP (APA+AAP) for patients with locally-advanced, high-risk biochemical recurrence or metastatic castration-sensitive prostate cancer (ASCO 2020). In this trial, ADT+AAP and APA+AAP achieved the primary endpoint of percentage of patients with PSA ≤ 0.2 ng/mL at week 25. Apalutamide alone showed a high PSA decline &gt; 50% rate, but did not achieve the pre-specified PSA threshold. Here we report patient-reported outcome data using Functional Assessment of Cancer Therapy-Prostate (FACT-P). Methods: HRQoL was measured in the overall population using the FACT-P questionnaire, comprising 5 subscales: physical wellbeing (PWB), functional wellbeing (FWB), emotional wellbeing (EWB), social/family wellbeing (SFWB), and prostate cancer subscale (PCS). Scores for each patient were measured at baseline and every four weeks until week 25. Questionnaire completion was defined as ≥ 1 question answered at an assessment time point. Analysis of HRQoL change from baseline and deterioration included only patients with baseline and ≥ 1 postbaseline score. Differences greater than 10-points in FACT-P total score and differences greater than 3-points in PWB, FWB, EWB, SFWB, and PCS scores were considered clinically significant. The time-to-event endpoint was estimated by Kaplan-Meier method and compared by stratified log-rank test. Results: 128 patients were included in LACOG0415 trial and 122 of them completed the HRQoL assessments (ranging from 95.3% at baseline to 79.7% at week 25). FACT-P and all subscales scores were similar for all three arms at baseline. There were no meaningful differences in FACT-P scores at baseline and at week 25 between the 3 arms. The subscales scores also showed no statistically differences at baseline and at week 25. Time to FACT-P deterioration did not show any statistically difference between three arms ( P=0.3371). Conclusions: ADT free alternatives with APA alone or APA+AAP did not show meaningful differences in HRQoL in patients with advanced castration-sensitive prostate cancer compared to ADT+AAP. The short follow-up period limited the ability to explore differences in HRQoL after 25 weeks. Larger studies with longer follow-up are needed to further evaluate HRQoL with ADT-free strategies. Clinical trial information: NCT02867020. [Table: see text]

Early Prostate-Specific Antigen (PSA) Change at Four Weeks of the First-Line Treatment Using Abiraterone and Enzalutamide Could Predict Early/Primary Resistance in Metastatic Castration-Resistant Prostate Cancer.

Simple SummarySerum prostate-specific antigen (PSA) level is the most valuable biomarker in prostate cancer. This study investigates the predictive value of achieving >30% PSA decline at four weeks of first-line androgen signaling inhibitors (ASIs) using a multi-institutional cohort dataset of 254 mCRPC patients. The achievement of >30% PSA decline at four weeks is an independent predictor for overall survival (OS). Interestingly, in patients who did not achieve >30% PSA decline at four weeks—an achievement of the >30% PSA decline at 12 weeks is eventually observed in 30.9% of those patients. To identify the variables that discriminate the patient survival in 97 patients without achieving >30% PSA decline at four weeks of the first-line treatment, a multivariate analysis is conducted. The duration of androgen deprivation therapy before CRPC < 12 months and Eastern Cooperative Oncology Group Performance Status ≥ 1 are identified as independent predictors for shorter OS for those patients.The identification of early or primary resistance to androgen signaling inhibitors (ASIs) is of great value for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the predictive value of prostate-specific antigen (PSA) response at dour weeks of first-line ASIs treatment for mCRPC patients. A total of 254 patients treated with ASIs (abiraterone acetate: AA and enzalutamide: Enz) at the first-line treatment are retrospectively analyzed. Patients are stratified according to the achievement of >30% PSA decline at 4 and 12 weeks from the treatment initiation. At four weeks of the treatment, 157 patients (61.8%) achieved >30% PSA decline from the baseline. Thereafter, 177 patients (69.7%) achieved >30% PSA decline at 12 weeks of the treatment. A multivariate analysis exhibits >30% PSA decline at four weeks as an independent predictor for overall survival (OS). We note that 30 of 97 (30.9%) patients who did not achieve >30% PSA decline at four weeks consequently achieved >30% PSA decline at 12 weeks, and had a comparable favorable three years OS rate as the 147 patients achieving >30% PSA decline at both 4 and 12 weeks. To identify the variables that discriminate the patient survival in 97 patients without achieving >30% PSA decline at four weeks, a multivariate analysis is performed. The duration of androgen deprivation therapy before CRPC ≤ 12 months and Eastern Cooperative Oncology Group Performance Status ≥ 1 are identified as independent predictors for shorter OS for those patients. These data offer a concept of early treatment switch after four weeks of first-line ASIs when not observing >30% PSA decline at four weeks—particularly in patients with a modest effect of ADT and poor performance status.

Systematic Literature Review of the Epidemiology of Advanced Prostate Cancer and Associated Homologous Recombination Repair Gene Alterations.

