Olaparib Without Androgen Deprivation for High-Risk Biochemically Recurrent Prostate Cancer Following Prostatectomy: A Nonrandomized Controlled Trial.

Importance: Olaparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that provides benefit in combination with hormonal therapies in patients with metastatic prostate cancer who harbor homologous recombination repair (HRR) alterations. Its efficacy in the absence of androgen deprivation therapy has not been tested. Objective: To determine the activity of olaparib monotherapy among patients with high-risk biochemically recurrent (BCR) prostate cancer after radical prostatectomy. Design, Setting, and Participants: This phase 2, single-arm nonrandomized controlled trial enrolled genetically unselected patients across 4 sites in the US from May 2017 to November 2022. Eligible patients had BCR disease following radical prostatectomy, a prostate-specific antigen (PSA) doubling time of 6 months or shorter, an absolute PSA value of 1.0 ng/mL or higher, and a testosterone level of 150 ng/dL or higher. Intervention: Treatment was with olaparib, 300 mg, by mouth twice daily until doubling of the baseline PSA, clinical or radiographic progression, or unacceptable toxic effects. Main Outcome and Measure: The primary end point was a confirmed 50% or higher decline in PSA from baseline (PSA50). Key secondary end points were outcomes by HRR alteration status, as well as safety and tolerability. Results: Of the 51 male patients enrolled (mean [SD] age, 63.8 [6.8] years), 13 participants (26%) had a PSA50 response, all within the HRR-positive group (13 of 27 participants [48%]). All 11 participants with BRCA2 alterations experienced a PSA50 response. Common adverse events were fatigue in 32 participants (63%), nausea in 28 (55%), and leukopenia in 22 (43%), and were consistent with known adverse effects of olaparib. Conclusions and Relevance: In this nonrandomized controlled trial, olaparib monotherapy led to high and durable PSA50 response rates in patients with BRCA2 alterations. Olaparib warrants further study as a treatment strategy for some patients with BCR prostate cancer but does not have sufficient activity in those without HRR alterations and should not be considered for those patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03047135.

Neoadjuvant Cisplatin, Gemcitabine, and Docetaxel in Sarcomatoid Bladder Cancer: Clinical Activity and Whole Transcriptome Analysis.

BACKGROUND: Sarcomatoid urothelial cancer of the bladder (SBC) is a rare, but aggressive histological subtype for which novel treatments are needed. OBJECTIVE: We evaluated the clinical activity and safety of neoadjuvant cisplatin plus gemcitabine plus docetaxel (CGD) in muscle-invasive patients with SBC and assessed SBC tumor biology by whole transcriptome RNA sequencing. METHODS: A single-institution, retrospective analysis of muscle-invasive SBC patients treated with neoadjuvant CGD with molecular analysis. Patients received cisplatin 35 mg/m2 + gemcitabine 800 mg/m2 + docetaxel 35 mg/m2 intravenously on days 1 and 8 + pegfilgrastim 6 mg subcutaneously on day 9 every 3 weeks for 4 cycles followed by cystectomy. The primary endpoint was pathologic complete response (ypCR) rate. RESULTS: Sixteen patients with SBC received neoadjuvant CGD with a ypCR rate of 38% and a < ypT2 rate of 50%. Grade 3 and 4 toxicity occurred in 80% and 40% of patients, but was manageable with 81% of patients completing > 3 CGD cycles. Whole transcriptome RNA sequencing demonstrates co-clustering of SBC with conventional urothelial tumors. SBC tumors are characterized by basal-squamous and stroma rich gene signatures with frequent increased expression of immune checkpoint (CD274 (PD-L1)), chemokine (CXCL9), and T-cell (CD8A) genes. CONCLUSIONS: SBC is a chemosensitive subtype, with ypCR rate similar to urothelial bladder cancer following CGD neoadjuvant therapy. Whole transcriptome tissue analyses demonstrate increased expression of immune checkpoint and T-cell genes with therapeutic implications.

Deciphering the genetic and epigenetic architecture of prostate cancer.

