Generation Androgen Receptor Inhibitor Research Articles

Abstract 4345: Molecular pathology studies reveal PD1+ CD8 T cell density correlates with response to supraphysiological testosterone treatment in pre-treatment biopsies and MYC mRNA and protein correlate with response after treatment

Abstract While most patients with metastatic prostatic adenocarcinoma respond initially, nearly all develop resistance to multiple lines of androgen deprivation therapies. This is related to overexpression of the androgen receptor (AR), which is frequently driven by AR amplification. In some patients, increased AR renders tumor cells sensitive to high dose androgens which paradoxically inhibits their growth. Bipolar Androgen Therapy (BAT) was introduced in which patients with castration resistant prostate cancer (CRPC) are treated intermittently with high dose testosterone. This produces biochemical and objective responses, and may re-sensitize prostate cancer to subsequent second generation AR inhibitors. This study utilizes samples from a recently performed clinical trial for patients with CRPC that included sequential biopsies of soft tissue metastases before BAT and after 3 cycles of BAT and before patients were treated with nivolumab.Tumor cells were present in FFPE blocks for both the pretreatment and C4D1 time points for 24 of the patients. These FFPE samples were stained using a recently validated iterative multiplex IHC assay containing 6 antibodies including: CD3 (T cells), CD4 (Helper T Cells), CD8 (Cytotoxic T Cells), PD1 (T Cell Checkpoint), FOXP3 (T-Reg cells), and Keratin 8 (epithelial cell marker). Biopsy slides were scanned after each round of staining and whole slide scans were imported into the HALO image analysis where they underwent color deconvolution, image registration and fusion. Regions of tumor were demarcated manually, and computerized automated image analysis was used to determine cell densities for 8 cell phenotypes (total CD3+, CD3+CD4+, CD3+CD8+, CD3+CD4+Foxp3+, CD3+CD4+PD1+, CD3+CD8+PD1+, CD3+CD4+PD1-, CD3+CD8+PD1-). There was a higher density of CD3+CD8+PD1+ cells in the pretreatment biopsies of men who responded (R) (to BAT) as compared with those who did not respond (NR)(p=0.015 Wilcoxon rank-sum test; mean 92.7 [R] vs 13.9 [NR]). The difference in R vs. NR was less and not significant in the CD3+CD8+PD1- population. There was a trend towards a higher density of CD3+CD4+PD1+ cells in the pretreatment samples in responders, but less so in the CD3+CD4+PD1- population. In the C4D1 biopsies, only CD3+ total cells were significantly higher in the R vs. NR (P=0.02), but the other phenotypes were not. We conclude that increased density of CD3+C8+PD1+, but not CD3+CD8+PD1- cells was present in pre-treatment biopsies in responders as compared with non-responders to BAT. These results indicate that men who are likely to respond to high dose testosterone treatment harbor tumors that are immunologically distinct prior to treatment than those men unlikely to respond. Additional spatial analysis and comparisons with RNAseq data will be presented. Citation Format: Carolina Gomes Alexandre, Jessica Hicks, Tracy Jones, John T Isaacs, Kiara Bowers, Alyza Skist, Laura Sena, Jennifer Meyers, Emmanuel Antonarakis, David Sanin, Hanfei Qi, Samuel Denmeade, Mark Markowski, Srinivasan Yegnasubramanian, Angelo De Marzo. Molecular pathology studies reveal PD1+ CD8 T cell density correlates with response to supraphysiological testosterone treatment in pre-treatment biopsies and MYC mRNA and protein correlate with response after treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4345.

Apalutamide in the treatment of a patient with non-metastatic castration-resistant prostate cancer

The treatment of patients with prostate cancer, who do not qualify for the radical therapy is based on the use of surgical or pharmacological castration methods. The effectiveness of the so-called androgen deprivation tends to decrease over time. Even in the absence of distant metastases on imaging studies, the resistance for the hormonal castration may be developed. At this moment, the use of new generation androgen receptor inhibitors may reduce the risk of metastases or death. The paper presents a case report of a patient with prostate cancer without distant metastases who started therapy with apalutamide at the moment of developing re-sistance to the pharmacological castration.

Utilization of metastatic hormone sensitive prostate cancer (mHSPC) treatment in a community oncology practice setting.

