Black Patients with Metastatic Castrate-Resistant Prostate Cancer Have a Shorter Time Interval Between PSA and Clinical Progression on Novel Hormonal Therapies plus Avelumab.

BACKGROUND: Black men are at higher risk for prostate cancer death. Previous studies showed a benefit of different therapies, including immune-based therapy, for Black men with metastatic prostate cancer. We sought to explore the efficacy of the PD-L1 inhibitor avelumab in Black men with metastatic castrate-resistant prostate cancer (mCRPC) progressing after abiraterone or enzalutamide. METHODS: This pilot phase II study enrolled self-identified Black patients who developed mCRPC on next-generation hormonal therapies (NHTs) abiraterone acetate or enzalutamide (NCT03770455). Enrolled patients received avelumab 10mg/kg IV every 2 weeks while remaining on the same NHTs. The primary endpoint of our study was ≥ 50% reduction in prostate specific antigen (PSA) at ≥8 weeks. RESULTS: A total of eight patients were enrolled. The median duration on NHTs prior to enrollment was 364 days (95% CI, 260.9-467.1). The median time to initiate avelumab was 8 days (3-14). With a median follow-up of 196 days, no patients achieved the primary endpoint. The median time to PSA progression was 35 days (95 CI%, 0-94.8) and the median time to radiographic and/or clinical progression was 44 days (95 CI%, 0-118.5). The study was closed prematurely due to safety concerns related to the rapid clinical progression observed in the patients enrolled on study. CONCLUSION: In conclusion, the addition of avelumab to NHT did not demonstrate clinical activity in Black men with new mCRPC. The unexpected short interval between PSA and radiographic and/or clinical progression observed in this study has potential clinical implications.ClinicalTrials.gov Identifier: NCT03770455 (IND number 139559).

Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.

BACKGROUND: The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations. METHODS: African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed. RESULTS: A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely-pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non-BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African-Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men. CONCLUSIONS: In metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non-BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.

Changes in taste and smell of food during prostate cancer treatment.

PURPOSE: The present study examined the prevalence of changes in the taste and smell of food among men with advanced prostate cancer who were receiving hormone therapy and/or chemotherapy. METHOD: Participants were 75 men with advanced prostate cancer treated at an academic medical center. They completed a prospective survey about nausea while eating, taste and smell of food, and appetite periodically during a mean of 1.3 years of follow-up. Demographics, treatments, and weight data were extracted from electronic health records. Logistic regression analyses were used to examine the associations between the presence of the symptoms surveyed, treatments, and weight loss of ≥10%. RESULTS: Participants experienced poor taste of food (17%) and poor smell of food (8%) during the study. Nausea was associated with an increased likelihood of experiencing poor taste (50.0% v 12.3%, OR=7.13, P=.008) and smell (30.0% v 4.6%, OR=8.86, P=.016) of food. Poor taste of food was associated with an increased likelihood of experiencing poor appetite (35.0% v 10.9%, OR=12.43, P<.001). Participants were more likely to experience poor taste of food at any point in the study if they were being treated with denosumab (35.0% v 10.9%, OR=4.40, P=.020) or docetaxel (41.7% v 12.7%, OR=4.91, P=.022). Participants were more likely to experience ≥10% weight loss if experiencing poor taste of food (38.4% v 8.6%, OR=6.63, P=.010) or poor appetite (60.0% v 6.6%, OR=21.38, P<.001). CONCLUSION: Clinicians should query patients for changes in taste and smell of food, especially if they are experiencing weight loss.

Randomized Phase II Trial of Sipuleucel-T with or without Radium-223 in Men with Bone-metastatic Castration-resistant Prostate Cancer.

