Clinical and molecular determinants of PSA response to bipolar androgen therapy in prostate cancer.

BACKGROUND: Bipolar androgen therapy (BAT) is a novel therapy known to be effective in a subset of men with metastatic castrate resistant prostate cancer (mCRPC). A better understanding of responders and nonresponders to BAT would be useful to clinicians considering BAT therapy for patients. Herein we analyze clinical and genetic factors in responders/nonresponders to better refine our understanding regarding which patients benefit from this innovative therapy. METHODS: mCRPC patients were assessed for response or no response to BAT. Patients with PSA declines of greater than 50% from baseline after 2 or more doses of testosterone were considered to be responders. Whereas, nonresponders had no PSA decline after 2 doses of testosterone and subsequently manifest a PSA increase of >50%. Differences between these two groups of patients were analyzed using clinical and laboratory parameters. All patients underwent genomic testing using circulating tumor DNA (ctDNA) and germline testing pre-BAT. RESULTS: Twenty five patients were nonresponders and 16 were responders. Baseline characteristics between nonresponders and responders varied. Responders were more likely to have had a radical prostatectomy as definitive therapy and were more likely to have been treated with an androgen receptor (AR) antagonist (enzalutamide or apalutamide) immediately before BAT (compared to abiraterone). Duration of prior enzalutamide therapy was longer in responders. Nonresponders were more likely to have bone-only metastases and responders were more likely to have nodal metastases. Assays detected ctDNA AR amplifications more often in responding patients. Responders trended toward having the presence of more TP53 mutations at baseline. CONCLUSIONS: BAT responders are distinct from nonresponders in several ways however each of these distinctions are imperfect. Patterns of metastatic disease, prior therapies, duration of prior therapies, and genomics each contribute to an understanding of patients that will or will not respond. Additional studies are needed to refine the parameters that clinicians can utilize before choosing among the numerous treatment alternatives available for CRPC patients.

Embracing the Practical Aspects of Theranostics With Prostate-Specific Membrane Antigen-Targeted Lutetium-177.

Treatment options for men with metastatic castration-resistant prostate cancer are rapidly changing. In addition to novel anti-androgens and taxane-based chemotherapy, radiopharmaceuticals are having an increasing role. Although calcium-mimetic theranostics have been in use for years, newer approaches use molecularly targeted radiation therapy by conjugating isotopes to prostate-specific membrane antigen (PSMA) and in so doing directly target prostate cancer cells; 177Lutetium-PSMA-617 is perhaps the best-known member of this new class. Expanding our capacity to deliver targeted beta-emitters requires additional planning and equipment. Having delivered close to 200 doses of 177Lutetium-PSMA-617 at our center, we offer practical advice about patient selection, radiation safety, treatment administration, and toxicity monitoring. Although this blueprint is not the only way to expand a theranostics program beyond Radium-223, we offer our institutional experience with 177Lutetium-PSMA-617 as an example to programs seeking to expand their radiopharmaceutical programs. We must rise to meet the patient-driven demand for these innovative and effective therapies.

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.

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.

Extreme Prostate-Specific Antigen Response to Infusional 5-Flourouracil in Castrate-Resistant Prostate Cancer.

Prostate cancer that has progressed after androgen deprivation, abiraterone, and taxane therapy is challenging to treat successfully. Herein we report a dramatic response to continuous-infusion 5-fluorouracil (5-FU) at a dose of 200 mg/m2 in a patient with rapidly progressive, heavily pretreated, metastatic castrate-resistant prostate cancer. Baseline prostate-specific antigen values declined from 1,890 ng/mL to <1 ng/mL after 5-FU therapy. We hypothesized that prostate-specific membrane antigen overexpression may result in cancer cells uniquely susceptible to antifolate therapies.