86 Background: Treatment options for mHSPC have continued to evolve. While androgen deprivation therapy (ADT) has been the backbone treatment, more recently early use of docetaxel and/or novel androgen receptor inhibitors (nARIs) has demonstrated improved clinical outcomes. This study assessed real-world treatment among mHSPC patients who received at least one line of therapy (LoT). Methods: A retrospective observational study utilizing de-identified health records from five Cancer Treatment Centers of America (CTCA) included patients with metastatic prostate cancer who were treated with ADT, docetaxel or nARIs at CTCA for 6+ months between 1/2015-3/2021. Treatment patterns were observed from first LoT to metastatic castration resistance, death, or lost-to-follow-up until 3/2022. LoT was defined as first to last date of active drug therapy, not including long-term hormone agonists. First LoT was defined as initial regimen with no new drugs added 30+ days after start date. Patient characteristics, proportion and duration of each LoT, and reasons for early discontinuation were gathered using structured data elements and chart abstraction. Results: The characteristics of the 523 patients in this study were as follows: mean (SD) age 62 (8) years, 60% white and 33% black, 53% with commercial insurance, 75% with ECOG 0-1, and 65% with bone metastasis at diagnosis. Median follow-up time was 2.9 years. The most common LoT 1 regimen was either ADT alone or ADT with first generation androgen receptor inhibitors (FGARI) (table below). 46% received a second and 15% received a third LoT. Mean (SD) duration of first and second active LoTs were 12 (11.8) and 10 (11.1) months, respectively. Among the 65% and 78% patients who discontinued therapy in LoT 1 and 2, respectively, the majority discontinued due to progression of disease (35% LoT 1 and 53% LoT 2) followed by patient choice (23% LoT 1 and 18% LoT 2). Conclusions: Despite recommendations from guidelines on early intensification of therapy in mHSPC, in this contemporary cohort we find that most patients received either ADT alone or ADT ± FGARI in LoT 1 while chemotherapy and nARIs were initiated predominantly in later lines. Most patients discontinued LoT 1 due to disease progression which may suggest undertreatment and need for improved outcomes. Further studies are needed to assess the factors associated with non-intensification of treatments. [Table: see text]

Oral EPI-7386 in patients with metastatic castration-resistant prostate cancer.

177 Background: EPI-7386 is a next generation aniten, a novel class of compounds designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain. Preclinical data supports disruption of AR regulated gene transcription even in the presence of resistance mechanisms including ligand-binding domain point mutations and truncated splice variants. Here we report results of the Part 1a first-in-human trial of EPI-7386 in mCRPC (NCT04421222). Methods: This Phase 1, open-label, multicenter, dose escalation (Part 1a) and expansion (Part 1b) trial was designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of EPI-7386 in mCRPC patients (pts) progressing on standard of care treatment, including next generation antiandrogen(s) and chemotherapy. Originally designed to assess up to 5 doses of EPI-7386 (200, 400, 600, 800, and 1000 mg QD), two additional cohorts were added examining 400 and 600 mg BID due to 600 mg QD showing exposure saturation while demonstrating a favorable safety profile. Results: 31 pts were enrolled in the QD cohorts and 8 in the BID cohorts. Pts had a median of 4 lines of prior therapy for mCRPC: 83% received abiraterone and at least one next generation AR inhibitor, and 58% had at least one line of prior chemotherapy. No DLTs were observed; EPI-7386 was safe and well tolerated at all doses/schedules evaluated. All related adverse events (AEs) were Grade 1 and 2 and consistent with AEs associated with second-generation antiandrogens. For doses above 400 mg QD, exposures were at or above those associated with antitumor activity in animal models. Evidence of antitumor activity (including significant and durable PSA responses and/or decreases in ctDNA, and/or radiographically documented tumor shrinkage) were observed in pts with fewer than 3 lines of treatment for mCRPC, no visceral metastases and no prior chemotherapy (9/31 pts). Conclusions: Part 1a treatment with EPI-7386 monotherapy was safe, well tolerated up to a daily dose of 1200 mg (600 mg BID), achieved target clinical exposures and showed preliminary signals of antitumor activity in heavily-pretreated mCRPC. Part 1b is open with enrollment focused on pre-chemotherapy, post-second generation antiandrogen treated mCRPC pts in one cohort, and treatment-naïve non-mCRPC pts in a window of opportunity proof-of-concept second cohort. Two doses will be evaluated (600 mg BID and QD) based on FDA Project Optimus recommendations. Clinical trial information: NCT04421222 .

Number needed to harm (NNH) in patients with non-metastatic, castration-resistant prostate cancer (nmCRPC): A final analysis from the darolutamide (D), enzalutamide (E), and apalutamide (A) clinical trials.

326 Background: Second generation androgen receptor inhibitors (ARI) D, A and E, approved for the treatment of nmCRPC, offer benefit in overall survival (OS) and metastasis-free survival (MFS), but do so with different risk-benefit profiles. Contextualizing risks of adverse events (AEs), or harm to patients, can be challenging. NNH is a trial-based measure that evaluates the number of patients who need to receive treatment before a harmful outcome occurs with the intervention, compared to the control. Thus, a higher NNH reflects a lower incremental likelihood of harm. This study is an update to a previous NNH analysis, utilizing final data from the ARI randomized controlled trials (RCTs). Methods: MEDLINE and EMBASE were searched for relevant RCTs. AEs occurring in ≥5% of either RCT arm were extracted from the final ARAMIS (D), SPARTAN (A) and PROSPER (E) publications. NNH by AE (all grade, grade 3 & 4) were calculated over the duration of each RCT based on reported rates, using the inverse of the absolute risk increase [1 / (experimental AE rate - control AE rate)]. An exploratory analysis considered the application of results to a US population, assuming trial-based AE rates to be representative of real-world rates. Results: Results show a trend of higher (i.e., favorable) NNH for AEs for D in ARAMIS across all grade and grade 3-4 AEs (Table), indicating a lower likelihood of incremental harm across AEs including fatigue, falls, hypertension and fracture for D versus A and E. Focusing on fatigue, fall and fractures, and selecting treatment with the highest (D) and lowest (A or E) NNH for an estimated 24,000 US high risk nmCRPC patients annually, treatment with D would translate to 4,073 fewer all-grade fatigue events, 2,928 fewer falls, and 2,383 fewer fractures compared to treatment with A (falls) or E (fatigue or fracture). Conclusions: The findings show a consistent trend of higher NNH (favorability) for D compared to A and E. The differences in their respective AE profiles are noteworthy not only for patients, but also for healthcare systems considering the overall risk-benefit amongst these three ARIs. Comparing D, A, and E directly in a single study may further inform their comparative profiles.[Table: see text]

