Metastatic Castration-resistant Cancer Research Articles

Treatment changes in prostate cancer patients on active treatment during the COVID-19 pandemic in a community cancer center in New York City.

e18750 Background: The surge of the SARS coronavirus-2 (COVID-19) pandemic posed great challenges in the oncology community for optimal management of cancer patients. We sought to analyze the treatment changes experienced by the prostate cancer patients in March, April and May 2020 and to compare these treatment decisions to the published guidelines. Methods: We focused on patients currently receiving androgen deprivation therapy (ADT) with leuprolide acetate, and/or oral anti-androgen agents (Androgen receptor axis targeted agent, ARAT), or chemotherapy. Electronic medical records were reviewed, and the oncologists and nurse practitioners were interviewed to understand the decision-making process. Results: Seventy-five patients were included, median age 72 years old (range 47-95). All were taking ADT, and 21 were also taking ARAT, and 3 were also receiving chemotherapy. The incidence and indications for their ADT treatments and schedule changes are shown in the table below. Twenty-seven patients (36%) experienced delays in their ADT treatment, and the percentage of treatment change was similar in categories of metastatic hormone sensitive prostate cancer (mHSPC), metastatic castration resistant cancer (mCRPC), biochemical recurrence as well as stage IVA post surgery. Four patients were receiving neoadjuvant ADT planned prior to definitive radiation, and none had schedule change. One patient with mHSPC and 2 patients with mCRPC continued chemotherapy as planned. One patient declined recommended chemotherapy for mCRPC. Two patients were given q 3 months dose of ADT instead of q 1m, while all the rest were already receiving q3 months dosing. Among the 27 patients who had schedule change, 12 (44.4%) patients had a discussion with their providers first, and 15 patients (55.6%) did not keep their treatment appointment. Conclusions: About one third of patients changed ADT injection schedule with a similar percentage in patients with mHSPC, or mCRPC or Biochemical recurrence, or IVA after surgery. Every 3 months dosing of ADT recommended by NCCN significantly decreases exposure to COVID -19, delaying or skipping treatment was still encountered due to health concern or travel limitations. On the other hand, all patients receiving neoadjuvant ADT, or chemotherapy stayed on schedule. Although NCCN guideline recommended delaying myelosuppressive therapy, palliative chemotherapy for symptomatic, refractory patients may still be a priority.[Table: see text]

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

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

Olaparib for Men with Metastatic Castration-Resistant Prostate Cancer

In the prior industry-sponsored, randomized, open-label, phase III PROfound study, progression-free survival (PFS) was longer with the poly(adenosine

Drug Sequencing in Metastatic Castration-Resistant Prostate Cancer

In patients with metastatic castration-resistant prostate cancer (mCRPC), the optimal sequence of administering approved therapeutic agents remains

Sensitivity of 18F-fluorodihydrotestosterone PET-CT to count statistics and reconstruction protocol in metastatic castration-resistant prostate cancer

ObjectivesWhole body [18F]-fluorodihydrotestosterone positron emission tomography ([18F]FDHT PET) imaging directly targets the androgen receptor and is a promising prognostic and predictive biomarker in metastatic castration-resistant cancer (mCRPC). To optimize [18F]FDHT PET-CT for diagnostic and response assessment purposes, we assessed how count statistics and reconstruction protocol affect its accuracy, repeatability, and lesion detectability.MethodsWhole body [18F]FDHT PET-CT scans were acquired on an analogue PET-CT on two consecutive days in 14 mCRPC patients harbouring a total of 336 FDHT-avid lesions. Images were acquired at 45 min post-injection of 200 MBq [18F]FDHT at 3 min per bed position. List-mode PET data were split on a count-wise basis, yielding two statistically independent scans with each 50% of counts. Images were reconstructed according to current EANM Research Ltd. (EARL1, 4 mm voxel) and novel EARL2 guidelines (4 mm voxel + PSF). Per lesion, we measured SUVpeak, SUVmax, SUVmean, and contrast-to-noise ratio (CNR). SUV was normalized to dose per bodyweight as well as to the parent plasma input curve integral. Variability was assessed with repeatability coefficients (RCs).ResultsCount reduction increased liver coefficient of variation from 9.0 to 12.5% and from 10.8 to 13.2% for EARL1 and EARL2, respectively. SUVs of EARL2 images were 12.0–21.7% higher than EARL1. SUVs of 100% and 50% count data were highly correlated (R2 > 0.98; slope = 0.97–1.01; ICC = 0.99–1.00). Intrascan variability was volume-dependent, and count reduction resulted in higher intrascan variability for EARL2 than EARL1 images. Intrascan RCs were lowest for SUVmean (8.5–10.6%), intermediate for SUVpeak (12.0–16.0%), and highest for SUVmax (17.8–22.2%). Count reduction increased test-retest variance non-significantly (p > 0.05) for all SUV types and normalizations. For SUVpeak at 50% of counts, RCs remained < 30% when small lesions were excluded. Splitting data reduced CNR by median 4.6% (interquartile range 1.2–8.7%) and 4.6% (interquartile range 1.2–8.7%) for EARL1 and EARL2 images, respectively.ConclusionsReducing [18F]FDHT PET acquisition time from 3 min to 1.5 per bed position resulted in a repeatability of SUVpeak (bodyweight) remaining ≤ 30%, which is generally acceptable for response monitoring purposes. However, EARL2 reconstruction was more affected, especially for SUVmax whose repeatability tended to exceed 30%. Lesion detectability was only slightly impaired by reducing acquisition time, which might not be clinically relevant in mCRPC.