To characterize the global epidemiology of metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic castration-resistant prostate cancer (mCRPC). Additionally, to assess the prevalence of homologous recombination repair gene alterations (HRRm) and their prognostic impact in advanced disease setting. A systematic literature review of real-world evidence published from January 2009 through May 2019 was conducted to assess global epidemiology and clinical practice trends for mCSPC, nmCRPC, mCRPC and HRRm; 4,732 papers were systematically screened for inclusion. Ten conference proceedings from 2014 through 2019 were reviewed. Of the screened articles 22 relevant publications were identified for this paper. Six publications reported global epidemiology of advanced prostate cancer. The prevalence of nmCRPC was estimated as 1.1% to 12.3% of prostate cancer cases and for mCRPC 1.2% to 2.1% of prostate cancer cases. No mCSPC prevalence was captured. Sixteen publications investigated HRRm prevalence in advanced prostate cancer with the majority conducted in mCRPC assessed using next-generation sequencing of tissue and germline samples. In mCRPC, the highest prevalence HRRm in both germline (3.3%-6.0%) and somatic (5.0%-15.1%) was BRCA2. Five publications reported the prognostic impact of HRRm in advanced prostate cancer. Published real-world evidence quantifying the prevalence of advanced prostate cancer and HRRm beyond mCRPC is sparse. Published data on HRRm, specifically BRCA2, are consistent with published clinical trial data for poly (ADP-ribose) polymerase inhibitors in mCRPC. In mCRPC, real-world evidence suggests that patients with HRRm have different clinical outcomes to noncarriers. More data are needed to better understand real-world patient segmentation and clinical outcomes for biomarkers given increasing interest in profiling.

Novel Therapeutic Strategies for CDK4/6 Inhibitors in Metastatic Castrate-Resistant Prostate Cancer.

The majority of patients with castrate-resistant prostate cancer will have metastatic disease at the time of diagnosis. Investigative efforts on new therapeutics for this patient population have improved with the development of androgen signaling inhibitors, such as abiraterone and enzalutamide, and PARP inhibitors, such as rucaparib and olaparib, to accompany the previously FDA-approved docetaxel, cabazitaxel, sipuleucel-T, and Radium 223. However, new therapeutic strategies are necessary to prolong survival as progression after these agents is inevitable. CDK4/6 inhibitors have advanced the field of estrogen receptor positive breast cancer treatment and are being investigated in prostate cancer given the role of androgen receptor signaling effects on the cell cycle. Response to CDK4/6 inhibitors may be predicted by the tumors’ genomic profile and may provide insight into combinatory therapy with CDK4/6 inhibitors in order to delay resistance or provide synergistic effects. Here, we review the use of CDK4/6 inhibitors in prostate cancer and potential combinations based on known resistance mechanisms to CDK4/6 inhibitors, prostate cancer regulatory pathways, and prostate-cancer-specific genomic alterations.

Abstract 1836: ONC201 shows synergistic effect with the androgen receptor AR-inhibitor darotulamide in prostate cancer models

Abstract Prostate cancer (PC) is the most frequently diagnosed cancer among men in the United States and is the 3rd cause of cancer mortality. Despite advances in the treatment and understanding of pathogenesis, patients with metastatic PC invariably progress to a lethal stage of castration-resistant prostate cancer (CRPC). Inhibition of androgen signaling remains crucial for the treatment of CRPC, but novel treatment strategies are urgently needed. ONC201 is a first-in-class, selective inhibitor of dopamine receptor D2 that upregulates death-receptor 5 and induces apoptosis. ONC201 induced apoptosis in PC cell lines and showed synergy with enzalutamide, docetaxel and everolimus (Lev A Mol Cancer Res 2018). Darolutamide (DARO) is a novel androgen receptor (AR) antagonist approved for treatment of patients with non-metastatic CRPC. DARO has higher affinity to AR and preclinical activity against enzalutamide-resistant PC cell lines including AR variants associated with enzalutamide agonism (Borgmann H Eur Urol 2018). We treated human PC cell lines (LNCAP [castration sensitive, AR wild-type], 22Rv1 [castration-resistant cell line that expresses AR splice variant AR-V7], DU145 [AR negative], PC3 [AR negative]) with DARO alone and combined with ONC201. Single-agent DARO decreased PC cell viability in Cell-Titer-Glo assays (IC50s of 10 and 693 nM for LNCAP and DU145, respectively). ONC201 showed strong synergism with DARO in LNCAP cells (combination indices &amp;lt; 1 at concentrations of 156, 312, 625 nM, and 1.25 µM of DARO with 2.5 μM ONC201). ONC201 induced robust apoptosis in 22Rv1 as measured by PARP cleavage, which was partially amplified by DARO. PARP cleavage was also observed in LNCAP cells with less intensity and not potentiated by DARO. ONC201 reduced the expression of phospho-AR (p-AR) in both 22Rv1 and LNCAP. The combination of ONC201 and DARO had a significant additive effect in reducing p-AR in 22Rv1, but not in LNCAP. ONC201 reduced PSA protein levels in LNCAP cells while DARO alone did not cause any significant change in PSA. Immunofluorescence experiments showed that DARO caused significant reduction of AR nuclear translocation in both 22rV1 and LNCAP cells. The combination with ONC201 potentiated this inhibition of AR translocation in both cell lines. ONC201 showed strong antiproliferative activity against PC cells lines independent of AR status. Combination of ONC201 with DARO demonstrated synergy in enzalutamide resistant 22Rv1 cells expressing AR-V7 with marked reduction of nuclear localization of AR. Our studies provide preclinical rationale for combination of ONC201 with DARO as a novel therapy of PC. Citation Format: Fabio Tavora, Lanlan Zhou, Ali Amin, Safran Howard, Navaraj Arunasalam, Andre de Souza, Anthony Mega, Dragan Golijanin, Wafik El-Deiry, Benedito Carneiro. ONC201 shows synergistic effect with the androgen receptor AR-inhibitor darotulamide in prostate cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1836.