EE447 Cost Implications of Adverse Event Profiles in Second Generation Androgen Receptor Inhibitor (SGARI) Treatments for Non-Metastatic Castration Resistant Prostate Cancer (NMCRPC)

EE447 Cost Implications of Adverse Event Profiles in Second Generation Androgen Receptor Inhibitor (SGARI) Treatments for Non-Metastatic Castration Resistant Prostate Cancer (NMCRPC)

Abstract 653: Molecular pathology of metastatic prostatic adenocarcinoma treated with bipolar androgen therapy (BAT) reveals a correlation between MYC mRNA and protein

Abstract Molecular analysis of tissue samples from metastatic cancer lesions can improve our understanding of drug response and resistance. Since prostate cancer cells initially require androgen signaling through the androgen receptor (AR) for proliferation, the treatment of metastatic prostate cancer involves surgical or chemical castration. While most patients respond initially, nearly all develop acquired resistance to combined androgen blockade using both first and second line agents. This resistance is often related to overexpression of AR, which is frequently driven by AR gene amplification. In some patients, this increased AR appears to render tumor cells sensitive to high dose androgens in a manner that paradoxically inhibits their growth. Bipolar Androgen Therapy (BAT) was introduced several years ago at our institution in which patients with castration resistant prostate cancer (CRPC) are treated intermittently with high dose testosterone. Prior clinical trials have shown that BAT can produce biochemical and objective responses, and may re-sensitize prostate cancer to subsequent second generation AR inhibitors. To define the mechanism(s) by which BAT results in tumor regression, we performed a clinical trial (NCT03554317) for patients with CRPC that included biopsies of soft tissue metastases before BAT and after 3 cycles of BAT (C4D1). Up to four tissue cores were taken per biopsy with two cores for formalin fixation and paraffin embedding (FFPE) and the others snap frozen. Histologically viable tumor cells were present for both the pretreatment and C4D1 time points for 24 of the 42 enrolled patients. The FFPE samples were stained for H&E and by IHC for AR, MYC and Ki67. MYC and Ki67 IHC stained slides were subjected to quantitative image analysis using HALO software (Indica Labs). Adequate frozen tumor tissue was available for laser capture microdissection and adequate amounts of RNA were obtained from 15 patients with paired pretreatment and C4D1 biopsies. RNAseq libraries were prepared using the NuGEN Ovation RNA-Seq System V2 and barcoded libraries were sequenced to an average depth of > 100 million reads per sample on an Illumina NovaSeq. Gene expression values were obtained with RSEM using Star aligner with GRCh38 (human). When comparing the C4D1 samples to the pretreatment samples, there were marked decreases in tumor MYC protein levels in approximately half of the treated patients, which was associated with decreased Ki67, decreased tumor volume, and prolonged progression-free survival on BAT. Using an image analysis computed H-SCORE for MYC, there was a strong correlation between MYC protein levels and MYC mRNA using RNAseq (r=0.81, p = 2.3 x 10-7). This indicates that MYC protein levels correlate with MYC mRNA and that reductions of MYC protein by BAT are likely related to reductions of MYC mRNA in clinical metastatic tissue samples. Citation Format: Carolina Gomes Alexandre, Tracy Jones, Jessica L. Hicks, John T. Isaacs, Anuj Gupta, Alyza Skaist, Laura Sena, Jennifer Meyers, Emmanuel Antonarakis, Mark Markowski, Samuel Denmeade, Srinivasan Yegnasubramanian, Angelo Michael De Marzo. Molecular pathology of metastatic prostatic adenocarcinoma treated with bipolar androgen therapy (BAT) reveals a correlation between MYC mRNA and protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 653.

Yatagarasu: A single-arm, open-label, phase 2 study of apalutamide (APA) plus goserelin (GOS) for patients (pts) with far locally advanced or recurrent/metastatic (fLA/RM) and androgen receptor (AR)-expressing salivary gland carcinoma (SGC).