Prostate cancer, one of the most frequently diagnosed cancers in men, leads to significant mortality worldwide. Its study is important due to the complexity and diversity in its progression, highlighting the urgent need for improved therapeutic strategies. This chapter probes into the genetic and epigenetic factors influencing prostate cancer progression, underscoring the importance of understanding the disease's molecular fundamentals for the development of targeted therapies. It specifically reviews the role of key genetic mutations in genes such as Androgen Receptor, TP53, SPOP, FOXA1 and PTEN which are crucial for the disease onset and a progression. Furthermore, it examines the impact of epigenetic modifications, including DNA methylation and histone modification, which contribute to the cancer's progression by affecting gene expression and cellular behavior. Further, in this chapter we delve into the underlying signaling mechanism, the advancements in targeting genetic and epigenetic alterations in prostate cancer. These findings have revealed promising targets for therapeutic advancements, aiming to understand and identify promising avenues for future therapies. This chapter improves our current understanding of prostate cancer genetic and epigenetic landscape, emphasizing the necessity of advancing our knowledge to refine and expand treatment options for prostate cancer patients.

Predictive Value of Multiparametric Magnetic Resonance Imaging in Risk Group Stratification of Prostate Adenocarcinoma.

Purpose: The aim of this study was to further assess the clinical utility of multiparametric magnetic resonance imaging (MP-MRI) in prostate cancer (PC) staging following 2023 clinical guideline changes, both as an independent predictor of high-stage (>T3a) or high-risk PC and when combined with patient characteristics. Methods and Materials: The present study was a retrospective review of 171 patients from 2008 to 2018 who underwent MP-MRI before radical prostatectomy at a single institution. The accuracy of clinical staging was compared between conventional staging and MP-MRI-based clinical staging. Sensitivity, specificity, positive predictive value, and negative predictive value were compared, and receiver operating characteristic curves were generated. Linear regression analyses were used to calculate concordance (C-statistic). Results: Of the 171 patients, final pathology revealed 95 (55.6%) with T2 disease, 62 (36.3%) with T3a disease, and 14 (8.2%) with T3b disease. Compared with conventional staging, MP-MRI-based staging demonstrated significantly increased accuracy in identifying T3a disease, intermediate risk, and high/very-high-risk PC. When combined with clinical characteristics, MP-MRI-based staging improved the area under the curve from 0.753 to 0.808 (P = .0175), compared with conventional staging. Conclusions: MP-MRI improved the identification of T3a PC, intermediate-risk PC, and high- or very-high-risk PC. Further, when combined with clinical characteristics, MP-MRI-based staging significantly improved risk stratification, compared with conventional staging. These findings represent further evidence to support the integration of MP-MRI into prostate adenocarcinoma clinical staging guidelines.

NCCN Guidelines® Insights: Prostate Cancer, Version 3.2024.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

Diagnosis of Metastatic Non-Small Cell Lung Cancer during Hospitalization: Missed Opportunity for Optimal Supportive Care?

PURPOSE: The usual workup for patients newly diagnosed with advanced non-small cell lung cancer (NSCLC) occurs in the ambulatory setting. A subset of patients present with acute care needs and receive the diagnosis while hospitalized. Palliative therapies are typically initiated when patients are outpatients, even when diagnoses are made when they are inpatients. Lengthy admission, rehabilitation needs after discharge, and readmissions are possible barriers to timely and adequate outpatient follow-up. The outcomes for these patients diagnosed in the hospital are not well characterized. We hypothesized that patients have been ill-served by current treatment patterns, as reflected by low rates of cancer-directed treatment and poor survival. PATIENTS AND METHODS: We performed a retrospective study of new inpatient diagnoses of metastatic NSCLC at our institution between 1 January 2012 and 1 January 2022. The primary outcome was the proportion of patients ultimately receiving cancer-directed therapy. Other outcomes included time to treatment, use of targeted therapy, palliative care/hospice utilization, and overall survival (OS). RESULTS: Seventy-three patients were included, with a median age of 57 years. Twenty-seven patients (37%) ultimately received systemic therapy with a median time from diagnosis to treatment of 37.5 days. Overall, 5.4% patients died while admitted, 6.8% were discharged to a hospice, 21.9% were discharged to a facility, and 61.6% were discharged home. Only 20 patients (27%) received palliative care consultation. The median OS for our entire population was 2.3 months, with estimated 6-month and 1-year OS rates of 32% and 22%, respectively. CONCLUSION: Patients with new inpatient diagnoses of metastatic NSCLC have extremely poor outcomes. Current management strategies resulted in few patients starting systemic therapy, yet most of the patients did not receive palliative care or hospice involvement. These findings demonstrate that there is a high unmet need to optimally support and palliate these patients.

