Biochemically recurrent prostate cancer in the era of EMBARK and PSMA PET imaging: everything has changed, except the patients.

PURPOSE OF REVIEW: Patients with biochemically recurrent prostate cancer (BCR) after unsuccessful curative therapies frequently have an indolent and asymptomatic disease course for years. There are no prospective data showing that treating BCR improves overall survival despite new imaging strategies and emerging therapeutic data. Managing BCR requires a unique perspective in oncology that balances toxicities and disease kinetics. RECENT FINDINGS: Prostate specific membrane antigen (PSMA) imaging is now widely available and can define subclinical disease in patients with BCR who otherwise have negative CT and bone scans, but limited data exists showing that treating PSMA-positive disease has long term impact. A phase 3 trial demonstrated that the androgen receptor pathway inhibitor enzalutamide either alone or with androgen deprivation therapy (ADT) was superior in delaying metastasis, relative to ADT alone. Survival benefits from this study remain unknown. SUMMARY: BCR is a heterogeneous population where overtreatment may present greater risk to patients than a disease course that is often indolent. Management of BCR should be individualized based on disease kinetics. Given the unique biology of BCR, future therapeutic research should emphasize an approach that alters disease trajectory without accompanying side effects and should explore options beyond ADT-based strategies.

Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS.

BACKGROUND: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment. PATIENTS AND METHODS: Patients with nmCRPC were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval-specific new and cumulative event rates were determined during the first 24 months of the double-blind period. RESULTS: Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months. CONCLUSION: Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment-related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment. TRIAL NUMBER: ClinicalTrials.gov identifier NCT02200614.

Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Analysis from JAVELIN Bladder 100 by Duration of First-line Chemotherapy and Interval Before Maintenance.

BACKGROUND: In the JAVELIN Bladder 100 phase 3 trial, avelumab first-line maintenance + best supportive care (BSC) prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (advanced UC) without progression after first-line platinum-based chemotherapy. OBJECTIVE: To report post hoc analyses of subgroups defined by the duration of first-line chemotherapy and interval before maintenance. DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced UC without progression after four to six cycles of platinum-based chemotherapy and a 4-10-wk interval after chemotherapy (n = 700) were randomized to receive avelumab + BSC or BSC alone. Subgroups were defined by duration (quartile [Q]) and estimated number of cycles of chemotherapy, and interval between chemotherapy and maintenance. The median follow-up was >19 mo in both arms. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS (primary endpoint), PFS, and safety were assessed. RESULTS AND LIMITATIONS: Hazard ratios (95% confidence interval) for OS with avelumab + BSC versus BSC alone were as follows: by chemotherapy duration-Q3: 0.63 (0.39-1.00); by number of cycles-four cycles: 0.69 (0.48-1.00), five cycles: 0.98 (0.57-1.71), and six cycles: 0.66 (0.47-0.92); and by interval-4-<6 wk: 0.75 (0.54-1.04), 6-<8 wk: 0.67 (0.43-1.06), and 8-10 wk: 0.69 (0.47-1.02). Results were similar for PFS. Safety was similar across subgroups. All analyses were exploratory. CONCLUSIONS: Post hoc analyses of OS and PFS in subgroups defined by first-line chemotherapy duration and interval before maintenance were generally consistent with the results in the overall population, with similar safety findings. Prospective trials are warranted to confirm these findings. PATIENT SUMMARY: Avelumab maintenance treatment helped patients with advanced urothelial cancer without disease progression after at least four cycles of prior chemotherapy, and who started maintenance treatment at least 4 wk after chemotherapy, to live longer.

Mechanistic Insights on Localized to Metastatic Prostate Cancer Transition and Therapeutic Opportunities.

Prostate cancer is the most common non-cutaneous cancer among American men. Multiple mechanisms are involved in tumorigenesis and progression to metastases. While androgen deprivation therapy remains the cornerstone of treatment, progression to castration-resistant disease becomes inevitable. Aberrant pathway activations of PI3K/AKT due to PTEN loss, epithelial-mesenchymal transition pathways, homologous recombination repair, and DNA repair pathway mechanisms of resistance and cross-talk lead to opportunities for therapeutic targeting in metastatic castration-resistant prostate cancer. This review focuses on mechanisms of progression and key trials that evaluate the drugs and combinations that exploit these pathways.

A systematic review evaluating the effectiveness of exercise training on physical condition in prostate cancer patients undergoing androgen deprivation therapy.