PURPOSE: To investigate whether radium-223 increases peripheral immune responses to sipuleucel-T in men with bone-predominant, minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: A total of 32 patients were randomized 1:1 in this open-label, phase II multicenter trial. Patients in the control arm received three sipuleucel-T treatments, 2 weeks apart. Those in the combination arm received six doses of radium-223 monthly, with sipuleucel-T intercalated between the second and fourth doses of radium-223. The primary endpoint was a comparison of peripheral antigen PA2024-specific T-cell responses (measured by proliferation index). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and PSA responses. RESULTS: We enrolled 32 patients, followed for a median of 1.6 years. Six weeks after the first sipuleucel-T dose, participants in the control arm had a 3.2-fold greater change in PA2024-specific T-cell responses compared with those who received combination treatment (P = 0.036). Patients in the combination arm were more likely to have a >50% PSA decline [5 (31%) vs. 0 patients; P = 0.04], and also demonstrated longer PFS [39 vs. 12 weeks; HR, 0.32; 95% confidence interval (CI), 0.14-0.76] and OS (not reached vs. 2.6 years; HR, 0.32; 95% CI, 0.08-1.23). CONCLUSIONS: Our data raise the possibility of greater clinical activity with the combination of sipuleucel-T and radium-223 in men with asymptomatic bone mCRPC, despite the paradoxically lower immune responses observed. Additional study to confirm these findings in a larger trial is warranted.

Outcomes With First-Line PD-1/PD-L1 Inhibitor Monotherapy for Metastatic Renal Cell Carcinoma (mRCC): A Multi-Institutional Cohort.

Introduction: The treatment landscape of metastatic renal cell carcinoma has advanced significantly with the approval of combination regimens containing an immune checkpoint inhibitor (ICI) for patients with treatment-naïve disease. Little information is available regarding the activity of single-agent ICIs for patients with previously untreated mRCC not enrolled in clinical trials. Methods: This retrospective, multicenter cohort included consecutive treatment-naïve mRCC patients from six institutions in the United States who received ≥1 dose of an ICI outside a clinical trial, between June 2017 and October 2019. Descriptive statistics were used to analyze outcomes including objective best response rate (ORR), progression-free survival (PFS), and tolerability. Results: The final analysis included 27 patients, 70% men, median age 64 years (range 42-92), 67% Caucasian, and 33% with ECOG 2 or 3 at baseline. Most patients had intermediate risk (85%, IMDC) with clear cell (56%), papillary (26%), unclassified (11%), chromophobe (4%), and translocation (4%) RCC. All patients had evidence of metastatic disease involving the lungs (59%), lymph node (41%), CNS (19%), liver (11%), adrenal gland (11%), and bone (11%). The median time on ICI was 3.1 (0.1-26.8) months, and the median PFS was 6.3 (95% CI, 0-18.6) months. Among the 21 patients with an evaluable response, the best ORR was 33%, including two complete responses and five partial responses. The ORR was 29% (n = 1 complete response, n = 5 partial response) in clear cell and 5% (n = 1 complete response) in non-clear cell RCC. Adverse events (AEs) of any cause were reported in 37% and included fatigue (11%), dermatitis (11%), diarrhea (7%), and shortness of breath (7%). Significant AEs (30%) included shortness of breath (7%), acute kidney injury (4%), dermatitis (4%), Clostridium difficile infection (4%), cerebrovascular accident (4%), and fatigue (7%). Three patients discontinued therapy due to grade 4 AEs. Conclusions: In this multi-institutional case series, single-agent ICI demonstrated objective responses and was well tolerated in a heterogeneous treatment-naïve mRCC cohort. ICI monotherapy is not the standard of care for patients with mRCC, and further investigation is necessary to explore predictive biomarkers for optimal treatment selection in this setting.

Circulating-tumor DNA as predictor of enzalutamide response post-abiraterone treatment in metastatic castration-resistant prostate cancer.

BACKGROUND: The crossover from abiraterone acetate (AA) to enzalutamide (ENZA) is a frequent approach in clinical practice. Our aim was to explore the role of genomic alterations as putative biomarkers of response to sequential AA followed by ENZA in mCRPC and their association with clinical outcomes. PATIENTS AND METHODS: This was a multi-center, retrospective analysis of mCRPC patients with circulating-tumor DNA (ctDNA) post-AA and prior to ENZA treatment. Objectives of this analysis were to assess PSA response, time to PSA progression (TTP) and overall survival (OS) in mCRPC patients treated with ENZA following progression on AA with respect to genomic aberrations detected by ctDNA. RESULTS: A total of 28 patients with mCRPC were identified. Median time between AA and ENZA was 3.1 months and median initial PSA prior to ENZA was 35.0 ng/mL. Nine patients (32.1%) achieved PSA responses to ENZA. Most patients (79.0%) achieved confirmed PSA progression with median TTP of 1.6 months (95% CI, 0.7-2.4). Somatic alterations in AR genes were detected in 36.0% of patients with other common alterations detected including 39.0% TP53, 11.0% DNA repair, and 11.0% PTEN. A lack of AR alterations was associated with better PSA response to ENZA (p = 0.04). CONCLUSION: While lack of AR alterations in ctDNA was associated with more favorable outcomes, the present dataset is insufficient to recommend the use of ctDNA to impact clinical decision-making in this setting. Further understanding of the implications of the genomic phenotype in ctDNA of castration-resistant tumors and the potential therapeutic implications is required.

