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.

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.

Selection of Germline Genetic Testing Panels in Patients With Cancer: ASCO Guideline.

PURPOSE: To guide use of multigene panels for germline genetic testing for patients with cancer. METHODS: An ASCO Expert Panel convened to develop recommendations on the basis of a systematic review of guidelines, consensus statements, and studies of germline and somatic genetic testing. RESULTS: Fifty-two guidelines and consensus statements met eligibility criteria for the primary search; 14 studies were identified for Clinical Question 4. RECOMMENDATIONS: Patients should have a family history taken and recorded that includes details of cancers in first- and second-degree relatives and the patient's ethnicity. When more than one gene is relevant based on personal and/or family history, multigene panel testing should be offered. When considering what genes to include in the panel, the minimal panel should include the more strongly recommended genes from Table 1 and may include those less strongly recommended. A broader panel may be ordered when the potential benefits are clearly identified, and the potential harms from uncertain results should be mitigated. Patients who meet criteria for germline genetic testing should be offered germline testing regardless of results from tumor testing. Patients who would not normally be offered germline genetic testing based on personal and/or family history criteria but who have a pathogenic or likely pathogenic variant identified by tumor testing in a gene listed in Table 2 under the outlined circumstances should be offered germline testing.Additional information is available at www.asco.org/molecular-testing-and-biomarkers-guidelines.

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.

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.

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.

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).

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).

PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape.

The treatment landscape of metastatic prostate cancer (mPCa) is rapidly evolving with the recent approvals of poly-ADP ribose polymerase inhibitors (PARPis) as monotherapy or as part of combination therapy with androgen receptor pathway inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC). Already part of the therapeutic armamentarium in different types of advanced cancers, these molecules have shaped a new era in mPCa by targeting genomic pathways altered in these patients, leading to promising responses. These agents act by inhibiting poly-ADP ribose polymerase (PARP) enzymes involved in repairing single-strand breaks in the DNA. Based on the PROfound and TRITON3 trials, olaparib and rucaparib were respectively approved as monotherapy in pretreated patients with mCRPC and alterations in prespecified genes. The combinations of olaparib with abiraterone (PROpel) and niraparib with abiraterone (MAGNITUDE) were approved as first-line options in patients with mCRPC and alterations in BRCA1/2, whereas the combination of talazoparib with enzalutamide (TALAPRO-2) was approved in the same setting in patients with alterations in any of the HRR genes, which are found in around a quarter of patients with advanced prostate cancer. Additional trials are already underway to assess these agents in an earlier hormone-sensitive setting. Future directions will include refining the treatment sequencing in patients with mCRPC in the clinic while taking into account the financial toxicity as well as the potential side effects encountered with these therapies and elucidating their mechanism of action in patients with non-altered HRR genes. Herein, we review the biological rationale behind using PARPis in mCRPC and the key aforementioned clinical trials that paved the way for these approvals.

Histologic patterns in prostatic adenocarcinoma are not predictive of mutations in the homologous recombination repair pathway.

Somatic or germline homologous recombination repair (HRR) pathway gene mutations are commonly detected in prostate cancer, especially in advanced disease, and are associated with response to poly (ADP-ribose) polymerase (PARP) inhibitors. In this study, we evaluated whether histological patterns are predictive of HRR pathway gene mutations. The study population comprised 130 patients with advanced prostate carcinoma who underwent comprehensive genomic profiling (CGP) of tumor tissue at a CLIA-certified laboratory. HRR genes in the study included BRCA1, BRCA2, ATM, BARD1, BRIP, CHEK2, MRE11A, NBN, PALB2, RAD51C, RAD51D, EMSY, ATR, CHEK1, and FAM175A. Overall, 38 patients had mutations in BRCA1/2, 36 in other HRR genes, and 56 were negative for HRR mutations. All cases were re-reviewed and quantified by two genitourinary pathologists blinded to mutational status for the following histological patterns of prostate carcinoma: cribriform, ductal, intraductal carcinoma (IDC), small cell carcinoma, signet ring-like pattern, and lobular carcinoma-like pattern. Discordances were resolved by consensus review. Histologic patterns were analyzed for any correlation with mutations in HRR pathway genes (grouped as BRCA1/2 mutated or non-BRCA1/2 mutated) compared to tumors without mutations in HRR genes by Chi-square testing. Patterns with >20 % and >30 % of tumor volume were additionally evaluated for correlation with mutational status. We found no significant association between HRR pathway mutations and cribriform pattern, IDC, ductal carcinoma, small cell carcinoma, signet ring-like pattern, or lobular carcinoma-like patterns. Tumors with >20 % or >30 % histologic patterns by volume also demonstrated no significant association with mutational status. This study suggests that histopathologic examination alone is insufficient to distinguish prostate cancer with germline or somatic mutations in HRR pathway genes, highlighting the continuing importance of ancillary molecular diagnostics in guiding therapy selection for prostate cancer patients who may benefit from PARP inhibitors.

Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4+ naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanoma.

BACKGROUND: Immune-related adverse events (irAEs) are major barriers of clinical management and further development of immune checkpoint inhibitors (ICIs) for cancer therapy. Therefore, biomarkers associated with the onset of severe irAEs are needed. In this study, we aimed to identify immune features detectable in peripheral blood and associated with the development of severe irAEs that required clinical intervention. METHODS: We used a 43-marker mass cytometry panel to characterize peripheral blood mononuclear cells from 28 unique patients with melanoma across 29 lines of ICI therapy before treatment (baseline), before the onset of irAEs (pre-irAE) and at the peak of irAEs (irAE-max). In the 29 lines of ICI therapy, 18 resulted in severe irAEs and 11 did not. RESULTS: Unsupervised and gated population analysis showed that patients with severe irAEs had a higher frequency of CD4+ naïve T cells and lower frequency of CD16+ natural killer (NK) cells at all time points. Gated population analysis additionally showed that patients with severe irAEs had fewer T cell immunoreceptor with Ig and ITIM domain (TIGIT+) regulatory T cells at baseline and more activated CD38+ CD4+ central memory T cells (TCM) and CD39+ and Human Leukocyte Antigen-DR Isotype (HLA-DR)+ CD8+ TCM at peak of irAEs. The differentiating immune features at baseline were predominantly seen in patients with gastrointestinal and cutaneous irAEs and type 1 diabetes. Higher frequencies of CD4+ naïve T cells and lower frequencies of CD16+ NK cells were also associated with clinical benefit to ICI therapy. CONCLUSIONS: This study demonstrates that high-dimensional immune profiling can reveal novel blood-based immune signatures associated with risk and mechanism of severe irAEs. Development of severe irAEs in melanoma could be the result of reduced immune inhibitory capacity pre-ICI treatment, resulting in more activated TCM cells after treatment.

Impact of Initial Timing of Metastatic Disease on Survival in Patients With Newly Diagnosed Metastatic Castration-Resistant Prostate Cancer Treated With Androgen Receptor Pathway Inhibitors.

INTRODUCTION: Patients with synchronous (de novo) metastatic castration-sensitive prostate cancer appear to have worse survival outcomes and shorter time to develop castration resistance than patients with metachronous disease. However, the impact of synchronous metastasis on outcomes in metastatic castration-resistant prostate cancer (mCRPC) setting is unknown in patients without prior exposure to androgen receptor pathway inhibitors (ARPIs). In this study, we assessed the impact of initial timing of metastasis (synchronous vs metachronous) on survival outcomes of patients with new-onset mCRPC in a real-world population treated with first-line abiraterone or enzalutamide. METHODS: Data were collected retrospectively from 323 patients with a confirmed diagnosis of mCRPC who received ARPIs as first-line therapy and had no prior exposure to ARPIs. The study endpoints were progression-free survival and overall survival. RESULTS: The results showed that median overall survival was significantly shorter in patients with synchronous disease than those with metachronous disease (26 vs 38.7 months, HR 1.42, 95% CI 1.09-1.86, P = .011). However, there was no difference in median progression-free survival. CONCLUSIONS: The initial presentation with synchronous metastasis remained an independent factor associated with shorter OS in the multivariable analysis. These hypothesis-generating data, after external validation, may have implications in patient counseling, prognostication, and design of future clinical trials in the new-onset mCRPC setting.

Predictors of response to neoadjuvant therapy in urothelial cancer.

