Pan-Cancer Interrogation of B7-H3 (CD276) as an Actionable Therapeutic Target across Human Malignancies.

B7-H3 (CD276) is a transmembrane glycoprotein of the B7 immune checkpoint superfamily that has emerged as a promising therapeutic target. To better understand the applicability of B7-H3-directed therapies, we analyzed 156,791 samples comprising 50 cancer types to interrogate the clinical, genomic, transcriptomic, and immunological correlates of B7-H3 mRNA expression. DNA (592-gene/whole-exome) and RNA (whole-transcriptome) sequencing was performed from samples submitted to Caris Life Sciences (Phoenix, AZ). B7-H3 high versus low expression was based on top and bottom quartiles for each cancer type. Patients' overall survival was determined from insurance claims data. Pathway analysis was performed using Gene Set Enrichment Analyses (GSEA). Immune cell fractions were inferred using quanTIseq. B7-H3 is expressed across several human malignancies including prostate, pancreatic, ovarian, and lung cancers. High B7-H3 expression is associated with differences in overall survival, possibly indicating a prognostic role of B7-H3 for some cancers. When examining molecular features across all cancer types, we did not identify recurrent associations between B7-H3 expression and genetic alterations in TP53, RB1, and KRAS. However, we find consistent enrichment of EMT, Wnt, TGF-beta, and Notch signaling pathways. Additionally, tumors with high B7-H3 expression are associated with greater proportions of M1 macrophages, but lower fractions of CD8+ T cells. We have begun to define the genomic, transcriptomic, clinical, and immunological features associated with B7-H3 expression in 50 cancer types. We report novel clinical and molecular features of B7-H3-high tumors which may inform how current B7-H3 therapeutics should be deployed and prioritized.

Treatment Patterns and Attrition With Lines of Therapy for Advanced Urothelial Carcinoma in the US.

Importance: The treatment paradigm for advanced urothelial carcinoma (aUC) has undergone substantial transformation due to the introduction of effective, novel therapeutic agents. However, outcomes remain poor, and little is known about current treatment approaches and attrition rates for patients with aUC. Objectives: To delineate evolving treatment patterns and attrition rates in patients with aUC using a US-based patient-level sample. Design, Setting, and Participants: This retrospective cohort study used patient-level data from the nationwide deidentified electronic health record database Flatiron Health, originating from approximately 280 oncology clinics across the US. Patients included in the analysis received treatment for metastatic or local aUC at a participating site from January 1, 2011, to January 31, 2023. Patients receiving treatment for 2 or more different types of cancer or participating in clinical trials were excluded from the analysis. Main Outcomes and Measures: Frequencies and percentages were used to summarize the (1) treatment received in each line (cisplatin-based regimens, carboplatin-based regimens, programmed cell death 1 and/or programmed cell death ligand 1 [PD-1/PD-L1] inhibitors, single-agent nonplatinum chemotherapy, enfortumab vedotin, erdafitinib, sacituzumab govitecan, or others) and (2) attrition of patients with each line of therapy, defined as the percentage of patients not progressing to the next line. Results: Of the 12 157 patients within the dataset, 7260 met the eligibility criteria and were included in the analysis (5364 [73.9%] men; median age at the start of first-line treatment, 73 [IQR, 66-80] years). All patients commenced first-line treatment; of these, only 2714 (37.4%) progressed to receive second-line treatment, and 857 (11.8%) advanced to third-line treatment. The primary regimens used as first-line treatment contained carboplatin (2241 [30.9%]), followed by PD-1/PD-L1 inhibitors (2174 [29.9%]). The PD-1/PD-L1 inhibitors emerged as the predominant choice in the second- and third-line (1412 of 2714 [52.0%] and 258 of 857 [30.1%], respectively) treatments. From 2019 onward, novel therapeutic agents were increasingly used in second- and third-line treatments, including enfortumab vedotin (219 of 2714 [8.1%] and 159 of 857 [18.6%], respectively), erdafitinib (39 of 2714 [1.4%] and 28 of 857 [3.3%], respectively), and sacituzumab govitecan (14 of 2714 [0.5%] and 34 of 857 [4.0%], respectively). Conclusions and Relevance: The findings of this cohort study suggest that approximately two-thirds of patients with aUC did not receive second-line treatment. Most first-line treatments do not include cisplatin-based regimens and instead incorporate carboplatin- or PD-1/PD-L1 inhibitor-based therapies. These data warrant the provision of more effective and tolerable first-line treatments for patients with aUC.