Evaluation of the genomic alterations in the androgen receptor gene during treatment with high-dose testosterone for metastatic castrate-resistant prostate cancer.

INTRODUCTION: Castration resistant prostate cancer (CRPC) has been characterized by a reactivation of the androgen receptor (AR) signaling pathway via alterations in androgen metabolism and AR aberrations. High-dose testosterone (HDT) is emerging as an active treatment in metastatic CRPC, however, biomarkers of response are unknown. We hypothesized that responses to HDT might impact the genomic expression of AR alterations found in circulating-tumor DNA (ctDNA). METHODS: Retrospective analysis of mCRPC patients treated with HDT (testosterone cypionate q 2-4 weeks) with available clinical and somatic genomic data using a commercially available assay (Guardant360, Redwood City, CA). Clinical outcomes included PSA response (PSA50), time to PSA progression (TPP) and safety. RESULTS: A total of 33 mCRPC patients were treated with ≥2 testosterone cypionate injections. ctDNA testing revealed alterations in AR (39%), TP53 (48%), and DNA repair genes (12%). HDT was given for median of 4.0 months (95% CI, 2.6-5.3) with 24% of PSA50. Twenty patients were re-challenged with abiraterone (n = 2) or enzalutamide (n = 18) with 30% PSA50. Significant (grade ≥3) adverse events were observed in 5% of patients (grade 4 thrombocytopenia and asthenia). Patients with median baseline ctDNA% of ≥1.10 had numerically worse TPP outcomes and all patients with AR alterations exhibited decreased AR expression post-HDT (n = 9), yet no association between clinical outcomes and ctDNA findings was observed. CONCLUSIONS: HDT led to a decrease in AR copy number and mutations which was independent from responses to therapy. Further understanding of the genomic alterations as potential predictor of response to HDT is needed.

TP53 Gain-of-Function Mutations in Circulating Tumor DNA in Men With Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Circulating tumor DNA (ctDNA), which can be assessed by liquid biopsy, can provide valuable genomic information that may affect treatment response in prostate cancer. The aim of this study was to characterize TP53 mutations and treatment history in prostate cancer. PATIENTS AND METHODS: This study included 143 patients with metastatic castration-resistant prostate cancer who had undergone ctDNA sequencing via Guardant360 testing. The presence or absence of TP53 mutations was analyzed along with treatment history for this group. TP53 mutations were further classified as gain of function (GOF) or not GOF, and analyzed with prior therapies. RESULTS: Chi-square analysis was performed for treatment history and TP53 status (further specified as all TP53 mutations or only TP53 GOF mutations). There were no associations between prior receipt of abiraterone/enzalutamide therapy and all TP53 mutations, or between docetaxel therapy and all TP53 mutations. However, TP53 GOF mutations had a positive association with prior abiraterone/enzalutamide therapy (P = .047). There was no association of TP53 GOF mutations with prior docetaxel therapy. The most frequent alterations co-occurring with all TP53 mutations were in AR, BRAF, EGFR, MYC, and PIK3CA. Common coalterations with TP53 GOF mutations included AR, BRAF, EGFR, RB1, NF1, and PIK3CA. There was an association of RB1 mutations with TP53 GOF mutations, versus RB1 mutations and no TP53 GOF mutations (P = .0036). CONCLUSION: TP53 GOF mutations may provide a valuable pathway to delineate metastatic castration-resistant prostate cancer TP53 mutations into therapeutic categories. Association with disease progression while receiving abiraterone/enzalutamide therapy was apparent in this study; however, further studies are needed to elaborate the therapeutic and prognostic implications.

Early prostate-specific antigen response post-abiraterone as predictor of overall survival in metastatic castrate-resistant prostate cancer.