Association of plasma NRP2 and VEGF-C levels with prostate cancer disease severity.

BACKGROUND: Neuropilin 2 (NRP2) expression in tissue is an independent prognostic factor for aggressive prostate cancer. Since the NRP2 pathway activation is thought to occur in part through secondary resistance, quantification of NRP2 in initial tissue biopsy specimens collected at diagnosis may have limited utility in identifying patients at highest risk for morbidity and mortality. Given that metastatic tissue is only occasionally obtained for analysis, there is a need for development of a plasma biomarker indicative of NRP2 pathway activation to potentially inform prostate cancer prognosis. Therefore, we investigated if plasma levels of NRP2 or vascular endothelial growth factor C (VEGF-C), a known soluble ligand of NRP2, are prognostic for prostate cancer. We hypothesized that plasma NRP2 and VEGF-C would be associated with more advanced disease or relapsed disease. METHODS: NRP2 and VEGF-C levels were quantified by enzyme-linked immunoassay in plasma samples obtained from 145 prostate cancer patients in an opportunistic biobank. These patients were either (1) newly diagnosed (N = 28), (2) in remission (N = 56), or (3) relapsed disease (N = 61). Plasma samples from 15 adult males without known malignancy served as a comparator cohort. Statistical analysis was performed to investigate the association of plasma NRP2/VEGF-C with patient outcomes, adjusting for age, race, prostate-specific antigen (PSA), Gleason score, and tumor stage at diagnosis. RESULTS: Neither NRP2 nor VEGF-C levels were significantly different in cancer patients compared to noncancer controls. We observed no clear association between plasma NRP2 and disease severity. Increased plasma VEGF-C was significantly associated with disease remission and correlated with Stage I/II and intermediate-risk Gleason score. Neither NRP2 nor VEGF-C correlated with PSA level. CONCLUSIONS: Although tissue NRP2 expression correlates with severe disease, this was not observed for plasma NRP2. Plasma NRP2 levels did not correlate with disease severity or relapse. VEGF-C was highest in patients in remission and with less severe disease. Future investigation is needed to identify noninvasive methods to assess tumor NRP2 status.

Androgen receptor inhibition suppresses anti-tumor neutrophil response against bone metastatic prostate cancer via regulation of TßRI expression.

Bone metastatic disease of prostate cancer (PCa) is incurable and progression in bone is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that bone neutrophils initially inhibit bone metastatic PCa growth yet metastatic PCa becomes resistant to neutrophil response. Further, neutrophils isolated from tumor-bone lost their ability to suppress tumor growth through unknown mechanisms. With this study, our goal was to define the impact of metastatic PCa on neutrophil function throughout tumor progression and to determine the potential of neutrophils as predictive biomarkers of metastatic disease. Using patient peripheral blood polymorphonuclear neutrophils (PMNs), we identified that PCa progression dictates PMN cell surface markers and gene expression, but not cytotoxicity against PCa. Importantly, we also identified a novel phenomenon in which second generation androgen deprivation therapy (ADT) suppresses PMN cytotoxicity via increased transforming growth factor beta receptor I (TßRI). High dose testosterone and genetic or pharmacologic TßRI inhibition rescued androgen receptor-mediated neutrophil suppression and restored neutrophil anti-tumor immune response. These studies highlight the ability to leverage standard-care ADT to generate neutrophil anti-tumor responses against bone metastatic PCa.

Prostate Cancer, Version 4.2023, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions regarding the workup of patients with prostate cancer, risk stratification and management of localized disease, post-treatment monitoring, and treatment of recurrence and advanced disease. The Guidelines sections included in this article focus on the management of metastatic castration-sensitive disease, nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). Androgen deprivation therapy (ADT) with treatment intensification is strongly recommended for patients with metastatic castration-sensitive prostate cancer. For patients with nonmetastatic CRPC, ADT is continued with or without the addition of certain secondary hormone therapies depending on prostate-specific antigen doubling time. In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, the presence or absence of visceral disease, symptoms, and potential side effects.