Optimizing the Use of Next-Generation Sequencing Assays in Patients With Urothelial Carcinoma: Recommendations by the 2023 San Raffaele Retreat Panel.

BACKGROUND: The application of precision medicine in clinical practice implies a thorough evaluation of actionable genomic alterations to streamline therapeutic decision making. Comprehensive genomic profiling of tumor via next-generation sequencing (NGS) represents a great opportunity but also several challenges. During the 2023 San Raffaele Retreat, we aimed to provide expert recommendations for the optimal use of NGS in urothelial carcinoma (UC). MATERIALS AND METHODS: A modified Delphi method was utilized, involving a panel of 12 experts in UC from European and United States centers, including oncologists, urologists, pathologists, and translational scientists. An initial survey, conducted before the meeting, delivered 15 statements to the panel. A consensus was defined when ≥70% agreement was reached for each statement. Statements not meeting the consensus threshold were discussed during the meeting. RESULTS: Nine of the 15 statements covering patient selection, cancer characteristics, and type of NGS assay, achieved a consensus during the survey. The remaining six statements addressing the optimal timing of NGS use, the ideal source of tumor biospecimen for NGS testing, and the subsequent need to evaluate the germline nature of certain genomic findings were discussed during the meeting, leading to unanimous agreement at the end of the conference. CONCLUSION: This consensus-building effort addressed multiple unanswered questions regarding the use of NGS in UC. The opinion of experts was in favor of broader use of NGS. In a setting where recommendations/guidelines may be limited, these insights may aid clinicians to provide informed counselling and raise the bar of precision and personalized therapy.

Differences in Tumor Gene Expression Profiles Between De Novo Metastatic Castration-sensitive Prostate Cancer and Metastatic Relapse After Prior Localized Therapy.

BACKGROUND AND OBJECTIVE: It has been reported that patients with de novo metastatic castration-sensitive prostate cancer (dn-mCSPC) have worse prognosis and outcomes than those whose cancer relapses after prior local therapy (PLT-mCSPC). Our aim was to interrogate and validate underlying differences in tumor gene expression profiles between dn-mCSPC and PLT-mCSPC. METHODS: The inclusion criteria were histologically confirmed prostate adenocarcinoma and the availability of RNA sequencing data for treatment-naïve primary prostate tissue. RNA sequencing was performed by Tempus or Caris Life Sciences, both of which have Clinical Laboratory Improvement Amendments certification. The Tempus cohort was used for interrogation, while the Caris cohort was used for validation. Differential gene expression analysis between the cohorts was conducted using the DEseq2 pipeline. The resulting gene expression profiles were further analyzed using Gene Set Enrichment software to identify pathways with enrichment in each cohort. KEY FINDINGS AND LIMITATIONS: Overall, 128 patients were eligible, of whom 78 were in the Tempus cohort (dn-mCSPC 37, PLT-mCSPC 41) and 50 were in the Caris cohort (dn-mCSPC 30, PLT-mCSPC 20). Tumor tissues from patients with dn-mCSPC had higher expression of genes associated with inflammation pathways, while tissues from patients with PLT-mCSPC had higher expression of genes involved in oxidative phosphorylation, fatty acid metabolism, and androgen response pathways. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our study revealed upregulation of distinct genomic pathways in dn-mCSPC in comparison to PLT-mCSPC. These hypothesis-generating data could guide personalized therapy for men with prostate cancer and explain different survival outcomes for dn-mCSPC and PLT-mCSPC. PATIENT SUMMARY: We measured gene expression levels in tumors from patients with metastatic castration-sensitive prostate cancer. In patients with metastatic disease at first diagnosis, inflammatory pathways were upregulated. In patients whose metastasis occurred on relapse after treatment, androgen response pathways were upregulated. These findings could help in personalizing therapy for prostate cancer and explaining differences in survival.