Background: Androgen deprivation therapy (ADT) is an effective prostate cancer (PCa) treatment strategy that can curb the development or progression of the disease. This review aimed to examine and summarize available systematic reviews/meta-analyses (SRs/MAs) of exercise training on physical condition of PCa patients undergoing ADT. Methods: A comprehensive search of 8 databases was conducted for relevant literature published before April 25, 2022 with the language restrictions of Chinese and English. Two reviewers independently assessed the methodological quality, risk of bias, reporting quality, and evidence quality of the included SRs/MAs using a range of evaluation tools, including A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2, Risk of Bias in Systematic Reviews (ROBIS), the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), and Grades of Recommendations, Assessment, Development and Evaluation (GRADE). Results: This review included 8 SRs/MAs which included a total of 94 studies. Ultimately, A total of 51 outcomes was included, regarding 11 different outcome categories. The AMSTAR-2 tool showed that 3 SRs/MAs had moderate methodological quality, 4 SRs/MAs had very low quality, and the remaining 1 had low quality. According to the ROBIS scale, 3 SRs/MAs had a high risk of bias. The PRISMA checklist showed that the primary reporting faults were protocol registration and funding source. The GRADE system was used to analyze the evidence quality of the 51 outcomes, and no high-quality evidence was found. However, moderate-quality evidence indicated that exercise training may improve body composition [by lowering body fat mass (BFM) and body fat rate (BFR)], muscular strength, and quality of life (QoL) in PCa patients undergoing ADT. Low-quality evidence demonstrated that exercise training could improve such symptoms as fatigue, depression, sexual function, and cardiometabolic changes. Conclusions: Available evidence suggests that exercise training may be used as an adjuvant treatment for PCa patients undergoing ADT to improve several aspects of general health. Studies with more rigorous designs and larger sample sizes are needed to support our findings with more robust evidence.

Emerging treatment options for prostate cancer.

INTRODUCTION: Prostate cancer treatment has rapidly evolved in the past few years. Androgen deprivation therapy has been the backbone of treatment for locally advanced and metastatic prostate cancer, but incremental benefits in survival have been shown by adding androgen-receptor pathway inhibitors (ARPI) across various spectrums of disease state. In addition, docetaxel chemotherapy remains the first-line chemotherapy regimen available with survival benefits shown with triplet therapy in those who are chemotherapy eligible. However, disease progression remains inevitable and novel agents such as radioligand therapy with lutetium have shown improvement in survival. AREAS COVERED: This review discusses the pivotal trials that led to the U.S. FDA approval of agents utilized in metastatic prostate cancer and explores the use of novel agents including prostate-specific membrane antigen-targeting agents, radioligands, cell-based therapy, chimeric antigen receptor T-cell, BiTE, and antibody drug conjugates. EXPERT OPINION: Treatment landscape for metastatic castrate-resistant prostate cancer (mCRPC) has evolved beyond additional agents with ARPI and/or docetaxel, including other treatments with sipuleucel-T, radium, cabazitaxel, PARP inhibitors, and lutetium, which have specific indications and roles in sequencing. Novel therapies remain critically needed after progression from lutetium.

Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Initial results from the phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier: NCT02603432) showed that avelumab first-line (1L) maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free after 1L platinum-containing chemotherapy. Avelumab 1L maintenance treatment is now a standard of care for aUC. Here, we report updated data with ≥ 2 years of follow-up in all patients, including OS (primary end point), PFS, safety, and additional novel analyses. Patients were randomly assigned 1:1 to receive avelumab plus BSC (n = 350) or BSC alone (n = 350). At data cutoff (June 4, 2021), median follow-up was 38.0 months and 39.6 months, respectively; 67 patients (19.5%) had received ≥2 years of avelumab treatment. OS remained longer with avelumab plus BSC versus BSC alone in all patients (hazard ratio, 0.76 [95% CI, 0.63 to 0.91]; 2-sided P = .0036). Investigator-assessed PFS analyses also favored avelumab. Longer-term safety was consistent with previous analyses; no new safety signals were identified with longer treatment duration. In conclusion, longer-term follow-up continues to show clinically meaningful efficacy benefits with avelumab 1L maintenance plus BSC versus BSC alone in patients with aUC. An interactive visualization of data reported in this article is available.

The role of switch maintenance therapy in urothelial cancers.

Maintenance therapy with immune checkpoint inhibitors (ICIs) has changed the treatment paradigm of metastatic urothelial carcinoma (mUC). The JAVELIN Bladder 100 trial established avelumab, one of several ICIs in use today, as a life-prolonging maintenance therapy for patients with advanced urothelial carcinoma. Platinum-based chemotherapy is most often used in the first-line treatment of mUC, and while response rates approach about 50%, disease control is usually short-lived upon completion of the standard three to six cycles of chemotherapy. Much progress has been made in recent years in the second-line space and beyond with the use of ICIs, antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs) in eligible patients at the time of disease progression post-platinum-based chemotherapy. However, many patients with progressive mUC after first-line chemotherapy suffer from rapid progression of disease, treatment toxicity with subsequent lines of therapy, and a limited life expectancy. Until the results of the JAVELIN Bladder 100 trial were presented in 2020, there were no maintenance strategies proven to be beneficial over best supportive care after disease control is achieved with first-line platinum-based chemotherapy. To date, standard of care frontline treatment of metastatic urothelial cancer remains to be four to six cycles of platinum-based chemotherapy followed by maintenance avelumab. This review summarizes the current evidence available on maintenance therapies in mUC, as well as several highly anticipated clinical trials that we hope will result in further progress in the management of this aggressive cancer and improve patient outcomes.

Non-urothelial and urothelial variants of bladder cancer.

