Citations

192 Background: In the setting of disease progression of metastatic castrate resistant prostate cancer (mCRPC) on docetaxel, abiraterone acetate (AA) and enzalutamide are two commonly used second line therapies with data demonstrating survival benefits. Less is known about patient specific factors that contribute to success with these therapies. The objective of this study is to improve patient selection for post-docetaxel second generation hormone therapy (AA or enzalutamide) by evaluating whether overall metastatic burden is associated with treatment response in this setting. Methods: By retrospective chart review, patients with mCRPC treated with AA or enzalutamide following docetaxel failure (defined as PSA rise and radiographic progression) were identified. Patients were categorized into low volume and high volume metastatic disease based on the number of pre-treatment metastatic lesions; where low volume disease describes patients with ≤ 5 metastatic lesions (e.g. oligometastatic disease), and high volume disease represents patients with > 5 individual lesions. The primary endpoint was cancer-specific mortality and the secondary endpoint was radiographic progression free survival. Median follow-up time was 29.5 months. Results: 75 patients were identified and included in our analysis: 39 with high volume metastatic disease, and 36 with low volume metastatic disease. Baseline characteristics of age and pre-treatment ECOG were not statistically different between these groups. Pre-treatment high-volume disease burden was significantly associated with increased risk of radiographic disease progression (HR 4.21, 95%CI 1.97-8.99, p < 0.0001) and cancer specific mortality (HR 5.84, 95% CI 1.58-21.53, p = 0.0026) during treatment with second generation androgen deprivation therapy. Conclusions: High volume metastatic disease burden is associated with significantly increased cancer specific mortality and decreased progression free survival for patients on second line therapy with AA or enzalutamide following docetaxel treatment failure.

189 Background: The objective of this study is to evaluate the prognostic value of early PSA decline following initiation of second-generation hormone therapy (2nd HT), namely abiraterone acetate or enzalutamide, in the post-chemotherapy setting in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods: We retrospectively identified 75 m-CRPC patients treated with 2nd HT following docetaxel failure (defined as PSA rise and radiographic progression). Patients were categorized into two groups based on first PSA within 3 months after initiation of therapy: PSA reduction ≥ 50% (Group A) and PSA reduction < 50% (Group B). The primary endpoint was cancer-specific mortality and the secondary endpoint was radiographic progression free survival. Results: There were 75 patients (52 in group A, 23 in group B) in the analytic cohort. Baseline clinical and demographic characteristics, including median age, primary Gleason score risk group, median pre-treatment PSA, disease burden, site of metastases, and pre-treatment ECOG score were not statistically different between the two groups. PSA reduction ≥50% was significantly associated with decreased risk of radiographic disease progression (HR 0.41, 95%CI 0.21-0.80, p = 0.0113) as well as decreased risk of cancer-specific mortality (HR 0.29, 95%CI 0.09-0.87, p = 0.0325). Conclusions: PSA reduction ≥50% within 3 months of starting 2nd HT for patients with mCRPC who have failed first-line docetaxel is associated with significantly improved 3-year cancer-specific mortality and progression free survival. Our data supports the use of PSA as an early prognosticating marker for patient outcomes on this second line therapy. [Table: see text]