Natural course of metastatic castration-resistant prostate cancer in the era of intensified androgen deprivation therapy in the hormone-sensitive setting.

BACKGROUND: Androgen deprivation therapy (ADT) intensification (ADTi) (i.e., ADT with androgen receptor pathway inhibitor or docetaxel, or both) has significantly improved survival outcomes of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of prior ADTi in the mHSPC setting on the disease presentation and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) is not well characterized. In this study, our objective was to compare the disease characteristics and survival outcomes of patients with new mCRPC with respect to receipt of intensified or nonintensified ADT in the mHSPC setting. METHODS: In this institutional review board-approved retrospective study, eligibility criteria were as follows: patients diagnosed with mCRPC, treated with an approved first-line mCRPC therapy, and who received either intensified or nonintensified ADT in the mHSPC setting. Progression-free survival (PFS) was defined from the start of first-line therapy for mCRPC to progression per Prostate Cancer Working Group 2 criteria or death, and overall survival (OS) was defined from the start of first-line therapy for mCRPC to death or censored at the last follow-up. A multivariable analysis using the Cox proportional hazards model was used, adjusting for potential confounders. RESULTS: Patients (n = 387) treated between March 20, 2008, and August 18, 2022, were eligible and included: 283 received nonintensified ADT, whereas 104 were treated with ADTi. At mCRPC diagnosis, patients in the ADTi group were significantly younger, had more visceral metastasis, lower baseline prostate-specific antigen (all p < 0.01), and lower hemoglobin (p = 0.027). Furthermore, they had significantly shorter PFS (median 4.8 vs. 8.4 months, adjusted hazard ratio [HR]: 1.46, 95% confidence interval [95% CI]: 1.07-2, p = 0.017) and OS (median 21.3 vs. 33.1 months, adjusted HR: 1.53, 95% CI: 1.06-2.21, p = 0.022) compared to patients in the nonintensified ADT group. CONCLUSION: Patients treated with ADTi in the mHSPC setting and experiencing disease progression to mCRPC had more aggressive disease features of mCRPC (characterized by a higher number of poor prognostic factors at mCRPC presentation). They also had shorter PFS on first-line mCRPC treatment and shorter OS after the onset of mCRPC compared to those not receiving ADTi in the mHSPC setting. Upon external validation, these findings may impact patient counseling, prognostication, treatment selection, and design of future clinical trials in the mCRPC setting. There remains an unmet need to develop novel life-prolonging therapies with new mechanisms of action to improve mCRPC prognosis in the current era.

Molecular subtypes as potential biomarkers in renal cell carcinoma.

The increasing number of approved treatment combinations for metastatic renal cell carcinoma highlights the need for actionable biomarkers to guide treatment selection. In this issue of Cancer Cell, Saliby et al. validate the distinct clinico-genomic profiles of expression-based molecular clusters identified in the IMmotion151 trial in the JAVELIN Renal 101 dataset.

Creatine supplementation and resistance training to preserve muscle mass and attenuate cancer progression (CREATINE-52): a protocol for a double-blind randomized controlled trial.