6079 Background: Overexpression of AR is identified as a potential molecular target of SGC treatment. Combined androgen blockade (CAB) with bicalutamide has been evaluated previously, but the clinical usefulness of CAB with a next generation AR inhibitor has been unclear in SGC. We prospectively assessed the efficacy and safety of APA+GOS for pts with AR-expressing SGC. Methods: Eligible pts had fLA/RM SGC, and AR expression with at least 1% of cell nuclei immunohistochemistry staining positive. Pts were treated with APA 240 mg orally once daily and GOS 3.6 mg subcutaneously once 28 days. Primary endpoint was overall response rate (ORR) by central review according to RECIST v1.1, and a response (complete response [CR] or partial response [PR]) was confirmed by repeat assessments at least 4 weeks after the initial evaluation showing a response. Primary analysis was performed based on first 24 response evaluable (RE) pts who had been observed at least 24 weeks (Primary RE pts). The ORR was tested using exact test based on the binominal distribution, the null hypothesis for ORR of 14% was rejected when at least 8 of the 24 Primary RE pts were responders, and the efficacy was to be declared. Key secondary endpoints included clinical benefit rate (CBR), disease control rate (DCR), duration of response (DOR), and time to response (TTR) in the Primary RE pts, and overall survival (OS), progression free survival (PFS), and safety in the treated pts. Results: Twenty-six of the 31 pts treated with APA+GOS were regarded as RE by central review. For the 24 Primary RE pts, ORR was 25.0% (6/24), while 37.5% (9/24) including unconfirmed PR. Clinical benefit rate and DCR in the Primary RE pts were 50.0% and 70.8%, respectively. At the data cut-off (Apr 28, 2021), 5 of 6 pts with confirmed response were still on protocol treatment. Median PFS and OS in the treated pts were 7.43 months (mos) and not reached, respectively, with the median follow-up period of 8.57 mos. Grade 3 or higher treatment-related adverse events were reported in 4/31 (12.9%) pts, and the events were rash maculo-papular (n=2), anemia (n=1), and leukopenia (n=1). Conclusions: This is the first prospective trial evaluating CAB with APA for AR-expressing SGC. Although this study did not meet the predefined criteria of efficacy, clinically meaningful activity with well-tolerated safety profile of APA+GOS was shown. Clinical trial information: NCT04325828. [Table: see text]

Attainment of early, deep prostate-specific antigen response in metastatic castration-sensitive prostate cancer: A comparison of patients initiated on apalutamide or enzalutamide.

43 Background: Deep prostate-specific antigen (PSA) response, defined as a ≥90% decline in PSA (PSA90), is an important early prognostic factor for achieving radiographic progression free survival and overall survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with a next generation androgen receptor inhibitor (ARI) or androgen biosynthesis inhibitor. This study compared PSA90 responses among patients with mCSPC at first use of a next generation ARI. Methods: Clinical data from 69 community urology practices in the United States were evaluated. Patients with mCSPC were classified into treatment cohorts based on their first filled prescription (index date) for apalutamide (APA) or enzalutamide (ENZ) after 12/16/2019. Patients were followed from index date until the earliest of index regimen discontinuation, treatment switch, end of clinical activity or end of data availability (03/05/2021). Included patients had ≥12 months of clinical activity to assess baseline characteristics. Inverse probability of treatment weighting (IPTW) was used to reduce baseline confounding by controlling for age, race, index year, androgen deprivation therapy (ADT) use ≥6 months, first-generation antiandrogen use, most recent PSA level, most recent testosterone level, Gleason score, and time between metastasis and the index date. PSA90 was defined as the earliest attainment of ≥90% decline in PSA relative to baseline PSA (most recent value within 13 weeks pre-index). The proportion of patients achieving a PSA90 and the time to PSA90 was compared using a weighted Kaplan-Meier (KM) analysis and weighted Cox proportional hazards models. Results: A total of 186 APA patients and 165 ENZ patients met the study criteria. Patients’ characteristics were generally well balanced after IPTW (Table). By 6 months, 73.6% of APA and 69.5% of ENZ patients had a post index PSA measurement. At 6 months, significantly more mCSPC patients initiated on APA attained PSA90 response than patients initiated on ENZ (p=0.014; Table). This result continued to remain significant at 9 months and at the end of the follow-up (Table). The median time to PSA90 was 3.1 months for APA patients and 5.2 months for ENZ patients. Conclusions: This real-world study of mCSPC cohorts demonstrates that initiation of APA leads to significantly more patients achieving a deep PSA response more rapidly than patients initiating ENZ. [Table: see text]

603P Objective computerized cognitive assessment in men with metastatic castrate-resistant prostate cancer (mCRPC) randomly receiving darolutamide or enzalutamide in the ODENZA trial

Darolutamide (Daro) and enzalutamide (Enza) are next generation androgen receptor inhibitors. Daro does not significantly penetrate the blood-brain barrier, which may reduce cognitive impairment. ODENZA is a prospective, cross-over, preference, randomized phase II trial of Daro and Enza in patients (pts) with mCRPC. Pts (n=249) were randomized 1/1 to receive Daro 1200 mg/d for 12 weeks followed by Enza 160 mg/d for 12 weeks or the reverse sequence. Numerically more pts with early mCRPC preferred Daro over Enza, although the difference did not reach significance (Colomba et al, ASCO 2021).

