Targeting androgen biosynthesis in prostate cancer: implications on endocrine physiology.

PURPOSE OF REVIEW: Targeting specific steroidogenic enzymes is effective in decreasing testosterone synthesis, resulting in significant antitumor effects in prostate cancer. Such treatments result in disruptions of complicated and intertwining pathways with systemic physiologic consequences via effects on the adrenal gland and renin-angiotensin-aldosterone axis. This review highlights some of these aspects that need to be taken into consideration when treating patients with androgen biosynthesis inhibitors. RECENT FINDINGS: Targeting CYP17A1, a key enzyme involved in androgen biosynthesis, is a well established treatment in prostate cancer. More recently, efforts are underway to target a gatekeeper enzyme of steroidogenesis, CYP11A1. This enzyme mediates conversion of cholesterol to pregnenolone, the first step in steroid hormone biogenesis. Studies are beginning to demonstrate antitumor effects of ODM-208, a CYP11A1 inhibitor in prostate cancer. Although anticipated to have a therapeutic role in prostate cancer, there are potential downstream effects of CYP11A1 targeting arising from suppression of the entire adrenal cortex, including long-term adrenal insufficiency and possibly cardiovascular dysregulation. SUMMARY: Agents targeting androgen biosynthesis can have systemic implications. Balancing management of prostate cancer with better understanding of the mechanisms associated with potential side effects will allow for patients to obtain improved antitumor benefit while mitigating against treatment-associated adverse effects.

Stereotactic ablative radiation therapy in metastatic prostate cancer.

PURPOSE OF REVIEW: The evolving role of stereotactic ablative radiation therapy (SABR) as metastasis-directed therapy (MDT) for oligometastatic prostate cancer (omPCa) will be discussed. RECENT FINDINGS: Oligometastatic disease (OMD) is an intermediate state between localized and wide-spread malignant disease. OMD has recently been spotlighted given the increasing demonstration of clinical benefit from local therapies despite presence of metastatic disease and allure of the curative potential of MDT in select cases. Among the different forms of MDT, SABR has rapidly become a widely adopted treatment modality. Significant efforts in this space have focused on omPCa, owing to its relatively indolent biology, presence of a sensitive and specific serum biomarker and recent advances in molecular imaging. While most studies have evaluated the role of SABR MDT in hormone sensitive omPCa, new emerging clinical data also suggests benefits of SABR MDT for even castration-resistant disease. SUMMARY: Treating omPCa with SABR MDT appears to generate an efficacy signal with minimal morbidity across both hormone-sensitive and castration-resistant disease. However, additional definitive omPCa trial data are needed. Future research efforts should investigate biomarkers for this heterogeneous disease space and the role of SABR MDT in combination with systemic agents to improve upon standard of care treatments.

Humoral immunity against SARS-CoV-2 variants including omicron in solid organ transplant recipients after three doses of a COVID-19 mRNA vaccine.

Objectives: Solid organ transplant recipients (SOTR) receiving post-transplant immunosuppression show increased COVID-19-related mortality. It is unclear whether an additional dose of COVID-19 vaccines can overcome the reduced immune responsiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Methods: We analysed humoral immune responses against SARS-CoV-2 and its variants in 53 SOTR receiving SARS-CoV-2 vaccination. Results: Following the initial vaccination series, 60.3% of SOTR showed no measurable neutralisation and only 18.9% demonstrated neutralising activity of > 90%. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titres against microbial recall antigens were higher. By contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titres against SARS-CoV-2 and its delta variants and fewer linear B-cell epitopes, indicating reduced B-cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titres and neutralising activity across alpha, beta and delta variants and to the induction of anti-SARS-CoV-2 CD4+ T cells in a subgroup of patients analysed. By contrast, we observed significantly lower antibody titres after the third dose with the omicron variant compared to the ancestral SARS-CoV-2 and the improvement in neutralising activity was much less pronounced than for all the other variants. Conclusion: Only a small subgroup of solid organ transplant recipients is able to generate functional antibodies after an initial vaccine series; however, an additional vaccine dose resulted in dramatically improved antibody responses against all SARS-CoV-2 variants except omicron where antibody responses and neutralising activity remained suboptimal.