BACKGROUND: Muscle mass is important for metastatic prostate cancer survival and quality of life (QoL). The backbone of treatment for men with metastatic castration sensitive prostate cancer (mCSPC) is androgen deprivation therapy (ADT) with an androgen signaling inhibitor. ADT is an effective cancer treatment, but it facilitates significant declines in muscle mass and adverse health outcomes important to mCSPC survivors, such as fatigue, and reductions in physical function, independence, insulin sensitivity, and QoL. In non-metastatic CSPC survivors, resistance training (RT) preserves muscle mass and improves these related health outcomes, but the biggest barrier to RT in CSPC survivors of all stages is fatigue. Creatine monohydrate supplementation coupled with RT (Cr + RT) may address this barrier since creatine plays a critical role in energy metabolism. Cr + RT in cancer-free older adults and other clinical populations improves muscle mass and related health outcomes. Evidence also suggests that creatine supplementation can complement cancer treatment. Thus, Cr + RT is a strategy that addresses gaps in survivorship needs of people with mCSPC. The purpose of this parallel, double-blind randomized controlled trial is to test the effects of 52-weeks of Cr + RT compared with placebo (PLA) and RT (PLA + RT) on muscle mass, other related health outcomes, and markers of cancer progression. METHODS: We will carry out this trial with our team's established, effective, home-based, telehealth RT program in 200 mCSPC survivors receiving ADT, and evaluate outcomes at baseline, 24-, and 52-weeks. RT will occur twice weekly with elastic resistance bands, and an established creatine supplementation protocol will be used for supplementation delivery. Our approach addresses a major facilitator to RT in mCSPC survivors, a home-based RT program, while utilizing a supervised model for safety. DISCUSSION: Findings will improve delivery of comprehensive survivorship care by providing a multicomponent, patient-centered lifestyle strategy to preserve muscle mass, improve health outcomes, and complement cancer treatment (NCT06112990).

Impact of smoking status on clinical outcomes in patients with metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based regimens.

BACKGROUND: Current tobacco smoking is independently associated with decreased overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) treated with targeted monotherapy (VEGF-TKI). Herein, we assess the influence of smoking status on the outcomes of patients with mRCC treated with the current first-line standard of care of immune checkpoint inhibitor (ICI)-based regimens. MATERIALS AND METHODS: Real-world data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were collected retrospectively. Patients with mRCC who received either dual ICI therapy or ICI with VEGF-TKI in the first-line setting were included and were categorized as current, former, or nonsmokers. The primary outcomes were OS, time to treatment failure (TTF), and objective response rate (ORR). OS and TTF were compared between groups using the log-rank test and multivariable Cox regression models. ORR was assessed between the 3 groups using a multivariable logistic regression model. RESULTS: A total of 989 eligible patients were included in the analysis, with 438 (44.3%) nonsmokers, 415 (42%) former, and 136 (13.7%) current smokers. Former smokers were older and included more males, while other baseline characteristics were comparable between groups. Median follow-up for OS was 21.2 months. In the univariate analysis, a significant difference between groups was observed for OS (P = .027) but not for TTF (P = .9), with current smokers having the worse 2-year OS rate (62.8% vs 70.8% and 73.1% in never and former smokers, respectively). After adjusting for potential confounders, no significant differences in OS or TTF were observed among the 3 groups. However, former smokers demonstrated a higher ORR compared to never smokers (OR 1.45, P = .02). CONCLUSION: Smoking status does not appear to independently influence the clinical outcomes to first-line ICI-based regimens in patients with mRCC. Nonetheless, patient counseling on tobacco cessation remains a crucial aspect of managing patients with mRCC, as it significantly reduces all-cause mortality.

Impact of Synchronous versus Metachronous Metastasis on Outcomes in Patients with Metastatic Renal Cell Carcinoma Treated with First-line Immune Checkpoint Inhibitor-based Combinations.