ODENZA: A French prospective, randomized, open-label, multicenter, cross-over phase II trial of preference between darolutamide and enzalutamide in men with asymptomatic or mildly symptomatic metastatic castrate-resistant prostate cancer (CRPC).

5046 Background: Darolutamide (Daro) and enzamutamide (Enza) are both next generation androgen receptor inhibitors with demonstrated activity in men with CRPC. Although both agents are associated with survival improvement, their toxicity profiles are different. To help decipher whether this may impact on patient preference, we designed the ODENZA trial. Methods: ODENZA is a prospective, randomized, open-label, multicenter, cross-over, phase II trial of preference between Daro and Enza in men with asymptomatic or mildly symptomatic metastatic CRPC. Patients were randomized 1/1 to receive Daro 1200 mg/d for 12 weeks followed by Enza 160 mg/d for 12 weeks (Daro-Enza arm) or the reverse sequence (Enza-Daro arm). In both arms, the second treatment was given in absence of evidence of cancer progression at week 12. The primary endpoint was patient preference between the two drugs, as assessed by a questionnaire at week 24. The Prescott's test was used to determine treatment preference in patients fullfilling pre planned criteria (exposure to both treatments, no progression at week 12, and completion of the preference questionnaire). A p-value greater than 0.05 indicates that there is no difference in preference between treatments. Stratification factors were performance status and prior taxane for mCSPC. After week 24, patients went on to an extension period during which they received the chosen treatment until progression or toxicity. The main secondary objectives included reasons for preference, response at week 12, cognitive assessment, and toxicity. Results: Overall 249 pts were randomized, median age 72y (68; 79), ECOG PS 0 (56%), prior taxanes (22%). Two hundred pts fulfilled the pre-planned criteria for evaluation of the preference primary endpoint : 97 (48.5% [41.3;55.7]), 80 (40.0% [33.0;47.0]), and 23 (11.5% [6.8;16.2]) chose Daro, Enza, and had no preference, respectively (unilateral p-value of 0.92). After preference assessment, 186 patients entered the extension period: 103 (55.4%) and 83 (44.6%) received Daro and Enza respectively. The most common factors influencing patient preference all numerically favored Daro over Enza, without significant differences were: less fatigue (44% vs 29%), ease of taking the medication (37% vs 31%), better quality of life (36% vs 28%), ability to be more active (26% vs 15%), ability to concentrate (22% vs 15%) and less falls (6% vs 3%). A PSA50 response was achieved in 76.2% and 83.9% at week 12 with Daro and Enza respectively (p = 0.13). Fatigue was the most frequently reported all grade adverse event at week 12, in 21% and 36% with Daro and Enza, respectively. Conclusions: More patients with early mCRPC preferred Daro over Enza, although the difference did not reach significance, with fatigue as the key influencing factor. Clinical trial information: NCT03314324.

Frequency, management, and resource use of adverse events (AEs) in nonmetastatic castrate-resistant prostate cancer (nmCRPC) patients receiving apalutamide or enzalutamide: A real-world study.

217 Background: Second generation androgen receptor inhibitors (SGARIs), apalutamide (APA) and enzalutamide (ENZ) and darolutamide, are approved in the United States (US) for the treatment of nmCRPC. The objectives of this study were to describe the frequency of AEs and actions taken to manage AEs among nmCRPC patients treated with APA or ENZ and their downstream resource implications. Methods: This is a further descriptive analysis of a retrospective chart review study conducted in 43 US nmCRPC-treating sites. In our sample, the 43 physicians identified 699 nmCRPC patients initiating treatment with APA (N = 368) or ENZ (N = 333) with 2 patients receiving both, between February 1, 2018 and December 31, 2018 and AEs were collected as reported in regular clinical practice. A representative subset of patients, experiencing at least 1 AE for either APA (N = 125) or ENZ (N = 125), were selected randomly from the initial cohort, and their detailed chart data were extracted to understand the actions taken to manage AEs. Results: Of the initial cohort of nmCRPC patients, 72.0% and 78.7% of men receiving APA (N = 368) and ENZ (N = 333) experienced ≥1 AE, respectively. The three most common AEs reported were fatigue/asthenia (APA, 30.2%; ENZ, 38.7%), hot flush (APA, 14.1%; ENZ, 13.5%), and arthralgia (APA, 14.4%; ENZ, 12.9%). Cognitive and mental changes were observed in 5.4% (APA) and 7.8% (ENZA) men. The subset analysis of randomly selected patients experiencing ≥1 AE (APA, 125; ENZ, 125) were mostly Caucasian (APA, 72.8%; ENZ, 71.2%), ECOG score 0-1 (APA, 84%; ENZ, 88%), median prostate specific antigen (PSA) value 13 ng/ml and 11 ng/ml (APA, ENZ; respectively). Actions to address AEs included treatment of AE, SGARI discontinuation, dose reduction and hospitalization (Table). Specifically, treatment discontinuation due to AE was observed in 8.0% (APA) and 12.8 (%) of men. AEs were often not resolved (APA, 43.6%; ENZ, 39.4%), and the median duration of days to resolve AEs were 60.0 for APA and 56.0 for ENZ. Conclusions: This real-world study highlights the clinical and resource use burden of AEs among nmCRPC patients treated with APA and ENZ. The results demonstrate the importance of safety and tolerability as key considerations in shared clinician-patient decision-making regarding SGARI therapy in nmCRPC. [Table: see text]

Severe-COVID-19 and mortality among patients (pts) with prostate cancer (PCa) receiving androgen deprivation therapy (ADT).