Comparison of sequential versus concurrent chemoradiation regimens in non-metastatic muscle-invasive bladder cancer.

PURPOSE: The treatment approach for non-metastatic bladder cancer is guided by an invasion of the muscular layer of the bladder wall. Radical cystectomy is the recommended treatment for muscle-invasive disease. However, it has considerable morbidity and mortality and is not suited for many patients. Trimodality therapy consisting of chemoradiation after transurethral resection of bladder tumor offers a definitive approach with bladder-sparing potential. However, there is a lack of research defining the optimal combination of chemotherapy and radiation in this setting. MATERIALS AND METHODS: We extracted patient data from the National Cancer Database to compare survival outcomes and demographic factors in 2,227 non-metastatic bladder cancer patients who were treated with chemotherapy sequential to or concurrently with radiation. Sequential treatment was defined as chemotherapy beginning >14 days before radiation, and concurrent was defined as beginning within 14 days of the first radiation. RESULTS: The sequential treatment group patients were younger (mean age, 74 vs. 78 years; p < 0.001) with more advanced disease. We found no difference in overall survival between patients who received chemotherapy sequential to radiation and those who received concurrent chemoradiation only (p = 0.533). CONCLUSION: Our data are concordant with a previous prospective study, and support that chemotherapy prior to radiation does not decrease survival outcomes relative to patients receiving only concurrent chemoradiation. Given that the sequential group had an overall higher stage but no difference in survival, downstaging chemotherapy prior to radiation may be helpful in these patients. Further studies including a larger, multi-institutional clinical trial are indicated to support clinical decision-making.

A case of metastatic adenoid cystic (basal cell) carcinoma of the prostate: Systemic therapy for a rare disease.

BACKGROUND: Metastatic adenoid cystic (basal cell) carcinoma of the prostate is an exceedingly rare disease entity. As a result, no current consensus exists for optimal systemic therapy. METHODS: We present a patient with metastatic adenoid cystic (basal cell) carcinoma of the prostate who subsequently received systemic treatment, including chemotherapy and immunotherapy. We comprehensively reviewed all published data on therapy outcomes in advanced disease. RESULTS: Our patient benefited from combination chemotherapy (carboplatin and paclitaxel), with objective radiographic response and reduction in cancer-related pain. However, chemotherapy was stopped due to cumulative neurotoxicity, and subsequent immunotherapy with atezolizumab did not produce any response. Our literature review revealed inconsistent outcomes with various treatments but showed most promise with chemotherapy. Targeted therapy and immunotherapy seem to benefit specific cases, and androgen deprivation therapy had minimal evidence of benefit. CONCLUSION: Based on the findings of our case report and literature review, we suggest platinum-based chemotherapy doublets as first-line treatment for metastatic cases of adenoid cystic (basal cell) carcinoma of the prostate, reserving targeted therapy or immunotherapy for select cases based upon molecular profiles.

NCCN Guidelines® Insights: Prostate Cancer, Version 1.2023.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, recurrent, and metastatic disease. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. These NCCN Guidelines Insights summarizes much of the panel's discussions for the 4.2022 and 1.2023 updates to the guidelines regarding systemic therapy for metastatic prostate cancer.

The evolving landscape of PARP inhibitors in castration-resistant prostate cancer: a spotlight on treatment combinations.