125 Background: Assessments of financial toxicity among patients with metastatic prostate cancer are lacking. We sought to describe the prevalence and severity of financial toxicity, identify coping mechanisms, and assess characteristics that may be protective of financial toxicity among such patients at our institution. Methods: All patients evaluated in the advanced prostate cancer clinic at Mayo Clinic, Rochester, MN, were approached to complete a survey between February and May 2022. The survey consisted of three parts: 1) demographic, cancer, and treatment characteristics; 2) a coping mechanism questionnaire; and 3) The Comprehensive Score for Financial Toxicity (COST-FACIT) questionnaire. COST-FACIT scores range from 0-44, with lower scores signifying higher financial toxicity. Patients were defined as having either high (COST-FACIT score >24) or low (COST-FACIT score ≤24) financial toxicity. Coping mechanisms were compared between patients with low and high financial toxicity using Fisher’s exact test. Multivariable linear regression was used to evaluate patient characteristics associated with high COST-FACIT scores. Results: Of the 786 patients approached, 417 (53.1%) completed the survey and 281 met inclusion criteria. The median COST-FACIT score was 30 (IQR 24-36). On multivariable analysis, characteristics associated with lower financial toxicity included older age, (estimate:0.36, 95%CI 0.21-0.52), applying for patient assistance programs (estimate:4.42, 95%CI 1.72-7.11), and an annual income of at least $100,000 (estimate:7.81, 95%CI 0.97,14.66). Patients with high financial toxicity were more likely to decrease spending on basic goods (34.6% vs. 2.5%, p<0.001) and leisure activities (61.5% vs. 16.9%, p>0.001), as well as use savings (61.5% vs. 16.9%, p<0.001) to pay for their treatment. However, few patients stopped or partially filled their prostate cancer treatments due to cost. Conclusions: In this cross-sectional study of patients with metastatic prostate cancer, older age, higher income, and applying for patient assistance programs were associated with lower financial toxicity. Greater self-reported financial toxicity was associated with decreased spending on basic goods, leisure activities, and tapping into savings. On rare occasion they delayed or skipped treatment. These findings are important to inform treatment shared decision-making and supportive interventions to mitigate financial toxicity in metastatic prostate cancer.

Abstract We utilized CD11a, an integrin up-regulated on effector and memory CD8+ T cells, as a biomarker to identify, measure, and monitor endogenous tumor-reactive cytotoxic lymphocytes (CTLs) in two mouse tumor models and in melanoma patients. CD11ahigh CD8+ T cells were detected in primary and metastatic tumor sites after tumor cell injection, as well as in spontaneous murine breast cancer tissues. In the peripheral blood of melanoma patients, tumor antigen-specific T cells were detected within the population of CD11ahigh CD8+ T cells that express high levels of PD-1. Infusion of lethally irradiated tumor cells failed to stimulate the expansion of CD11ahigh CD8+ T cells, suggesting that the access of tumor cells to target tissues is required to induce CD11ahigh CD8+ T cell responses. Phenotypic analysis revealed that the CD11ahigh CD8+ T cells detected in our studies were proliferating (Ki67+) activated T cells (CD62L-, CD69+). Although CD11ahigh CD8+ T cells were differentiated effector cells with CTL effector functions, they were typically unable to control tumor growth in our mouse models, possibly due to high expression of PD-1. Our results demonstrate that CD11a can be used as a biomarker to identify and track endogenous tumor-reactive CTLs.

AbstractBackgroundProstatic specific antigen (PSA) has well‐recognized limitations as a marker for treatment response and disease progression. Post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve metastatic castration‐resistant prostate cancer (mCRPC) patients on enzalutamide had radiographic progression on conventional imaging with nonrising PSA. In this study, we sought to study the discordance of imaging with PSA kinetics in mCRPC patients on second generation anti‐androgens (SGA) post‐chemotherapy using combined conventional imaging, and new generation imaging in the form of C‐11 choline positron emission tomography/computed tomography (C[11] choline PET/CT) scan.MethodsWe retrospectively reviewed the medical records of 123 patients with mCRPC treated with SGA (Abiraterone or Enzalutamide) after docetaxel between 2016 and 2019. Patients underwent PSA testing, and C[11] choline PET/CT scan at baseline level before starting treatment with SGA, then every 3–6 months as part of their follow up evaluation. Loss of response to SGA was defined by increase in corrected maximum standardized uptake value (SUVmax) of pretreatment lesions on C‐11 Choline PET/CT, and/or development of new lesions. Suspicious new lesions were confirmed by biopsy and/or conventional imaging.ResultsWe identified 123 mCRPC patients who received SGA (Abiraterone, n = 106; Enzalutamide, n = 17) after docetaxel. Median duration of therapy was 13.9 months (interquartile range: 8.75–21.14). Approximately 43% (n = 53) of subjects in this study exhibited an increase in choline avidity while on SGA. Of this group, 60.4% of patients experienced a parallel rise in PSA (Group‐A), whereas 39.6% displayed a paradoxical response (PR) (Group‐B), defined as increased choline avidity combined with stable or down‐trending PSA. Median PSA at time of increase in choline avidity was 3.1 ng/ml for Group‐A, and 1.3 ng/ml for Group‐B (p = 0.0176). Median SUVmax was similar in both groups (4.9 for Group‐A, 4.6 for Group‐B; p = 0.6072). The median time for increase in choline avidity was 9.5 versus 3.9 months for Group‐A versus Group‐B, respectively (Log‐Rank = 0.0063).ConclusionNearly 40% of mCRPC patients placed on SGA post docetaxel chemotherapy will exhibit paradoxical responses to therapy, therefore, warranting close follow up with imaging. C‐11 choline PET/CT imaging is a useful tool that can help in early predication of disease progression or treatment failure.