BACKGROUND: Abiraterone is an important agent in the treatment of advanced prostate cancer. Early changes in prostate-specific antigen while on abiraterone in patients with metastatic castrate-resistant prostate cancer potentially have financial and health implications for patients. Limited data is available on early prostate-specific antigen change and subsequent survival given phase III trials did not measure prostate-specific antigen changes before 12 weeks. METHODS: A single-center retrospective study was performed. Metastatic castrate-resistant prostate cancer patients treated with abiraterone (without prior enzalutamide) at Tulane Cancer Center were reviewed with a focus on early prostate-specific antigen decline and relationship to overall survival. RESULTS: A total of 110 patients were analyzed for prostate-specific antigen response of ≥ 30 and > 50% at 4, 8, and 12 weeks. A prostate-specific antigen response of either > 30% or > 50% at 4, 8, or 12 weeks was associated with improved overall survival at all time points except > 50% decline at 8 weeks. Multivariate analysis indicated, for all time points, that early prostate-specific antigen declines were predictive of overall survival. The neutrophil to lymphocyte ratio and docetaxel pretreatment also were predictive in many, but not all, of the multivariate analyses. CONCLUSIONS: A > 30% or > 50% prostate-specific antigen decline at 4, 8, or 12 weeks provides important information regarding subsequent overall survival for patients with metastatic castrate-resistant prostate cancer. While these data require validation with a large, multi-institutional trial, they can provide physicians with information regarding prognosis and the timing of expected outcomes. These data affirms the notion that prostate-specific antigen responses as early as 4 weeks after abiraterone initiation can be used to inform both patients and physicians about metastatic castrate-resistant prostate cancer outcomes after initiating treatment with this important but costly therapeutic choice.

Relationship between serum markers and volume of liver metastases in castration-resistant prostate cancer.

BACKGROUND: Prostate cancer patients with liver metastases have a poor prognosis. To date, no study exists investigating the relationship between liver tumor burden and clinical laboratory markers. MATERIALS AND METHODS: Metastatic castrate-resistant prostate cancer (mCRPC) patients with radiographic evidence of liver metastases were selected for this study. Volumetric measurements of liver metastases were ascertained for all available patients. Prostate specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (ALB), total bilirubin and hemoglobin (HGB) levels were then assessed to coincide with the scan dates. Univariate and multivariate mixed-model regression analysis were performed to evaluate the relationship between laboratory markers and liver lesion volume. Data sets with non-normal distribution were logarithmically transformed. Akaike information criteria (AIC) was used to identify the most reliable multivariate model. RESULTS: In our heavily pretreated liver-metastatic patient population, univariate analysis demonstrated a statistically significant positive correlation between PSA (p = 0.0002), ALP (p = 0.0305), AST (p < 0.0001), ALT (p = 0.0049), and LDH (p = 0.0019) and liver lesion volume. Additionally, ALB (p = 0.0006) and HGB (p = 0.0103) had statistically significant negative correlation. Multivariate analysis identified AST and hemoglobin assessments as the best predictors of increasing liver lesion burden. Preliminary data on circulating tumor DNA (ctDNA) mutational and amplification findings are also reported. CONCLUSIONS: Analysis identified AST and hemoglobin as optimal predictors of liver lesion volume. These patients have a heavy burden of ctDNA abnormalities. Further studies with a larger patient population are needed to verify these results. Micro Abstract: This study investigates the association between liver lesion burden and clinical laboratory markers in castrate-resistant prostate cancer patients with hepatic metastases. Our univariate analysis identified multiple laboratory markers as significant indicators of worsening hepatic disease. Multivariate analysis demonstrated that AST and hemoglobin were the most effective predictors of change in liver lesion volume.

Biomarkers for Programmed Death-1 Inhibition in Prostate Cancer.

Prostate cancer is the second leading cause of cancer death in American men. Despite the common nature of this disease, there is a poor understanding of biomarkers that predict responsiveness to immunotherapeutic agents such as the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. Herein we describe a case of complete remission with pembrolizumab therapy in a metastatic castrate-resistant prostate cancer patient with a complex germline MSH2 alteration (Boland inversion) in association with a tumor demonstrating high microsatellite instability. Potential utility of high mutational burden assessed by an experimental circulating tumor DNA assay is also shown. The literature concerning biomarkers for PD-1 inhibition is reviewed, including data for various mismatch repair gene deficiencies, microsatellite instability, tumor mutational burden, PD-L1 3' untranslated region mutations, selected POLE mutations, and biallelic CDK12 mutations. Taken together, although prostate cancer is generally believed to be a tumor unresponsive to PD-1 inhibition, careful dissection of tumor biology is able to provide an approach toward predictive biomarkers that has the potential for expanded clinical utility. KEY POINTS: Biomarkers for anti-PD1 and anti-PDL1 therapy are poorly defined in prostate cancer.Recent advances are defining new important classes of responsive patients.