BACKGROUND AND OBJECTIVE: The impact of time of metastasis onset with respect toprimary renal cell carcinoma (RCC) diagnosis on survival outcomes is not well characterized in the era of immune checkpoint inhibitor (ICI)-based combinations. Herein, we assessed differences in clinical outcomes between synchronous and metachronous metastatic RCC (mRCC). METHODS: Data for patients with mRCC treated with first-line ICI-based combination therapies between 2014 and 2023 were retrospectively collected. Patients were categorized as having synchronous metastasis if present within 3 mo of RCC diagnosis; metachronous metastasis was defined as metastasis >3 mo after primary diagnosis. Time to treatment failure (TTF), overall survival (OS), and the disease control rate (DCR) were assessed. KEY FINDINGS AND LIMITATIONS: Our analysis included 223 eligible patients (126 synchronous and 97 metachronous). Median TTF did not significantly differ between the synchronous and metachronous groups (9 vs 19.8 mo; p = 0.063). Median OS was significantly shorter in the synchronous group (28.0 vs 50.9 mo; p = 0.001). Similarly, patients with synchronous metachronous metastasis (58.7% vs. 78.4%; p = 0.002). On multivariable analyses, synchronous metastasis remained independently associated with worse OS and DCR. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this hypothesis-generating study, patients with mRCC with synchronous metastasis who were treated with first-line ICI-based combinations have a poorer OS and worse DCR than those with metachronous mRCC. If these results are externally validated, time to metastasis could be included in prognostic models for mRCC. PATIENT SUMMARY: Our study demonstrates that patients treated with current first-line immunotherapies, who present with metastasis at the initial diagnosis of kidney cancer have worse overall survival compared to those who develop metastasis later. These results can help physicians and patients understand life expectancy.

Emerging racial disparities among Medicare beneficiaries and Veterans with metastatic castration-sensitive prostate cancer.

BACKGROUND: Previous studies have shown that Black men receive worse prostate cancer care than White men. This has not been explored in metastatic castration-sensitive prostate cancer (mCSPC) in the current treatment era. METHODS: We evaluated treatment intensification (TI) and overall survival (OS) in Medicare (2015-2018) and Veterans Health Administration (VHA; 2015-2019) patients with mCSPC, classifying first-line mCSPC treatment as androgen deprivation therapy (ADT) + novel hormonal therapy; ADT + docetaxel; ADT + first-generation nonsteroidal antiandrogen; or ADT alone. RESULTS: We analyzed 2226 Black and 16,071 White Medicare, and 1020 Black and 2364 White VHA patients. TI was significantly lower for Black vs White Medicare patients overall (adjusted odds ratio [OR] 0.68; 95% confidence interval [CI] 0.58-0.81) and without Medicaid (adjusted OR 0.70; 95% CI 0.57-0.87). Medicaid patients had less TI irrespective of race. OS was worse for Black vs White Medicare patients overall (adjusted hazard ratio [HR] 1.20; 95% CI 1.09-1.31) and without Medicaid (adjusted HR 1.13; 95% CI 1.01-1.27). OS was worse in Medicaid vs without Medicaid, with no significant OS difference between races. TI was significantly lower for Black vs White VHA patients (adjusted OR 0.75; 95% CI 0.61-0.92), with no significant OS difference between races. CONCLUSIONS: Guideline-recommended TI was low for all patients with mCSPC, with less TI in Black patients in both Medicare and the VHA. Black race was associated with worse OS in Medicare but not the VHA. Medicaid patients had less TI and worse OS than those without Medicaid, suggesting poverty and race are associated with care and outcomes.

First-line combination treatment with PARP and androgen receptor-signaling inhibitors in HRR-deficient mCRPC: Applying clinical study findings to clinical practice in the United States.

INTRODUCTION: Metastatic castration-resistant prostate cancer (mCRPC) remains incurable and develops from biochemically recurrent PC treated with androgen deprivation therapy (ADT) following definitive therapy for localized PC, or from metastatic castration-sensitive PC (mCSPC). In the mCSPC setting, treatment intensification of ADT plus androgen receptor (AR)-signaling inhibitors (ARSIs), with or without chemotherapy, improves outcomes vs ADT alone. Despite multiple phase 3 trials demonstrating a survival benefit of treatment intensification in PC, there remains high use of ADT monotherapy in real-world clinical practice. Prior studies indicate that co-inhibition of AR and poly(ADP-ribose) polymerase (PARP) may result in enhanced benefit in treating tumors regardless of alterations in DNA damage response genes involved either directly or indirectly in homologous recombination repair (HRR). Three recent phase 3 studies evaluated the combination of a PARP inhibitor (PARPi) with an ARSI as first-line treatment for mCRPC: TALAPRO-2, talazoparib plus enzalutamide; PROpel, olaparib plus abiraterone acetate and prednisone (AAP); and MAGNITUDE, niraparib plus AAP. Results from these studies have led to the recent approval in the United States of talazoparib plus enzalutamide for the treatment of mCRPC with any HRR alteration, and of both olaparib and niraparib indicated in combination with AAP for the treatment of mCRPC with BRCA alterations. SUMMARY: Here, we review the newly approved PARPi plus ARSI treatments within the context of the mCRPC treatment landscape, provide an overview of practical considerations for the combinations in clinical practice, highlight the importance of HRR testing, and discuss the benefits of treatment intensification for patients with mCRPC.