Abstract NRG-1 signals through epidermal growth factor receptor (EGFR) family members. Despite promising preclinical data, HER2 blockade in prostate cancer has failed to improve outcomes in clinical trials.1-4 We have discovered a novel complex systemic role of NRG-1 that drives sensitivity and resistance to androgen deprivation therapy (ADT) in castration-sensitive (CSPC) and castration resistant prostate cancer (CRPC), respectively. Significantly, sensitivity to ADT can be restored in CRPC by manipulating NRG-1 signaling. Our data posit NRG-1 as a systemic “switch” in prostate cancer. Plasma NRG-1 is elevated in our cohort of patients with metastatic CRPC (mean 4.9ng/ml) versus healthy controls (mean 3.2ng/ml, p&lt;0.0001) or metastatic CSPC (mean 3.4ng/ml, p&lt;0.0001). Paradoxically, high systemic NRG-1 predicted superior OS and PFS in CSPC but inferior clinical outcomes in CRPC. Consistently, opposite cell survival between LNCaP (CSPC) vs Du145 & PC3 (CRPC) was observed with recombinant human NRG-1 and enzalutamide (ENZ). ENZ combined with increasing NRG-1 concentration induced LNCaP cell death in an additive manner, but NRG-1 rescued Du145 & PC3 from ENZ-induced death in a dose-dependent manner. We next hypothesized that differential NRG-1 downstream signaling is mediated by engagement with distinct EGFR receptor dimers. While HER2 expression is similar, LNCaP express higher HER3 than Du145 & PC3. High ratio of HER2 to HER3 in Du145 & PC3 mirrors clinical reports of HER2 upregulation in CRPC5,6 and also predicts patient survival in the Stand Up to Cancer cohort.7 Significantly, we recapitulated the CRPC phenotype in LNCaP by inducing HER2 overexpression, HER3 suppression, and chemically-mediated HER2/HER3 dimerization. Conversely, HER2 knockdown sensitized Du145 cells to ENZ. Next, we queried composite single-cell whole human8 and CRPC9 transcriptomes for NRG-1 expression and discovered that the source of NRG-1 is the patients’ own mesenchymal stem cells (MSCs). Bone-derived MSC outgrowth cells produced copious NRG-1, which was increased substantially by coincubation with prostate cancer cell supernatants. Importantly, we were able to manipulate MSCs to reduce their NRG-1 production as a possible clinical translation. Similarly, patients treated with these compounds showed significant reduction in plasma NRG-1 levels after treatment. Additional clinical studies are pending. Together, our observations confirm that NRG-1 has differential signaling: HER3 homodimerization leads to prostate cancer cell death, whereas heterodimerization of HER3 with HER2 leads to prostate cancer cell survival via ADT resistance in a plasma NRG-1 dependent manner. Consequently, HER2 and HER3 receptor availability determine the molecular switch of NRG-1 in prostate cancer. Therefore, NRG-1 can be both a prognostic marker and therapeutic target in CRPC, and multiple clinical trials are pending. Citation Format: Jacob Orme, Roman Thaler, Dejie Wang, Siven Chinniah, Jacob Hirdler, Fernando Quevedo, Lance Pagliaro, Kwon Eugene, Alan Bryce, Brian Costello, Haojie Huang, Sean Park. Mesenchymal stem cell-derived systemic NRG-1 mediates a targetable molecular switch in metastatic prostate cancer [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 397.