39 Background: The presence of progressing cancer, male sex and advanced age have been shown to increase the severity of coronavirus disease 2019 (COVID-19). Given that the androgen regulated gene TMPRSS2 has been implicated in SARS-CoV-2 viral entry, we hypothesized that ADT may improve COVID-19 outcomes. This analysis evaluated clinical outcomes of pts with PCa with concurrent SARS-CoV-2 infection and investigated the impact of ADT on occurrence of severe-COVID-19 and mortality. Methods: Data was obtained via the COVID-19 and Cancer Consortium (CCC19), a multicenter registry including >120 cancer centers with de-identified data from pts with COVID-19 and cancer. Men with confirmed SARS-CoV-2 infection and a primary diagnosis of prostate cancer were included: data cutoff of July 31, 2020. The primary endpoint was the development of severe-COVID-19 (death, ICU admission, or mechanical ventilation) among pts on ADT vs. those not on ADT at time of COVID-19 infection. Secondary endpoints included 30-day mortality based on ADT use. Mortality and development of severe-COVID-19 were assessed in Pts grouped by therapy: 1st generation androgen receptor inhibitor (ARI-1), 2nd generation ARI (darolutamide, enzalutamide, apalutamide, ARI-2), abiraterone/prednisone, and chemotherapy. Propensity score matching was utilized. Logistic regression was utilized to adjust for age, ECOG PS, comorbidities, and race. Results: 589 pts were included; median follow-up was 42 days (IQR 25-90) and 62% (363/589) were hospitalized. Severe-COVID-19 developed in 28% of pts and the all-cause 30-day mortality rate was 19%. There was no significant difference in the development of severe-COVID-19 or 30-day mortality between Pts on ADT vs not on ADT, whether using descriptive statistics with the entire population or using the propensity score matched population (Table). Among the descriptive population, the numerical rates of severe-COVID-19 and mortality were lowest in Pts receiving ARI-2, but sample size was low. Conclusions: The overall 30-day mortality rate and percentage developing severe-COVID-19 were high. There was no statistical difference in the development of severe-COVID-19 or mortality based on receipt of ADT; however, this analysis is limited by the retrospective nature and small N after propensity-matching. [Table: see text]

GABARAPL1 Promotes AR+ Prostate Cancer Growth by Increasing FL-AR/AR-V Transcription Activity and Nuclear Translocation.

The next generation Androgen receptor (AR)-targeted therapies are now in widespread clinical use and prolong prostate cancer (CaP) patient survival. However, the therapies are not curative due to diverse range of resistance mechanisms. AR variants (AR-V), one major mechanism of resistance, has recently gained momentum. Here, we found that GABARAPL1 knockdown inhibits the growth of AR-positive LNCaP and CWR22rv1 CaP cells in vitro and in vivo, decreases AR/AR-V transcription activity and AR nuclear translocation. Pulldown assay shows that both of Full-length (FL)-AR and AR-V were able to interact with GABARAPL1, suggesting that GABARAPL1 may play its role through directly scaffolding AR. The further analysis from Oncomine database showed that negative correlation between GABARAPL1 expression and 5-years survival in CaP cases. Our findings have identified GABARAPL1 as critical regulator of FL-AR/AR-V, suggesting the potential benefit of targeting GABARAPL1 to treat AR-positive CaP that is resistant to next generation AR inhibitors.

Enzalutamide: A Review in Castration-Resistant Prostate Cancer.

Oral enzalutamide (Xtandi®), a second generation androgen receptor inhibitor, is indicated for the treatment of castration-resistant prostate cancer (CRPC) in numerous countries worldwide, with specific indications in this patient population varying between individual countries. Based on extensive experience in the clinical trial and/or real-world settings, oral enzalutamide 160 mg once daily is an effective and generally well tolerated treatment in a broad spectrum of patients with CRPC, including in nonmetastatic and metastatic disease and in chemotherapy-naive and -experienced metastatic CRPC. Enzalutamide is an emerging option for the treatment of men with nonmetastatic CRPC who are at high-risk for developing metastatic disease, and remains an important first-line option in chemotherapy-naive or -experienced patients with metastatic CRPC.