Progress in the study about androgen receptor splicing variants 7 and the drug resistant of prostate cancer

Prostate cancer is an urogenital malignancy which is common in older men. Androgen deprivation therapy is an usual treatment for metastatic prostate cancer significantly inhibiting the progression of advanced prostate cancer via blocking androgen synthesis, or competitive binding to androgen receptors. Nevertheless, most of the patients end up with metastatic castration-resistant prostate cancer (mCRPC) on the account of androgen resistance. It has been shown that androgen receptor splice variant 7 is strongly associated with the development of mCRPC and its drug resistance to androgen receptor signal transduction inhibitors (enzalutamide and abiraterone) in studies of recent years. Key words: Metastatic castration-resistant prostate cancer; Androgen-receptor splice variant 7; Drug resistance to androgen deprivation therapy

Safety and efficacy of 177Lu-PSMA-617 therapy in metastatic castration-resistant prostate cancer

Objective To investigate the safety and efficacy of 177Lu-prostate specific membrane antigen (PSMA)-617 in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Methods From August 2017 to September 2018, 11 patients(average age 70.6 years) with mCRPC who underwent 177Lu-PSMA-617 therapy in Nanjing First Hospital were studied. All patients underwent 68Ga-PSMA-11 PET/CT before therapy to assess the tumor radioactive uptake. Blood routine examination and renal function test results were documented before and after therapy to assess the safety. The efficacy was reflected by the changes of prostate specific antigen (PSA) levels and maximum standardized uptake value (SUVmax) on 68Ga-PSMA-11 PET/CT imaging. Paired t test and Wilcoxon′s sign rank test were used to analyze the data. Results No acute side effects were observed after therapy of 177Lu-PSMA-617. There were no statistically significant differences after therapy in WBC counts, RBC counts, and PLT, as well as Hb levels (t values: -0.28-1.11, all P>0.05). No kidney toxicity was found. The PSA level after 177Lu-PSMA-617 therapy was significantly lower than that before therapy (80.70(14.29, 1 538.00) μg/L vs 604.60(88.41, 3 980.00) μg/L; u=59, P=0.023). Of the 11 patients, only 2 had elevated PSA levels and disease progression, while the other 9 patients had varying decreases, of which 2/11 decreased by >30% and 7/11 decreased by >50%. After therapy, SUVmax of metastatic lesions and metastatic lymph nodes were decreased in 9 and 2 patients respectively. Conclusions 177Lu-PSMA-617 has a good therapeutic value for mCRPC. It is safe and has no obvious side effects. Key words: Prostatic neoplasms, castration-resistant; Prostate-specific membrane antigen; Isotope labeling; Lutetium; Radiotherapy; Treatment outcome

Research progress in chemo-resistance mechanism of castration resistant prostate cancer

Prostate cancer is one of the most common malignancies in old males. While chemotherapy remains an effective method for metastatic castration resistant prostate cancer (mCRPC), most patients develop chemo-resistance with median survival less than 1 year after six to eight cycles of systematic chemotherapy. Therefore, it is very important to elucidate the mechanisms of CRPC and chemotherapy resistance. This article is to focus on the androgen receptor signaling pathway, micro-RNA, tumor microenvironment, cancer stem cells as well as related molecular events, and to summarize the research progress. Key words: Castration resistant prostate cancer; Chemotherapy resistance; Mechanism

Predicting Discontinuation of Docetaxel Treatment for Metastatic Castration-Resistant Prostate Cancer (mCRPC) With Hill-Climbing and Random Forest