Deep dissection of the antiviral immune profile of patients with COVID-19.

In light of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants potentially undermining humoral immunity, it is important to understand the fine specificity of the antiviral antibodies. We screened 20 COVID-19 patients for antibodies against 9 different SARS-CoV-2 proteins observing responses against the spike (S) proteins, the receptor-binding domain (RBD), and the nucleocapsid (N) protein which were of the IgG1 and IgG3 subtypes. Importantly, mutations which typically occur in the B.1.351 "South African" variant, significantly reduced the binding of anti-RBD antibodies. Nine of 20 patients were critically ill and were considered high-risk (HR). These patients showed significantly higher levels of transforming growth factor beta (TGF-ß) and myeloid-derived suppressor cells (MDSC), and lower levels of CD4+ T cells expressing LAG-3 compared to standard-risk (SR) patients. HR patients evidenced significantly higher anti-S1/RBD IgG antibody levels and an increased neutralizing activity. Importantly, a large proportion of S protein-specific antibodies were glycosylation-dependent and we identified a number of immunodominant linear epitopes within the S1 and N proteins. Findings derived from this study will not only help us to identify the most relevant component of the anti-SARS-CoV-2 humoral immune response but will also enable us to design more meaningful immunomonitoring methods for anti-COVID-19 vaccines.

Anti-SARS-CoV-2 Immune Responses in Patients Receiving an Allogeneic Stem Cell or Organ Transplant.

Patients after autologous (autoSCT) and allogeneic stem cell transplantation (alloSCT) are at an increased risk of COVID-19-related morbidity and mortality, compounded by an immune system weakened by the underlying malignancy and prior treatments. Allogeneic transplantation, including stem cell and solid organ transplants, requires intensive immunosuppressive prophylaxis, which may further undermine the development of a protective vaccine-induced anti-viral immunity. Herein, we report on short- and long-term antiviral immune responses in two peri-stem cell transplant recipients and a third patient who received a COVID-19 vaccination after kidney transplantation. Our data indicate that: (1) patients post-alloSCT may be able to mount an anti-COVID-19 immune response; however, a sufficient time interval between transplant and exposure may be of critical importance; (2) alloSCT recipients with preexisting anti-SARS-CoV-2 immunity are at risk for losing protective humoral immunity following transplantation, particularly if the stem-cell donor lacks antiviral immunity, e.g., vaccine-derived immunity; and (3) some post-transplant patients are completely unable to build an immune response to a COVID-19 vaccine, perhaps based on the prophylactic suppression of T cell immunity.

Race as a predictor of pathologic response to neoadjuvant chemotherapy at time of cystectomy for bladder cancer.

INTRODUCTION Complete pathologic response (pT0) at time of cystectomy after neoadjuvant chemotherapy (NAC) has been associated with significantly improved clinical outcomes. The goal of this study is to examine whether race is a predictor of pT0 response to NAC at time of cystectomy. MATERIALS AND METHODS: We analyzed the records of patients diagnosed with a non-metastatic (M0) muscle-invasive (cT2+) urothelial cell bladder cancer in the National Cancer Database (NCDB) who underwent a cystectomy from 2006 to 2014. The cohort was stratified by whether the patient received NAC prior to cystectomy. Univariate and multivariate logistic regression models were used to assess for the effect of race on pathologic complete response after NAC. RESULTS: We identified 16,036 patients of which 3,195 patients (19.9 %) were treated with NAC prior to cystectomy. The total number of African American (AA) patients in this study was 848 (5.3 %). Compared to Caucasian patients receiving NAC, AA patients had a greater proportion of females and had lower income and education. The rate of pT0 in the surgery only group was 2.7% compared to 15.0% (p < 0.001) for patients treated with NAC. On multivariate analysis, patients of AA race that received NAC were less likely to achieve pT0 (OR = 0.55, 95% CI: 0.31-0.98, p = 0.04) when controlling for age, sex, co-morbidities income, education and timing of cystectomy after starting NAC. CONCLUSIONS: Our results suggest that African American patients are less likely to achieve pathologic complete response to NAC prior to cystectomy.

Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer.

LESSONS LEARNED: The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC).The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. BACKGROUND: Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). METHODS: This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. RESULTS: The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). CONCLUSION: Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

A Phase II Study Evaluating Bone Marrow-Sparing, Image-guided Pelvic Intensity-Modulated Radiotherapy (IMRT) With Cesium-131 Brachytherapy Boost, Adjuvant Chemotherapy, and Long-Term Hormonal Ablation in Patients With High Risk, Nonmetastatic Prostate Cancer.

PURPOSE/OBJECTIVE(S): Management of localized high-risk prostate cancer remains challenging. At our institution we performed a prospective phase II study of 2 years of androgen deprivation therapy (ADT), pelvic radiation, Cesium (Cs)-131 brachytherapy boost, and adjuvant docetaxel in high risk, localized prostate cancer with a primary endpoint of 3-year disease-free survival. MATERIALS/METHODS: Acute/chronic hematologic, gastrointestinal (GI) and genitourinary (GU) toxicities were scored based on the CTCAE v3.0/RTOG-EORTC criteria, respectively. Actuarial biochemical recurrence free survival (bRFS), bRFSdisease free survival (DFS) and overall survival (OS) were calculated. Patients had a median age of 62 years (range, 45 to 82), median Gleason score 8 (74% Gleason 8-10), median PSA of 11.2 (range, 2.8 to 96), and 47% cT2-T3a stage disease. Androgen deprivation was given for 2 years, 45 Gy whole-pelvis IMRT was followed by an 85 Gy Cs-131 boost to the prostate gland, and adjuvant docetaxel was given for 4 cycles. RESULTS: In total 38 patients enrolled from 2006 to 2014, with 82% completing protocol specified treatment, and 84.2% completing 4 cycles of docetaxel. Median follow-up for the entire and alive cohorts were 44 months and 58 months (range, 3.4 to 118), respectively. Acute grade ≥2 GI and GU toxicity rates were 18.4% and 23.7%, respectively. Chronic grade ≥2 GI and GU toxicity rates were 2.6% and 2.6%, respectively. Twelve patients (31.6%) developed grade 4 hematologic toxicity, with no grade 5 toxicity. The 5-year DFS, bRFS and OS rates were 74.1%, 86.0%, and 80.3%, respectively. CONCLUSIONS: This aggressive pilot multimodal approach appears to be safe and well-tolerated, providing disease control in a significant proportion of patients with particularly high-risk prostate cancer.

Update on testicular germ cell tumors.

PURPOSE OF REVIEW: This overview discusses several important developments in testicular germ cell tumors (TGCTs) over the past year. RECENT FINDINGS: Genomic studies continue to investigate gene expression as possible markers for disease relapse and metastatic potential. Optimal treatment strategies for early-stage seminomas continue to evolve toward surveillance versus chemotherapy, although developing radiation delivery modalities may ultimately provide a safe alternative. The role of retroperitoneal lymph node dissection in postorchiectomy early-stage nonseminoma germ cell tumors remains a topic of debate. SUMMARY: Treatment paradigms continue to be refined for TGCTs as research in these areas continues.

Testicular germ cell tumors: biology and clinical update.