INTRODUCTION: PARP inhibition in prostate cancer has become a standard-of-care option for men with metastatic castration-resistant prostate cancer (mCRPC) with deficiency in homologous recombination repair (HRRd). The benefit varies based upon the characteristics of the PARP inhibitor used and the underlying HRR defect. Optimal patient selection remains a clinical challenge, and investigations are underway to identify effective combination therapies to expand the population that benefits. AREAS COVERED: We review the clinical development of the FDA-approved PARP inhibitors olaparib and rucaparib. Additionally, we explore the status of other PARP inhibitors that remain experimental in prostate cancer, based upon review of published abstracts, articles, and clinicaltrials.gov. Most new studies, including phase 3 trials for talazoparib and rucaparib, involve combinations with novel androgen receptor signaling inhibitors. We review the landscape of emerging PARP inhibitor-based combination therapies. EXPERT OPINION: For men with BRCA1 or BRCA2 mutations, olaparib has a clear role for early use in the disease course of mCRPC. For men with other HRR mutations, that benefit remains less well defined, particularly with the availability of other treatment choices. Ultimately, combination strategies are likely to be the best avenue for men without BRCA1 or BRCA2 mutations to be treated with PARP inhibition.

Neuropilin-2 axis in regulating secretory phenotype of neuroendocrine-like prostate cancer cells and its implication in therapy resistance.

Neuroendocrine (NE)-like tumors secrete various signaling molecules to establish paracrine communication within the tumor milieu and to create a therapy-resistant environment. It is important to identify molecular mediators that regulate this secretory phenotype in NE-like cancer. The current study highlights the importance of a cell surface molecule, Neuropilin-2 (NRP2), for the secretory function of NE-like prostate cancer (PCa). Our analysis on different patient cohorts suggests that NRP2 is high in NE-like PCa. We have developed cell line models to investigate NRP2's role in NE-like PCa. Our bioinformatics, mass spectrometry, cytokine array, and other supporting experiments reveal that NRP2 regulates robust secretory phenotype in NE-like PCa and controls the secretion of factors promoting cancer cell survival. Depletion of NRP2 reduces the secretion of these factors and makes resistant cancer cells sensitive to chemotherapy in vitro and in vivo. Therefore, targeting NRP2 can revert cellular secretion and sensitize PCa cells toward therapy.

Impact of Performance Status on Response and Survival Among Patients Receiving Checkpoint Inhibitors for Advanced Solid Tumors.

PURPOSE: Clinical trials, which led to the approval of immune checkpoint inhibitors (ICI), have been almost exclusively performed in patients with good Eastern Cooperative Oncology Group performance status (ECOG PS of 0-1). However, ICI remains an attractive option for patients with advanced tumors and poor PS. We hypothesized that patients with ECOG PS ≥ 2 would have worse outcomes with ICI. METHODS: We retrospectively identified patients with advanced solid tumors who were treated with ICI at our institution. The log-rank test compared the survival among patients with different ECOG PS. We used a proportional hazards model to assess association between ECOG PS and overall survival (OS) with adjustment for covariates including age, sex, malignancy type, time from advance disease diagnosis, and line of therapy. We compared overall response rates between groups with Pearson chi-square exact test. We also analyzed in-hospital mortality and hospice referral rates. RESULTS: We identified 257 patients treated with ICI. One hundred eighty-two patients had ECOG PS 0-1, and 75 had ECOG PS ≥ 2. The median overall survival was 12.6 months for the ECOG PS 0-1 group compared with 3.1 months for the ECOG PS ≥ 2 group (P < .001). The overall response rate for patients with ECOG PS 0-1 was 23% compared with 8% for those with poor PS (P = .005). Patients with poor PS treated with ICI had similar hospice referral rates (67% for ECOG PS ≥ 2 v 61.9% for ECOG PS 0-1, P = .50) but were more likely to have in-hospital death as compared with the good PS group (28.6% v 15.1%, P = .035). CONCLUSION: Despite the appeal of ICI in patients with advanced malignancy and poor PS, outcomes in this cohort were poor. Prospective trials defining the activity and role of ICI in poor PS are urgently needed.

Impact of Proton Pump Inhibitor Use on the Effectiveness of Immune Checkpoint Inhibitors in Advanced Cancer Patients.