Neoadjuvant cisplatin-based chemotherapy (NACC) followed by radical cystectomy is the standard treatment for localized muscle-invasive bladder cancer (MIBC). Patients who achieve a complete pathological response following NACC have better overall survival than those with residual disease. However, a subset of patients does not derive benefit from NACC while experiencing chemotherapy-related side effects that may delay cystectomy, which can be detrimental. There is a need for predictive and prognostic biomarkers to better stratify patients who will derive benefits from NACC. This review summarizes the currently available literature on various predictors of response to neoadjuvant chemotherapy. Covered predictors include clinical factors, treatment regimens (including chemotherapy and immunotherapy), histological predictors, and molecular predictors such as DNA repair genes, p53, FGFR3, ERBB2, Bcl-2, EMMPRIN, survivin, choline-phosphate cytidylyltransferase-α, epigenetic markers, immunological markers, other molecular predictors and gene expression profiling. Further, we elaborate on the potential role of neoadjuvant immunotherapy and the correlative biomarkers of response.

Access to Care and Healthcare Quality Metrics for Patients with Advanced Genitourinary Cancers in Urban versus Rural Areas.

Compared to the urban population, patients in rural areas face healthcare disparities and experience inferior healthcare-related outcomes. To compare the healthcare quality metrics and outcomes between patients with advanced genitourinary cancers from rural versus urban areas treated at a tertiary cancer hospital, in this retrospective study, eligible patients with advanced genitourinary cancers were treated at Huntsman Cancer Institute, an NCI-Designated Comprehensive Cancer Center in Utah. Rural-urban commuting area codes were used to classify the patients' residences as being in urban (1-3) or rural (4-10) areas. The straight line distances of the patients' residences from the cancer center were also calculated and included in the analysis. The median household income data were obtained and calculated from "The Michigan Population Studies Center", based on individual zip codes. In this study, 2312 patients were screened, and 1025 eligible patients were included for further analysis (metastatic prostate cancer (n = 679), metastatic bladder cancer (n = 184), and metastatic renal cell carcinoma (n = 162). Most patients (83.9%) came from urban areas, while the remainder were from rural areas. Both groups had comparable demographic profiles and tumor characteristics at baseline. The annual median household income of urban patients was $8604 higher than that of rural patients (p < 0.001). There were fewer urban patients with Medicare (44.9% vs. 50.9%) and more urban patients with private insurance (40.4% vs. 35.1%). There was no difference between the urban and rural patients regarding receiving systemic therapies, enrollment in clinical trials, or tumor genomic profiling. The overall survival rate was not significantly different between the two populations in metastatic prostate, bladder, and kidney cancer, respectively. As available in a tertiary cancer hospital, access to care can mitigate the difference in the quality of healthcare and clinical outcomes in urban versus rural patients.

A single center case series of immune checkpoint inhibitor-induced type 1 diabetes mellitus, patterns of disease onset and long-term clinical outcome.

Background: Type 1 diabetes mellitus (T1DM) is a rare, but serious immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). Our goal was to characterize treatment outcomes associated with ICI-induced T1DM through analysis of clinical, immunological and proteomic data. Methods: This was a single-center case series of patients with solid tumors who received ICIs and subsequently had a new diagnosis of T1DM. ICD codes and C-peptide levels were used to identify patients for chart review to confirm ICI-induced T1DM. Baseline blood specimens were studied for proteomic and immunophenotypic changes. Results: Between 2011 and 2023, 18 of 3744 patients treated at Huntsman Cancer Institute with ICIs were confirmed to have ICI-induced T1DM (0.48%). Eleven of the 18 patients received anti-PD1 monotherapy, 4 received anti-PD1 plus chemotherapy or targeted therapy, and 3 received ipilimumab plus nivolumab. The mean time to onset was 218 days (range 22-418 days). Patients had sudden elevated serum glucose within 2-3 weeks prior to diagnosis. Sixteen (89%) presented with diabetic ketoacidosis. Three of 12 patients had positive T1DM-associated autoantibodies. All patients with T1DM became insulin-dependent through follow-up. At median follow-up of 21.9 months (range 8.4-82.4), no patients in the melanoma group had progressed or died from disease. In the melanoma group, best responses were 2 complete response and 2 partial response while on active treatment; none in the adjuvant group had disease recurrence. Proteomic analysis of baseline blood suggested low inflammatory (IL-6, OSMR) markers and high metabolic (GLO1, DXCR) markers in ICI-induced T1DM cohort. Conclusions: Our case series demonstrates rapid onset and irreversibility of ICI-induced T1DM. Melanoma patients with ICI-induced T1DM display excellent clinical response and survival. Limited proteomic data also suggested a unique proteomic profile. Our study helps clinicians to understand the unique clinical presentation and long-term outcomes of this rare irAE for best clinical management.