Non-urothelial bladder cancers make up a rare minority of all genitourinary (GU) tract histologic cancers since urothelial cancer (UC) makes up the most common histologic subtype. Bladder cancer variant histology (BCVH) or urothelial variants also occur rarely though distinction is important given aggressive presentation and natural history. While methods for diagnosis and treatment of typical urothelial cancers (UC) are well-established, there are no clear guidelines with regard to the diagnosis of non-urothelial bladder cancers, which often results in misdiagnosis and treatment delay. This review will focus on the clinicopathologic characteristics of the most common non-urothelial bladder cancers, to be distinguished from bladder cancer variant histology containing a UC component. The role of genomics in non-urothelial bladder cancers is evolving and the use of biomarkers to guide the diagnosis and treatment of these tumors remains a key area of unmet need. Treatment of these cancers will be discussed in a companion review.

Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors.

BACKGROUND: Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naïve, refractory solid tumors. METHODS: Phase 1 evaluated the safety of varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures. RESULTS: 175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%). CONCLUSION: Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian cancer where the changes were associated with better clinical outcomes. TRIAL REGISTRATION NUMBER: NCT02335918.

Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial.

The RANGE study (NCT02426125) evaluated ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with platinum-refractory advanced urothelial carcinoma (UC). Here, we use programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) and transcriptome analysis to evaluate the association of immune and angiogenesis pathways, and molecular subtypes, with overall survival (OS) in UC. Higher PD-L1 IHC and immune pathway scores, but not angiogenesis scores, are associated with greater ramucirumab OS benefit. Additionally, Basal subtypes, which have higher PD-L1 IHC and immune/angiogenesis pathway scores, show greater ramucirumab OS benefit compared to Luminal subtypes, which have relatively lower scores. Multivariable analysis suggests patients from East Asia as having lower immune/angiogenesis signature scores, which correlates with decreased ramucirumab OS benefit. Our data highlight the utility of multiple biomarkers including PD-L1, molecular subtype, and immune phenotype in identifying patients with UC who might derive the greatest benefit from treatment with ramucirumab.

Plain language summary of results from the JAVELIN Bladder 100 study: avelumab maintenance treatment for advanced urothelial cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of an article originally published in The New England Journal of Medicine. It is about initial results (collected in October 2019) from the JAVELIN Bladder 100 study (a clinical trial), which looked at avelumab maintenance treatment in people with advanced urothelial cancer. Urothelial cancer is the most common type of bladder cancer. People with advanced urothelial cancer often receive chemotherapy. If this is the first treatment people with advanced disease are given, it is called first-line treatment. If the cancer stops growing or shrinks with first-line chemotherapy, people can be given different treatment to try to prevent the cancer from growing again. This is called maintenance treatment. It may help people live longer. WHAT HAPPENED IN THE JAVELIN BLADDER 100 STUDY?: In the JAVELIN Bladder 100 study, researchers wanted to find out if maintenance treatment with avelumab would help people with advanced urothelial cancer live longer. Avelumab is a type of medicine called immunotherapy. Immunotherapy helps the body's immune system fight cancer. 700 people took part in the study. To take part, they must have already been treated with first-line chemotherapy. Also, their cancer must have shrunk or not grown with this treatment. They were then treated with either avelumab maintenance treatment plus best supportive care or best supportive care alone. Best supportive care means treatments that help improve symptoms and quality of life. These treatments do not affect the cancer directly and can include medicines to relieve pain. WHAT WERE THE RESULTS?: Researchers found that people treated with avelumab maintenance treatment plus best supportive care lived, on average, 7 months longer than people who received best supportive care alone. People treated with avelumab had more side effects than those not treated with avelumab, but most were not severe. Common side effects with avelumab included persistent tiredness, itchy skin, urinary tract infection, and diarrhea. WHAT DO THE RESULTS OF THE STUDY MEAN?: Results from the JAVELIN Bladder 100 study support the use of avelumab as maintenance treatment for people with advanced urothelial cancer whose cancer has shrunk or not grown with first-line chemotherapy. ClinicalTrials.gov NCT number: NCT02603432.

Advances with androgen deprivation therapy for prostate cancer.

INTRODUCTION: Androgen deprivation therapy (ADT) has been a treatment of choice for prostate cancer in almost all phases, particularly in the locally advanced, metastatic setting in both hormone-sensitive and castration-resistant diseaseand in those who are unfit for any local therapy. Different ways of administering ADT comes in the form of surgical or chemical castration with the use of gonadotropin-releasing hormone (GnRH-agonists) being the foremost way of delivering ADT. AREAS COVERED: This review encompasses ADT history, use of leuprolide, degarelix, and relugolix, with contextual use of ADT in combination with androgen-signaling inhibitors and potential mechanisms of resistance. Novel approaches with regard to hormone therapy are also discussed. EXPERT OPINION: The use of GnRH-agonists and GnRH-antagonists yields efficacy that is likely equivalent in resulting in testosterone suppression. While the side-effect profile with ADT are generally equivalent, effects on cardiovascular morbidity may be improved with the use of oral relugolix though this is noted with caution since the cardiovascular side-effects were a result of secondary subgroup analyses. The choice of ADT hinges upon cost, availability, ease of administration, and preference amongst physicians and patients alike.