BACKGROUND: The gut microbiome plays a critical role in modulating the therapeutic effect of immune checkpoint inhibitors (ICIs). Proton pump inhibitors (PPIs) are commonly used in cancer patients and may affect the gut microbiome by altering gut pH. OBJECTIVE: To evaluate if concurrent use of PPI is associated with overall survival (OS) and progression-free survival (PFS) in patients with stage IV non-small-cell lung cancer (NSCLC), melanoma, renal cell carcinoma, transitional cell carcinoma, or head and neck squamous cell carcinoma. METHODS: This was a single-center retrospective cohort study of advanced cancer adult patients who received nivolumab or pembrolizumab between September 1, 2014, and August 31, 2019. Concomitant PPI exposure was defined as PPI use 0 to 30 days before or after initiation of ICIs. Treatment outcome was OS and PFS. RESULTS: A total of 233 patients were included in our study. Concomitant PPI use was not significantly associated with OS (hazard ratio [HR] = 1.22; 95% CI = 0.80-1.86) or PFS (HR = 1.05; 95% CI = 0.76-1.45) in patients with ICI use. The effect estimates were robust after adjusting for covariates in multivariate analysis and in patients with NSCLC. CONCLUSION AND RELEVANCE: Concomitant PPI use was not associated with the effectiveness of nivolumab or pembrolizumab. Certain predictors of survival outcomes related to PPI use in patients receiving immunotherapy, such as the time window and indication of PPI exposure and autoimmune disorders, should be explored in the future to better carve out the impact of PPI on the effectiveness of ICI use.

Development of bullous pemphigoid following radiation therapy combined with nivolumab for renal cell carcinoma: A case report of abscopal toxicities.

RATIONALE: Concern for immune-related adverse events from immunotherapy and radiation therapy are well-documented; however, side effects are mostly mild to moderate. However, high-grade, potentially life-threatening adverse events are increasing. While case reports regarding immunotherapy-related bullous pemphigoid (BP) have been rising, only 1 has described BP following concomitant use of both nivolumab and radiation therapy (RT). For that patient, nivolumab was used for 10 weeks prior to RT and development of PB followed 7 weeks later. This case presents a patient who tolerated nivolumab well for 38 months prior to developing BP less than 2 weeks after completing RT. PATIENT CONCERNS: We present the case of DH, a 67-year-old gentleman on nivolumab for metastatic renal cell carcinoma to the lung since May of 2017. Following progressing lung nodules, the patient had his nivolumab paused and completed a course of short-beam radiation therapy. After restarting nivolumab post-radiation, the patient presented with itchy rash and blisters on his arm, legs, and trunk. DIAGNOSIS: DH consulted dermatology following development of rash and was diagnosed with bullous dermatosis, likely bullous pemphigoid. Bullous pemphigoid following concomitant nivolumab (OPDIVO), despite prior tolerance and no history of autoimmune disease, was confirmed by biopsy a month later. INTERVENTIONS: Initial treatment was betamethasone 0.05% cream mixed 1:1 with powder to form paste applied twice daily. Given progressive symptoms and confirmatory biopsy of BP, nivolumab was held and 100 mg doxycycline and 80 mg prednisone daily was prescribed for a week, reduced to 60 mg during the second week. OUTCOMES: A week following discontinuation of nivolumab and beginning of doxycycline and prednisone, the blistering and rash was almost entirely resolved. Four months later, nivolumab was restarted and the patient continued low-dose tapering of prednisone until December. Since completing prednisone, the patient has shown no recurrence of bullous pemphigoid and has not developed any other immune-related adverse events to nivolumab upon rechallenge. Follow-up through October 2021 demonstrates the patient's sites of disease, both in- and out-field, have remained responsive to treatment. LESSONS: Treating physicians should be aware of off-target effects of radiotherapy for oligoprogressive disease, which may include abscopal toxicities and the development of new immune-related adverse effects.

Biomarkers for Treatment Response in Advanced Prostate Cancer.

Multiple treatment options with different mechanisms of action are currently available for the management of metastatic prostate cancer. However, the optimal use of these therapies-specifically, the sequencing of therapies-is not well defined. In order to obtain the best clinical outcomes, patients need to be treated with the therapies that are most likely to provide benefit and avoid toxic therapies that are unlikely to be effective. Ideally, predictive biomarkers that allow for the selection of the therapies most likely to be of benefit would be employed for each treatment decision. In practice, biomarkers including tumor molecular sequencing, circulating tumor DNA, circulating tumor cell enumeration and androgen receptor characteristics, and tumor cell surface expression (PSMA), all may have a role in therapy selection. In this review, we define the established prognostic and predictive biomarkers for therapy in advanced prostate cancer and explore emerging biomarkers.