Predicting Discontinuation of Docetaxel Treatment for Metastatic Castration-Resistant Prostate Cancer (mCRPC) With Hill-Climbing and Random Forest

Theranostic research of radiolabeled prostate-specific membrane antigen ligands in metastatic castration-resistant prostate cancer

Prostate cancer is the most common cancer among males. Advanced prostate cancer could develop into metastatic castration-resistant prostate cancer (mCRPC), which is a challenge in the diagnosis and treatment. The prognosis and quality of life of patients can be significantly improved by using radiolabeled prostate-specific membrane antigen (PSMA) ligands for localization and targeted therapy of mCRPC. This review summarizes the research progress of radiolabeled PSMA ligands in theranostics of mCRPC including SPECT imaging, PET imaging, and brachytherapy. Key words: Prostatic neoplasms, castration-resistant; Radioactive tracers; Prostate-specific membrane antigen; Trends

Serum levels of neuroendocrine differentiation markers predict the prognosis of patients with metastatic castration resistant prostate cancer treated with abiraterone acetate

Objective To determine the influence of abiraterone acetate (AA) on neuroendocrine differentiation (NED) in metastatic castration-resistant prostate cancer (mCRPC) and the prognostic predicting value of the serum NED markers in mCRPC patients treated with AA. Methods We conducted an analysis in 115 chemotherapy-naive mCRPC patients who were treated with chemotherapy in Renji hospital from 2013 to 2017. The median age was 70, ranged from 65 to 76 years old. The median CgA, NSE and PSA levels were 101.1 ng/ml(78.5-150.0 ng/ml), 13.4 ng/ml(10.5-17.6 ng/ml)and 38.8 ng/ml(11.2-123.2 ng/ml), respectively. Among them, 48 cases were classified as the group without AA treatment. The other 67 cases were classified as group after AA failure. In group without AA treatment, the median CgA, NSE and PSA levels were 109.1 ng/ml(80-151.5 ng/ml); 13.8 ng/ml(10.8-18.2 ng/ml)and 39.2 ng/ml(8.6-200 ng/ml), respectively. In group after AA failure, the median CgA, NSE and PSA levels were 105.4 ng/ml(78.8-175.5 ng/ml), 13.8 ng/ml(10.8-17.6 ng/ml)and 39.0 ng/ml(8.4-219.8 ng/ml), respectively. In the group with serial evaluation of NED markers during AA treatment, the median serum CgA, NSE levels at baseline were 115.9 ng/ml(90.1-201.5 ng/ml), 13.3 ng/ml(10.4-18.1 ng/ml), respectively. The endpoints were PSA PFS(progression-free survival) and radiographic PFS(rPFS). Results In 34 patients with serial evaluation, serum NED markers level in 19 patients increased after the failure of AA treatment. Median serum CgA and NSE levels were 115.9 ng/ml(90.1-201.5 ng/ml) and 13.25 ng/ml (10.37-18.14 ng/ml)at baseline. Median serum CgA and NSE levels were 129.6 ng/ml (75.5-230.5 ng/ml) and 14.7 ng/ml(11.8-19.1 ng/ml) after 6 months treatment, respectively. The median serum CgA and NSE levels were 130.4 ng/ml (95.7-205.7 ng/ml) and 15.2 ng/ml(12.4-18.7 ng/ml) at the time of failure of AA treatment, respectively. There was no significant difference of NED markers between baseline and failure of AA treatment (P=0.243). In logistic univariate analysis, AA treatment and its duration were not independent factors influencing NED(P=0.30; P=0.52). Compared with the NED markers elevation group in the first 6 months of AA treatment and baseline supranormal NED markers group, the NED markers decline group(PSA PFS(17.1 vs. 10.4 months, P<0.001)and rPFS(17.0 vs. 10.4 months, P=0.003)) and baseline normal NED markers group(PSA PFS(14.1 vs. 9.5 months, P=0.001)and rPFS(16.4 vs. 10.5 months, P<0.001)) has a longer median PSA PFS and rPFS respectively. In multivariate Cox analysis, baseline NED markers level and NED markers variation during the first 6 months of AA treatment remained significant predictors of rPFS(P<0.05), and PSA-PFS(P<0.05). Conclusions We found there was heterogeneity in changes of NED markers in different mCRPC patients during AA treatment, and AA might not significantly lead to progression of NED of mCRPC in general. Serial CgA and NSE evaluation might help clinicians guide clinical treatment of mCRPC patients. Serum NED markers elevation during the first 6 months of AA treatment and elevated baseline NED markers levels indicated poor prognosis in mCRPC treated with AA. Key words: Abiraterone acetate; Neuroendocrine differentiation; Chemotherapy naive; Castration-resistant prostate cancer