Laboratory-Based Biomarkers and Liver Metastases in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Metastatic castrate-resistant prostate cancer (mCRPC) patients with liver metastases have a poor prognosis. No large studies have investigated the clinical and biochemical parameters associated with liver metastases in this population. MATERIALS AND METHODS: Patient data made available via Project Data Sphere were collected from 1,281 men with mCRPC who were enrolled on to three phase III clinical trials for the treatment of their disease. Multiple logistic regression was performed on eight clinical and biochemical baseline variables to test their association with the presence of liver metastases on baseline radiographic imaging. Variables of interest included prior docetaxel exposure, Eastern Cooperative Oncology Group performance status, albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase (AST), hemoglobin (HGB), lactate dehydrogenase (LDH), prostate-specific antigen, and total bilirubin. Final models were compared when treating the variables as either continuous or categorized. RESULTS: Multiple variable analysis demonstrated that an increasing serum AST or LDH or a decreasing HGB was associated with an increased probability of having documented radiographic liver metastases (p < .0001). The area under the curve for the continuous model was 0.6842 and 0.6890 for the categorical one, with the latter model containing a dichotomized AST and LDH based on the upper limit of normal and tertile ranges of HGB based on the distribution of the outcome. CONCLUSION: Our analysis demonstrated a significant association between the presence of liver metastases and laboratory levels of AST, LDH, and HGB. These have implications for patient management. More research is needed to validate these biomarkers and prospectively determine their application in the clinical setting. IMPLICATIONS FOR PRACTICE: The purpose of this study was to evaluate biochemical and clinical biomarkers associated with the presence of liver metastases in men diagnosed with metastatic castrate-resistant prostate cancer. The results indicate that quantitative assessments of aspartate transaminase, lactate dehydrogenase, and hemoglobin are significantly associated with an increased probability of having documented radiographic liver metastases. Analysis of these simple variables can alert clinicians to those at high risk for prostate cancer that has spread to the liver, a finding of clear importance for clinical management.

Characterizations of Clinical and Therapeutic Histories for Men With Prostate Cancer-Specific Mortality.

BACKGROUND: Careful descriptions of men with prostate cancer (PCa)-specific mortality are scant in nontrial settings. The present retrospective review describes the clinical characteristics, timelines, and treatment histories from initial presentation to death in a cohort of men with metastatic, castrate-resistant PCa (mCRPC). Unique to the present study is the unequivocal attribution of PCa death by a single experienced clinician. PATIENTS AND METHODS: A total of 119 patients who had been treated at Tulane Cancer Center and had died of mCRPC from 2008 to 2015 were studied through a retrospective review of the medical records. RESULTS: The median age at diagnosis was 65 years (range, 40-85 years), and 34.4% of the patients presented with metastatic disease (stage M1). Of these patients, 56% had received definitive primary therapy, all had received androgen-deprivation therapy, and 52% had received docetaxel. The patients had received a median of 7 (1-14) systemic therapies before death. Most were secondary hormonal manipulations after the diagnosis of mCRPC (median, 4; range, 0-9). The median survival was 69 months (range, 5-270 months) after diagnosis, and the median age at death was 73 years (range, 47-95 years). The presence of metastases at diagnosis was a significant predictor of early death (hazard ratio, 4.33; P < .001), and definitive primary therapy was a significant predictor of longer survival (P < .001). The median survival for patients presenting with metastases was 39 months (range, 5-235 months) compared with 100 months (range, 6-270 months) for those with localized disease (P < .001). The median age at diagnosis between the docetaxel- and non-docetaxel-treated patients was significantly different at 62 and 71 years, respectively (P = .002). CONCLUSION: The present retrospective analysis provides initial views clarifying the clinical characteristics of men dying of mCRPC and the therapies they received before death. Additional data are needed in multi-institutional settings to confirm these findings.