Abstract 1775: Development of fully humanized N-cadherin monoclonal antibodies for treatment of castration resistant prostate cancer

Abstract Enzalutamide (ENZ) is an androgen receptor (AR) antagonist that targets various stages of the AR signaling pathway, and approved for the treatment of castration resistant prostate cancer (CRPC). Studies show increased survival in men with metastatic CRPC after chemotherapy when treated with ENZ. However, emergence of potential AR-independent mechanisms of castration resistance and resistance to these next generation AR inhibitors has proven to be a challenge. Previously, we reported an association of N-cadherin, a mesenchymal cadherin expressed on the cell surface, with tumor progression and castration resistance and resistance to AR inhibitors may lead to increase in N-cadherin. Targeting N-cadherin positive cells with specific monoclonal antibodies (mAb) affect tumor growth in both AR positive and negative prostate cancers. Co-targeting AR and N-cadherin with ENZ and mAb respectively show promise in addressing not only castration resistant tumor progression but also ENZ resistance. Ectopic expression of N-cadherin in N-cadherin negative cells enhanced cell growth and invasion in androgen-deprived conditions. Endogenously expressing N-cadherin prostate cancer cell lines (PC3, LAPC9) and androgen dependent prostate cancer cells ectopically expressing N-cadherin (LNCaP, MDA-PCa-2b, VCaP) were evaluated in vitro for invasion, growth, and self-renewal in the presence of monoclonal antibodies raised against various extracellular domains of N-cadherin and their effects in combination with ENZ. In vivo studies on promising candidates were performed using castration resistant N-cadherin and AR positive, as well as androgen-dependent tumors implanted subcutaneously in mice as xenografts. The tumors were analyzed for response to ENZ, mAb alone, or in combination. At end-point, tumors were harvested and further analyzed. Final candidate mAbs were then selected and re-formatted into fully humanized N-cadherin monoclonal antibodies and further evaluated. A molecular model of the mouse chimeric antibodies were built based on structure of similar antibodies and the CDR loops were grafted to the human framework region and back-translated into nucleotide sequences. Codon-optimized DNA encoding the humanized variable domains connected by a 15 glycine-rich amino acid linker was synthesized by GeneArt and sub-cloned into expression vectors containing light and heavy chain constant regions. Clones were then screened and selected. Candidates were transiently expressed in 293 cells and supernatant were collected and purified for further analysis. These newly generated humanized mAbs engineered from the promising human anti-mouse N-cadherin antibody candidates exhibited similar outcomes to their chimeric counterparts, revealing potential in providing methods for diagnosis and treatment of advanced diseases. Citation Format: Evelyn A. Kono, Naoko Kobayashi, Kirstin Zettlitz, Keyu Li, Joyce Yamashiro, Chun Wang, Anna Wu, Robert E. Reiter. Development of fully humanized N-cadherin monoclonal antibodies for treatment of castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1775.

Drug Resistance of Enzalutamide in CRPC.

Enzalutamide (MDV3100, XTANDI) is a second generation androgen receptor inhibitor that is designed for the treatment of castration-resistant prostate cancer (CRPC) and has prolonged survival time. The mechanisms of mdv3100 resistance have not yet been clearly clarified and the majority of treated patients, innate or acquiring resistance invariably arises. The purpose of this review is to summarize the main data available on the mechanisms of resistance to mdv3100. Understanding how the resistance aroused may have clinical implications in underlying the usefulness of prognostic and predictive biomarkers in daily practice and improving the strategies. Resistance to MDV3100 could be basically divided into two distinct pathways, either dependent or independent of the androgen receptor activity. Androgen receptor (AR) axis is sitll the most important pathway for prostate cancer cells and it is still currently regarded as a critical resistant mechanism. Targeting these newly identified signals, especially AR axis, could be potentially overcome through novel therapeutic agents, synergically improve the ADT in CRPC.

Efficacy of additional chemotherapy following failure of currently approved therapies in patients with castration-resistant prostate cancer.

274 Background: Approved therapies for patients with castration resistant prostate cancer (CRPC) include next generation androgen receptor inhibitors as well as taxanes which are given sequentially. After failure of these drugs, physicians may use additional chemotherapy such as carboplatin, paclitaxel, mitoxantrone and vinorelbine. The clinical benefit of these drugs in this setting remains fully unknown. Methods: A retrospective monocentric study of patients treated for CRPC was performed. Presence of metastasis and visceral involvement at diagnosis and at castration resistance, time between start of hormonotherapy and castration resistance were recorded as well as several clinical and biological parameters at start of CRPC first line. The cohort was divided into two groups according to the use of additional chemotherapies following failure of currently approved therapies. Results: Fourty subjects out of 138 cases (28.9%) fulfilled the inclusion criteria. At diagnosis, median patients age was 68 years (range, 53-86), median Gleason grade was 8 (6-10) and 53% of them harbored distant metastasis. At castration-resistance stage, 93% were metastatic including 27% out of them wihich harbored visceral involvement. Median overall survival (OS) of patients since castration-resistance was 34.9 months (range, 7.4-88.0). The two groups were comparable in terms of age, PSA level, and Gleason grade. Median OS for patients in the additional chemotherapy group (n = 16) was 42.4 months as compared to 37.3 months in the non additional treatment group (n = 24), with no statistical difference (p = 0.961). Main treatments administered consisted of carboplatin (n = 6), paclitaxel (n = 4) and mitoxantrone (n = 4). PSA response rate (decrease > 50%) obtained with use of additional treatment was 12%. Median progression-free survival was 1.9 months (range, 0.7-13.1) and median overall survival was 4.2 months (range, 2.2-17.8). Conclusions: Our retrospective study suggests that additional treatment after standard treatment failure for CRPC is associated with limited benefit. Further studies are needed to clarify the role of new agents therapies in this setting.