PURPOSE OF REVIEW: To discuss several important developments in the diagnosis, management, and risk stratification of testicular germ cell tumors (TGCTs) in the past year. RECENT FINDINGS: Germ cell function and tumorigenesis may be influenced by exposure to a variety of agents, including metals and cannabinoids. Genome-wide association studies have identified variants in several genes that may produce susceptibility to the development of testicular malignancies, and expression of certain proteins predicts a poorer prognosis and may, thus, play a role in neoplastic progression. Retroperitoneal lymph node dissection continues to play a crucial role in definitive treatment of patients with nonseminoma germ cell tumor, whereas radiotherapy, as a standard treatment for early-stage seminoma, has been declining due both to the efficacy of platinum-based chemotherapy and to the increased risk of radiation-related secondary malignancies. Advanced and platinum-refractory disease states continue to be challenging entities in terms of optimizing therapy and outcome. SUMMARY: Preclinical and clinical studies continue to enhance our insights into the complex biology of TGCTs, and are helping to further refine risk stratification and optimize treatment of patients with TGCTs.

Testicular germ cell tumors: biology and clinical update.

PURPOSE OF REVIEW: This overview discusses several important developments in testicular germ cell tumors in the past year. RECENT FINDINGS: Genomic studies continue to investigate gene expression as possible markers for disease relapse and chemotherapy resistance. Optimal treatment strategies for early-stage seminomas are evolving toward surveillance versus chemotherapy and away from radiation, and the role of retroperitoneal lymph node dissection in disseminated nonseminomatous cancers in complete remission is becoming less certain. SUMMARY: Treatment and surveillance paradigms continue to be defined and refined for both early and late-stage disease as research in these areas continues and the data from multiple large studies mature.

Long-term follow-up of a prospective trial of trimodality therapy of weekly paclitaxel, radiation, and androgen deprivation in high-risk prostate cancer with or without prior prostatectomy.

PURPOSE: Weekly paclitaxel, concurrent radiation, and androgen deprivation (ADT) were evaluated in patients with high-risk prostate cancer (PC) with or without prior prostatectomy (RP). METHODS AND MATERIALS: Eligible post-RP patients included: pathological T3 disease, or rising prostate-specific antigen (PSA) ≥ 0.5 ng/mL post-RP. Eligible locally advanced PC (LAPC) patients included: 1) cT2b-4N0N+, M0; 2) Gleason score (GS) 8-10; 3) GS 7 + PSA 10-20 ng/mL; or 4) PSA 20-150 ng/mL. Treatment included ADT (4 or 24 months), weekly paclitaxel (40, 50, or 60 mg/m(2)/wk), and pelvic radiation therapy (total dose: RP = 64.8 Gy; LAPC = 70.2 Gy). RESULTS: Fifty-nine patients were enrolled (LAPC, n = 29; RP, n = 30; ADT 4 months, n = 29; 24 months, n = 30; whites n = 29, African Americans [AA], n = 28). Baseline characteristics (median [range]) were: age 67 (45-86 years), PSA 5.9 (0.1-92.1 ng/mL), GS 8 (6-9). At escalating doses of paclitaxel, 99%, 98%, and 95% of doses were given with radiation and ADT, respectively, with dose modifications required primarily in RP patients. No acute Grade 4 toxicities occurred. Grade 3 toxicities were diarrhea 15%, urinary urgency/incontinence 10%, tenesmus 5%, and leukopenia 3%. Median follow-up was 75.3 months (95% CI: 66.8-82.3). Biochemical progression occurred in 24 (41%) patients and clinical progression in 11 (19%) patients. The 5- and 7-year OS rates were 83% and 67%. There were no differences in OS between RP and LAPC, 4- and 24-month ADT, white and AA patient categories. CONCLUSIONS: In addition to LAPC, to our knowledge, this is the first study to evaluate concurrent chemoradiation with ADT in high-risk RP patients. With a median follow-up of 75.3 months, this trial also represents the longest follow-up of patients treated with taxane-based chemotherapy with EBRT in high-risk prostate cancer. Concurrent ADT, radiation, and weekly paclitaxel at 40 mg/m(2)/week in RP patients and 60 mg/m(2)/week in LAPC patients is feasible and well-tolerated.