Effect of Cisplatin and Gemcitabine With or Without Berzosertib in Patients With Advanced Urothelial Carcinoma: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Preclinical studies suggest that inhibition of single-stranded DNA repair by ataxia telangiectasia and Rad3 (ATR) may enhance the cytotoxicity of cisplatin, gemcitabine, and other chemotherapeutic agents. Cisplatin with gemcitabine remains the standard up-front therapy for treatment in patients with metastatic urothelial cancer. OBJECTIVE: To determine whether the use of the selective ATR inhibitor, berzosertib, could augment the activity of cisplatin with gemcitabine. DESIGN, SETTING, AND PARTICIPANTS: In a phase 2 randomized clinical trial, 87 patients across 23 centers in the National Cancer Institute Experimental Therapeutics Clinical Trials Network were randomized to receive either cisplatin with gemcitabine alone (control arm) or cisplatin with gemcitabine plus berzosertib (experimental arm). Key eligibility criteria included confirmed metastatic urothelial cancer, no prior cytotoxic therapy for metastatic disease, 12 months or more since perioperative therapy, and eligibility for cisplatin receipt based on standard criteria. The study was conducted from January 27, 2017, to December 15, 2020. INTERVENTIONS: In the control arm, cisplatin, 70 mg/m2, was given on day 1 and gemcitabine, 1000 mg/m2, was given on days 1 and 8 of a 21-day cycle. In the experimental arm, cisplatin, 60 mg/m2, was given on day 1; gemcitabine, 875 mg/m2, on days 1 and 8; and berzosertib, 90 mg/m2, on days 2 and 9 of a 21-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point of the study was progression-free survival. The analysis was on all patients who started therapy. RESULTS: Of the total of 87 patients randomized, 41 patients received cisplatin with gemcitabine alone and 46 received cisplatin with gemcitabine plus berzosertib. Median age was 67 (range, 32-84) years, and 68 patients (78%) were men. Median progression-free survival was 8.0 months for both arms (Bajorin risk-adjusted hazard ratio, 1.22; 95% CI, 0.72-2.08). Median overall survival was shorter with cisplatin with gemcitabine plus berzosertib compared with cisplatin with gemcitabine alone (14.4 vs 19.8 months; Bajorin risk-adjusted hazard ratio, 1.42; 95% CI, 0.76-2.68). Higher rates of grade 3 vs grade 4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with cisplatin with gemcitabine and berzosertib compared with cisplatin with gemcitabine alone; consequently, more dose reductions were needed in the experimental arm. Patients in the experimental arm received a median cisplatin dose of 250 mg/m2, which was significantly lower than the median dose of 370 mg/m2 in the control arm (P < .001). CONCLUSIONS AND RELEVANCE: The addition of berzosertib to cisplatin with gemcitabine did not prolong progression-free survival relative to cisplatin with gemcitabine alone in patients with metastatic urothelial cancer, and a trend toward inferior survival was observed with this combination. Berzosertib plus cisplatin with gemcitabine was associated with significantly higher hematologic toxicities despite attenuated dosing of cisplatin with gemcitabine. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02567409.

Current Management of Refractory Germ Cell Tumors.

PURPOSE OF REVIEW: Germ cell tumors (GCTs) are the most common solid tumors affecting men between ages of 20 and 34 years. Most of the cases, even in advanced disease, will have good prognosis. However, around 20-30% of advanced disease will be refractory or develop relapse after treatment. Herein, we review the current management of refractory/relapsed GCTs. RECENT FINDINGS: Salvage treatment of GCTs has been a controversial topic for the last few decades. Conventional dose chemotherapy (CDCT), high-dose chemotherapy (HDCT) with stem cell infusion, and surgical salvage were proven to be effective and curative options in some cases. The international randomized trial (TIGER) will ultimately answer which chemotherapy approach may be optimal. Furthermore, the usage of immunotherapy is still under investigation with limited data so far in the setting of relapsed/refractory GCTs. Curative paradigms including with CDCT and HDCT are possible, although novel approaches beyond HDCT are still needed to eliminate mortality from this disease.