Clinicopathological features of metastatic castration-resistant prostate cancer

Objective To investigate the histopathological characteristics of metastatic castration-resistant prostate cancer. Methods Clinical findings, morphologic features, immunophenotypes of androgen receptor(AR), prostatic specific antigen(PSA), chromogranin A(CgA), and phosphatase and tensin homolog deleted on chromosome ten(PTEN)(by EnVision method)of 178 core biopsies from patients with metastatic castration-resistant prostate cancer encountered from January 2010 to January 2015 from West Coast Dream Team were analyzed. Results In the 178 cases, 51(28.7%)were diagnosed with typical adenocarcinoma, 41 cases(23.0%)with intermediate atypical carcinoma and 24 cases(13.5%)with small cell carcinoma.The expression of PSA was significantly lower in patients with intermediate atypical carcinoma or with small cell carcinoma(31/39, 79.5%)than in those with adenocarcinoma(20/20, 100%). The expression of PTEN was significantly higher in patient with intermediate atypical carcinoma or with small cell carcinoma(31/46, 67.4%)than in those with adenocarcinoma(19/41, 46.3%). Conclusions Three histopathological subtypes exists in metastatic castration-resistant prostate cancer, including adenocarcinoma, intermediate type atypical carcinoma and small cell carcinoma.They are entities with unique pathological features.The expression of PTEN is significantly lower in the patients with intermediate atypical carcinoma or with small cell carcinoma than in those with adenocarcinoma, indicating that intermediate atypical carcinoma and small cell carcinoma are different from typical adenocarcinoma in tumor occurrence and progression. Key words: Prostatic neoplasms; Neoplasm metastasis; Testosterone

Eight cases of metastatic castration resistant prostate cancer treated with autologous natural killer cells

Objective To evaluate the efficacy and safety of autologous natural killer (NK) transfusion to treat the patients of metastatic castration resistant prostate cancer (mCRPC). Methods Eight consecutive patients of mCRPC were enrolled from Jan 2014 to Jun 2015 and written informed consent was provided. The patients were evaluated by using laboratory tests, medical imaging and scores. Fifty milliliter blood sample was drawn and the peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll density centrifugation, then the NK population were induced to proliferate for approximately 1 000 times. The Patients received autologous NK transfusion every one week when the NK cells passed quality and functional tests. The patients were evaluated again three days following last transfusions (3-4 time in total). Results The averaged NK cells’ population were proliferated to 4.39×109 cells (range 3.36-6.44×109 cells) in (18±3) days. The purity of NK was 84.3% (range 68.8%-94.7%). No pathogens, endotoxin and mycoplasma were detected. The NK cells could lyze the K562 and PC-3 cells at cell concentration ratio of 10∶1 and above for 4 hours, 82% and78% and above, respectively. The NK population were increased in 7/8 patients; and the CD8+ T cells population were increased in 6/8 patients (P=0.078); cytokine interleukin (IL)-2, IL-12, interferon (IFN) and tumor necrosis factor (TNF) did not show significant variation (P=0.235). The quality of life (Kamofshy score) and ostealgia (numeric rating scale, NRS) were ameliorated. No adverse events were observed. Conclusion To some extent, the immune response of mCRPC patients could be evoked following autologous NK cells transfusion. Key words: Cellular immunotherapy; Prostate cancer; Natural killer cells

Mixing, matching and modifying the prostate cancer microenvironment

Lu et al . (1) introduce a novel chimeric model of prostate cancer to interrogate the tumor microenvironment and signaling pathways in response to single targeting agents given alone or in combination with checkpoint inhibitors. This provides new preclinical data that reinforces clinical observations that combinatorial approaches for treating metastatic castration-resistant prostate cancer (mCRPC) may be more beneficial when compared with monotherapies ( Figure 1 ). It also provides a rationale for the combination of biologic receptor and pathway targeting agents with the family of different checkpoint inhibitors. While the first demonstration of survival benefit by an immunotherapy for a solid tumor was in patients with minimally symptomatic or asymptomatic CRPC using an autologous dendritic cell product, sipuleucel-T (Provenge ® ) (3), immunotherapeutic approaches with single agent peptide or DNA vaccines using novel viral platforms, CAR T cells, and checkpoint inhibitors have all shown limited or minimal impact on the disease.