Race and Treatment Outcomes in Patients With Metastatic Castration-Sensitive Prostate Cancer: A Secondary Analysis of the SWOG 1216 Phase 3 Trial.

Importance: Black patients present with more aggressive disease and experience higher mortality than White patients with prostate cancer. Race and social determinants of health influence prostate cancer-specific mortality and overall survival (OS); however, in a previous trial, Black patients did not have inferior outcomes compared with White patients, possibly because of equitable access to care available in a clinical trial setting. Objective: To compare differences in survival outcomes of patients with metastatic castration-sensitive prostate cancer (mCSPC) by race in a phase 3 trial with a large proportion of Black patients. Design, Setting, and Participants: This secondary analysis of patient-level data of a prospective phase 3 randomized clinical trial included patients with newly diagnosed mCSPC enrolled between March 1, 2013, and July 15, 2017. Analysis was conducted between December 2022 and February 2023. Interventions: Patients receiving androgen deprivation therapy were randomized (1:1) to receive either orteronel 300 mg orally twice daily (experimental group) or bicalutamide 50 mg orally daily (control group). Main Outcomes and Measures: OS, with progression-free survival (PFS) as a secondary end point. Results: Among 1313 participants, 135 (10%) identified as Black and 1077 (82%) as White, with an equal racial distribution between groups. Black patients were younger (median [IQR] age, 65.8 [60-70] vs 68.4 [62.5-74.1] years; P = .001) and had a higher median (IQR) baseline prostate-specific antigen response rate than White patients (54.7 [19.8-222.0] vs 26.7 [9.2-96.0] ng/mL; P < .001). At a median follow-up of 4.9 years, Black and White patients had similar median PFS (2.3 years; 95% CI, 1.8-1.4 years vs 2.9 years; 95% CI, 2.5-3.3 years; P = .71) and OS (5.5 years; 95% CI, 4.8-NR vs 6.3 years; 95% CI, 5.7-NR; P = .65). The multivariable analysis confirmed similar PFS and OS after adjusting for known prognostic factors. No interaction between race and treatment was observed. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial studying androgen deprivation therapy with first- or second-generation androgen receptor pathway inhibitors, both Black and White patients demonstrated similar OS and PFS. Equitable access to care may reduce historical differences in outcomes between Black and White patients with advanced prostate cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT01809691.

Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden.

BACKGROUND: Pembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe the landscape of frameshift mutations (FSs) and evaluated their role as a predictive biomarker to ICI in a clinical cohort of patients. METHODS: Comprehensive genomic profiling was performed on a cohort of solid tumor samples examining at least 324 genes. The clinical cohort included patients with metastatic solid malignancies who received ICI monotherapy and had tumor sequencing. Progression-free survival (PFS), overall survival, and objective response rates (ORR) were compared between the groups. RESULTS: We analyzed 246,252 microsatellite stable (MSS) and 4561 samples with microsatellite instability across solid tumors. Histologies were divided into groups according to TMB and FS. MSS distribution: TMB-L (<10 mut/Mb)/FS-A (absent FS) (N=111,065, 45%), TMB-H (≥10 mut/Mb)/FS-A (N=15,313, 6%), TMB-L/FS-P (present ≥1 FS) (N=98,389, 40%) and TMB-H/FS-P (N=21,485, 9%). FSs were predominantly identified in the p53 pathway. In the clinical cohort, 212 patients were included. Groups: TMB-L/FS-A (N=80, 38%), TMB-H/FS-A (N=36, 17%), TMB-L/FS-P (N=57, 27%), TMB-H/FS-P (N=39, 18%). FSs were associated with a higher ORR to ICI, 23.8% vs 12.8% (p=0.02). TMB-L/FS-P had superior median PFS (5.1 months) vs TMB-L/FS-A (3.6 months, p<0.01). The 12-month PFS probability was 34% for TMB-L/FS-P vs 17.1% for TMB-L/FS-A. CONCLUSIONS: FSs are found in 47% of patients with MSS/TMB-L solid tumors in a pan-cancer cohort. FS may complement TMB in predicting immunotherapy responses, particularly for tumors with low TMB.