Update on testicular germ cell tumors.

PURPOSE OF REVIEW: This overview discusses several important developments in testicular germ cell tumors in the last year. RECENT FINDINGS: Genomic studies are examining gene expression as possible markers for disease relapse and chemotherapy resistance. Optimal treatment strategies for early-stage nonseminomatous tumors continue to evolve, and advanced disease states continue to be challenging entities in terms of optimizing therapy and outcome. Long-term survivorship issues are also being evaluated in this patient population. SUMMARY: Significant challenges remain for treatment of certain categories of testicular germ cell tumors. Treatment and surveillance paradigms continue to be defined and refined as research in these areas continues.

Update on testicular germ cell tumors.

PURPOSE OF REVIEW: To discuss several important developments in testicular germ cell tumors in the past year. RECENT FINDINGS: Genomic studies are examining gene expression as possible markers for disease relapse and chemotherapy resistance. Optimal treatment strategies for early-stage nonseminomatous tumors continue to evolve and patient compliance with posttreatment surveillance schedules remains problematic. Advanced and platinum-refractory disease states continue to be challenging entities in terms of optimizing therapy and outcome. SUMMARY: Significant challenges remain for treatment of certain categories of testicular germ cell tumors. Treatment and surveillance paradigms continue to be defined and refined as research in these areas continues.

Update on testicular germ cell tumors.

PURPOSE OF REVIEW: This overview discusses several important developments in testicular germ cell tumors in the past year. RECENT FINDINGS: Genomic studies are examining gene expression as possible markers for disease relapse and chemotherapy resistance. Optimal posttreatment surveillance strategies continue to evolve. Retroperitoneal lymph node dissection remains a prominent treatment modality, although the sequencing and extent of surgical intervention is controversial. Platinum-based chemotherapy remains the gold standard for treatment of systemic disease. Poor risk, platinum-refractory and late relapse disease states continue to be challenging entities in terms of optimizing therapy and outcome. SUMMARY: Significant challenges remain for treatment of certain categories of testicular germ cell tumors. Treatment and surveillance paradigms continue to be defined and refined as research in these areas continues.

Evolving role of surgery, radiation, hormone therapy, and chemotherapy in high-risk locally advanced prostate cancer.

Locally advanced prostate cancer encompasses several disease states that vary in the risk for progression and recurrence after initial treatment. Further, the optimal treatment strategies for locally advanced prostate cancer are continuing to evolve, reflecting the complex nature of this disease state. For many patients, clinical experience demonstrates that a combined approach of locally directed therapy and systemic therapy is likely to provide better long-term outcome than single-modality therapy. Randomized studies have established hormone ablation with external-beam radiation as an important form of treatment for this group of patients. However, additional progress needs to be made, particularly in the subgroup of patients with very high-risk disease features. As the optimal integration of local and systemic treatments becomes more clearly defined, the long-term prognosis for patients with high-risk locally advanced prostate cancer will improve.

What constitutes high-risk locally advanced prostate cancer?

Excluding basal and squamous cell cancers of the skin, prostate cancer is the most common malignancy diagnosed in the United States. With increasing awareness and routine prostate-specific antigen testing, a remarkable migration in the clinical presentation of the disease has occurred in the past 20 years. An increasingly greater proportion of men are diagnosed with clinically organ-confined disease. In parallel, the incidence of men presenting with clinically bulky locoregional or metastatic disease has decreased. Despite the stage migration, when clinical and pathologic parameters are taken into account, a significant number of men with clinically localized prostate cancer do not have truly organ-confined disease. Such men might not to be cured with single modality, locally directed therapies. Thus, prostate cancer represents a disease spectrum with a number of biologic and clinical factors determining disease extent. An overview of some of these aspects of the disease is presented.