Modified docetaxel regimen for prostate cancer patients who got poor tolerance to chemotherapy

Objective To evaluate the efficacy and safety of the modified docetaxel plus prednisone scheme for the metastatic castration resistant prostate cancer patients who got poor tolerance to chemotherapy. Method The clinical data of 50 metastatic castration resistant prostate cancer who received docetaxel+ prednisone chemotherapy from March 2010 to October 2015 were analyzed retrospectively. 23 cases received the modified DP regimen (modified group), 27 cases received the standard DP regimen (standard group). The median age of the modified group and the standard group were 69 years (47-80 years) and 63 years (52-77 years)(P=0.005). There were 19 and 24 cases with pain in modified group and standard group respectively; 10 and 19 cases with lymph node metastasis respectively; 3 and 4 cases of visceral metastasis respectively; all of the 50 patients were complicated with bone metastasis. For the pathological Gleason score, there were 7 cases scored ≤7 points, 13 cases scored ≥8 points and 3 cases unscored in the modified group; 7 cases scored ≤7 points, 15 cases scored ≥8 points and 5 cases unscored in standard group. There was no significant difference of the pain, metastasis, and Gleason score between the two groups (P>0.05). Progression free survival(PFS), overall survival(OS)and adverse events were analyzed using Kaplan-Meier curves, and the differences were assessed using the log-rank test. Results In the modified group and standard group, the median follow-up times were 11.0 months and 14.0 months respectively, the median chemotherapy cycles were 4.5 cycles and 5.0 cycles respectively; OS were 18.0 months and 27.5 months respectively (P=0.746). The PFS of the two groups were 6.0 months and 5.2 months, respectively (P=0.822). The PSA response were 13 cases and 17 cases in the modified group and standard group respectively(P=0.615), and the pain response were 8 cases and 7 cases (P=0.927), grade 3 to 4 adverse events were 3 cases and 14 cases (P=0.003). The main adverse events were blood toxicity , neutrophils, gastrointestinal reaction, edema, fatigue and oral mucositis etc. Conclusions Compared with the standard DP scheme, the modified DP scheme had no significant difference in OS, PFS, pain response rate and PSA response rate, while the incidence of grade 3 to 4 adverse events was significantly reduced. Modified DP scheme may be a better choice for patients with metastatic castration resistant prostate cancer who get poor tolerance to chemotherapy. Key words: Metastatic castration resistant prostate cancer; Docetaxel; Chemotherapy

A Treatment-Specific Predictive Biomarker in Metastatic Castration-Resistant Prostate Cancer

Despite the introduction of next-generation androgen receptor (AR)–targeted agents for patients with metastatic prostate cancer, resistance — either

Efficacy and safety of abiraterone combined with prednisone for treating chemotherapy-naive metastatic castration-resistant prostate cancer

Efficacy and safety of abiraterone combined with prednisone for treating chemotherapy-naive metastatic castration-resistant prostate cancer

Optimal Number of Docetaxel Cycles in Castration-Resistant Metastatic Prostate Cancer

Docetaxel remains an important therapeutic option for patients with metastatic castration-resistant prostate cancer (mCRPC), despite the approval of many new agents. In a pivotal study that led to approval of docetaxel for mCRPC (N Engl J Med 2004; 351:1502), patients received a median of 9.5 cycles of docetaxel administered every 3 weeks. However, the optimal number of cycles remains undefined. To determine whether the number of docetaxel cycles …

Gene Mutations as a Target in Metastatic Prostate Cancer

The recent report of a high response to PARP1 inhibitors among heavily treated metastatic castration-resistant prostate cancer patients with DNA-repair defects (NEJM JW Oncol Hematol Dec 2015 and N Engl J Med 2015; 373:1697) has led to additional efforts to more fully characterize the potential role of germline DNA-repair mutations, which, although limited in unselected patients with localized prostate cancer, is undefined in advanced disease. To analyze …

Radium Ra 223 Dichloride Therapy in the Private Practice Environment.

Independent urology groups are currently availing themselves of the numerous life-extending therapies that have been US Food and Drug Administration–approved for patients with metastatic castration-resistant prostate cancer (mCRPC). As they bolster their groups’ capabilities to impact and extend patient lives, they are expanding their account offerings by integrating infusion suites (sipuleucel-T), dispensing pharmacies (abiraterone, enzalutamide), and hot laboratories (radium-223 [223Ra]). Each of these medicines has a unique mechanism of action that allows physicians to tailor treatment to an individual’s disease characteristics.