Abstract 3342: Galiellalactone derivative targets stem cell population in ENZ-resistant prostate cancer through inhibition of STAT3

Abstract Background: Androgen ablation remains the most effective therapy for patients with advanced disease. Unfortunately, most patients progress to castrate resistant prostate cancer (CRPC) characterized with hyper-activation of the androgen receptor (AR). Enzalutamide, a potent AR inhibitor showed efficacy by prolonging survival in CRPC patients. However, ENZ resistance (ENZR) rapidly occurs in patients and in our pre-clinical model targeting AR in ENZ resistant tumors with a 3rd generation AR inhibitor is short lived. The role of signal transducer and activator of transcription (STAT) 3 in the progression of prostate cancer is well established and has been repeatedly linked with maintenance of a stem cell phenotype across cancers. Additionally, drug resistance has been hypothesized to occur via enrichment of cancer stem-like cells (CSC), a phenotype associated with poor survival in patients. Therefore, we propose a shift of focus to target CSC phenotype using small molecule inhibitor of STAT3 called GPA500, instead of the AR axis to deal with ENZ resistance. Methods and Results: We developed a unique model of ENZ-resistance and found that cell lines derived from serially passaged ENZR tumors displayed broad genetic diversity and differential AR activity. Notably, the cell lines 42DENZR and 42FENZR are PSAlow, harbor an expanded CSC population and have STAT3 hyper-activation compared to CRPC controls measured by STAT3-luc reporter. Accordingly, Crystal Violet and MTT proliferation assays showed that 42DENZR and 42FENZR cell lines were more sensitive to the STAT3 inhibitor GPA500 compared to CRPC control. Targeting the ENZ-R cells with GPA500 reduced mRNA levels of CD133, CD44, SOX2, OCT4 and Nanog. The reduction of these CSC markers was accompanied by reduced self-renewal capacity measured by spheroid assay. Cytometry analysis revealed that treatment with GPA500 reduced α2β1+, CD44+ and CD133+ (CSC) population in the 42D and 42F cells. Conclusion: In this study, we provide pre-clinical proof that targeting the STAT3 pathway using GPA500 in ENZ resistance as well as CRPC reduces cell proliferation as well as expression of stem cell markers. Impact: Exploring mechanisms of ENZR resistance serves a critical unmet need in PCa oncology, as the number of men with ENZ resistant CRPC continues to rise. Targeting STAT3 with the small molecule inhibitor GPA500 may provide an effective method to treat ENZR patients or delay the emergence of ENZ resistance in CRPC by reducing the emergence of stem cells. Citation Format: Sepideh Vahid, Daksh Thaper, Alistair Davies, Micaela Janse Van Rensburg, Kate Gibson, Krisi Ketola, Martin Johansson, Jennifer L. Bishop, Amina Zoubeidi. Galiellalactone derivative targets stem cell population in ENZ-resistant prostate cancer through inhibition of STAT3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3342.

Correlation of baseline serum testosterone (T) and serum prostate-specific antigen (PSA) at 7 months (7 mo PSA) in patients (pts) with new hormone sensitive metastatic prostate cancer (mHSPC) treated with continuous androgen deprivation therapy (cADT).

231 Background: Based on data from > 1,000 men with new mHSPC undergoing ADT in the SWOG-9346 study, a failure to achieve a 7 mo PSA of ≤4 ng/mL, is a powerful negative predictor of survival (Hussain et al., JCO 2006). Following baseline clinical variables predicted lack of achieving 7 mo PSA ≤ 4.0 ng/mL: increased age, PSA, and bone pain, poor performance status, and Gleason sum ≥ 8. We hypothesized that the baseline serum T is also an independent predictor of 7 mo PSA. Methods: Eligible pts were identified from an institutional database. The association of baseline clinical and disease characteristics with 7 mo PSA were analyzed using multivariate regression model (Table). Results: 54 pts were eligible for inclusion. 44% achieved undetectable 7 mo PSA, and 25% had a 7 mo PSA ≥ 4 ng/mL suggesting a representative population, similar to that in the SWOG-9346 study. Significant association between covariates and 7 mo PSA was observed (Prob > F = 0.0107; R2 = 0.404). Baseline serum T and PSA were independent predictors of 7 mo PSA. Baseline serum T, as a continuous variable, showed negative correlation with 7 mo PSA, while baseline PSA showed a positive correlation (Table). Conclusions: Baseline serum T independently predicts 7 mo PSA. Pts with new mHSPC with lower baseline T may have improved outcomes with deeper androgen blockade with ADT along with a 17,20-lyase and 17-alpha-hydroxylase inhibitor or a second generation androgen receptor inhibitor at the time of induction. Data need further validation in a larger cohort. [Table: see text]