Cabozantinib with immune checkpoint inhibitor versus cabozantinib monotherapy in patients with metastatic clear cell renal cell carcinoma progressing after prior immune checkpoint inhibitor.

INTRODUCTION: Rechallenge with antibodies targeting programmed cell death protein-1 or its ligand (PD-1/L1) after discontinuation or disease progression in solid tumors following a prior PD-1/L1 treatment is often practiced in clinic. This study aimed to investigate if adding PD-1/L1 inhibitors to cabozantinib, the most used second-line treatment in real-world patients with metastatic clear cell renal cell carcinoma (mccRCC), offers additional benefits. METHODS: Using de-identified patient-level data from a large real-world US-based database, patients diagnosed with mccRCC, who received any PD-1/L1-based combination in first-line (1L) setting, followed by second-line (2L) therapy with either cabozantinib alone or in combination with PD-1/L1 inhibitors were included. Patients given a cabozantinib-containing regimen in 1L were excluded. The study end points were real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) by 2L. RESULTS: Of 12,285 patients with metastatic renal cell carcinoma in the data set, 348 patients met eligibility and were included in the analysis. After propensity score matching weighting, cabozantinib with PD-1/L1 inhibitors versus cabozantinib (ref.) had similar rwTTNT and rwOS in the 2L setting. Hazard ratios and 95% confidence interval (CI) for rwTTNT and rwOS are 0.74 (95% CI, 0.49-1.12) and 1.15 (95% CI, 0.73-1.79), respectively. CONCLUSION: In this study, the results align with the phase 3 CONTACT-03 trial results, which showed no additional benefit of adding PD-L1 inhibitor to cabozantinib compared to cabozantinib alone in 2L following PD-1/L1-based therapies in 1L. These results from real-world patients strengthen the evidence regarding the futility of rechallenge with PD-1/L1 inhibitors.

CD70-Targeted Allogeneic CAR T-Cell Therapy for Advanced Clear Cell Renal Cell Carcinoma.

Therapeutic approaches for clear cell renal cell carcinoma (ccRCC) remain limited; however, chimeric antigen receptor (CAR) T-cell therapies may offer novel treatment options. CTX130, an allogeneic CD70-targeting CAR T-cell product, was developed for the treatment of advanced or refractory ccRCC. We report that CTX130 showed favorable preclinical proliferation and cytotoxicity profiles and completely regressed RCC xenograft tumors. We also report results from 16 patients with relapsed/refractory ccRCC who received CTX130 in a phase I, multicenter, first-in-human clinical trial. No patients encountered dose-limiting toxicity, and disease control was achieved in 81.3% of patients. One patient remains in a durable complete response at 3 years. Finally, we report on a next-generation CAR T construct, CTX131, in which synergistic potency edits to CTX130 confer improved expansion and efficacy in preclinical studies. These data represent a proof of concept for the treatment of ccRCC and other CD70+ malignancies with CD70-targeted allogeneic CAR T cells. SIGNIFICANCE: Although the role of CAR T cells is well established in hematologic malignancies, the clinical experience in solid tumors has been disappointing. This clinical trial demonstrates the first complete response in a patient with RCC, reinforcing the potential benefit of CAR T cells in the treatment of solid tumors.

A Signal-finding Study of Abemaciclib in Heavily Pretreated Patients with Metastatic Castration-Resistant Prostate Cancer: Results from CYCLONE 1.

BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC). METHODS: Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg BID was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%. RESULTS: At trial entry, forty (90.9%) of 44 patients had objective radiographic disease progression, four (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months (95% CI: 3.2, NA); median radiographic PFS; 2.7 months (95% CI: 1.9, 3.7); and median OS: 8.4 months (95% CI: 5.6, 12.7). Most frequent grade ≥3 TEAEs were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib. CONCLUSION: Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer.

Randomized, Double-Blind Phase III Study of Pazopanib Versus Placebo in Patients With Metastatic Renal Cell Carcinoma Who Have No Evidence of Disease After Metastasectomy: ECOG-ACRIN E2810.

PURPOSE: Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy. PATIENTS AND METHODS: Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate. RESULTS: From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; Pone-sided = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo (Ptwo-sided = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period. CONCLUSION: Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.

Three- and Seven-month Prostate-specific Antigen Levels as Prognostic Markers for Overall Survival in Metastatic Hormone-sensitive Prostate Cancer: Results from SWOG S1216, a Phase 3 Randomized Trial of Androgen Deprivation Plus Orteronel or Bicalutamide.

BACKGROUND: A robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with metastatic hormone-sensitive prostate cancer (mHSPC) since 2006, but the treatment of mHSPC has since evolved to include intensified therapy. OBJECTIVE: We assessed the association of PSA levels at 3 (PSA-3mo) and 7 (PSA-7mo) mo with overall survival (OS) in patients with mHSPC treated with ADT combined with either bicalutamide or orteronel in the S1216 phase 3 clinical trial. DESIGN, SETTING, AND PARTICIPANTS: PSA responses to treatment of patients in the S1216 trial were categorized as: complete response (CR) if PSA was ≤0.2 ng/ml, partial response if PSA was >0.2 and ≤4 ng/ml, and no response (NR) if PSA was >4 ng/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A Cox analysis (adjusted for treatment arm and three stratification factors: performance status, severity of disease, and early vs late induction) was used for OS association. While PSA-7mo association was a prespecified objective, PSA-3mo association was also evaluated. RESULTS AND LIMITATIONS: A total of 1251 and 1231 patients from the S1216 study were evaluable for PSA-3mo and PSA-7mo, respectively. A PSA-7mo CR was associated with improved OS compared with NR (HR: 0.20; p < 0.0001). A PSA-3mo CR showed a similar association to NR (HR: 0.34; p < 0.0001). The association of a PSA response with survival did not differ by treatment arm at either time point. CONCLUSIONS: The PSA-3mo and PSA-7mo responses were strongly associated with OS; taken with other emerging prognostic biomarkers, these markers may allow for early identification of patients at the highest risk of death, aid with counseling in clinical practice, and permit design of future clinical trials targeting these patients. PATIENT SUMMARY: A low prostate-specific antigen level at 3 or 7 mo after starting treatment for metastatic hormone-sensitive prostate cancer predicts longer survival regardless of the first treatment given with androgen deprivation therapy.

Promoting Millets: Charting a Journey from Food Security to Health.

Millets have been the staple food in many parts of the world, but in recent times they have been losing ground because of the increased use of processed foods and grains, such as wheat and rice. India has been the granary of millets due to the largest production and export of Indian millets globally. The very nature of millets being drought-resistant, small seeded grass, which can be grown in arid conditions, with less water and less farming intensive, makes it a great choice for ecological agriculture and sustainable source of food for combating hunger in the rapidly changing global climate and constructing climate-resistant agri-food systems. The various health benefits of millets make them an excellent choice for patients with celiac disease, type 2 diabetes mellitus, ischemic heart disease, dyslipidemia, obesity, etc.

A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR).

BACKGROUND: Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. METHODS: This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600 mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. RESULTS: The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. CONCLUSION: Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).

NCCN Guidelines® Insights: Kidney Cancer, Version 2.2024.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with advanced RCC and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Kidney Cancer.