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Relevant Articles About Research and Clinical Trials in Genitourinary Cancer

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Impact of HRR Mutations on mCRPC Treatment

KEY TAKEAWAYS

  • The PROREPAIR-B, PROSENZA, PROSTAC, and PROSABI observational trial aimed to investigate the impact of HRR gene mutations beyond BRCA2 in patients with mCRPC.
  • Researchers noticed significant variations in mCRPC survival based on HRR mutations, underscoring the need for early screening, particularly for BRCA1/2, to optimize tailored treatments and outcomes.

Almost 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor pathogenic mutations in DNA damage repair genes, notably BRCA2, which correlates with adverse outcomes. However, the impact of mutations in other homologous recombination repair (HRR) genes on patient prognosis amidst standard therapies remains ambiguous despite their potential association with novel targeted agents’ anticancer efficacy.

David Olmos and the team aimed to address the uncertainty surrounding the prognostic significance of non-BRCA HRR gene mutations in mCRPC patients receiving standard treatments.

They performed an inclusive analysis encompassing data from multiple clinical trials, including PROREPAIR-B (NCT03075735), PROSENZA (NCT02922218), PROSTAC (NCT02362620), and PROSABI (NCT02787837). Utilizing next-generation sequencing (NGS), they scrutinized HRR genes within patients’ DNA, categorizing them into distinct subgroups: mutations in BRCA1/2, absence of BRCA1/2 mutations (non-BRCA), and non-BRCA mutations in other HRR genes. Both somatic and germline DNA were subjected to analysis. Associations between HRR mutations and patient outcomes were evaluated using inverse probability-weighted Cox models, ensuring baseline characteristic balance across subgroups.

About 223 of 729 (30.6%) patients with mCRPC identified Mutations in ≥1 HRR gene, including 96 patients (13.2%) who had a BRCA1/2 mutation. Among these patients, 60.4% received first-line (1L) novel hormonal therapy (NHT), while 39.6% received 1L taxane therapy, and 80.7% underwent at least 2L treatment. Baseline characteristics, including median age (72.2 years), Gleason score >7 (63.5%), Eastern Cooperative Oncology Group performance status ≥1 (53.1%), and presence of visceral metastases (13.3%), were comparable across subgroups after adjustment.

Patients with BRCA1/2 mutations exhibited significantly inferior prognosis compared to non-BRCA patients, manifesting shorter radiographic progression-free survival (rPFS), progression-free survival on next-line therapy (PFS2), and overall survival (OS). BRCA1/2 mutations also correlated with decreased PFS2 and OS relative to mutations in other non-BRCA HRR genes.

The study concluded that survival outcomes were significantly impacted by HRR gene mutations in mCRPC patients, with the poorest prognosis observed in those with BRCA1/2 alterations, intermediate outcomes in non-BRCA HRR mutations, and the most favorable prognosis in patients without BRCA alterations. Early screening for HRR gene mutations, especially BRCA1/2, is crucial for timely initiation of targeted treatments and improved patient outcomes in mCRPC management.

The trial was sponsored by Centro Nacional de Investigaciones Oncologicas CARLOS III.

Source: https://ons.confex.com/ons/2024/meetingapp.cgi/Paper/15602

Clinical Trial: https://clinicaltrials.gov/study/NCT03075735

https://clinicaltrials.gov/study/NCT02922218

https://clinicaltrials.gov/study/NCT02362620

https://clinicaltrials.gov/study/NCT02787837

Olmos D, Castro E, Francis P, et al. (2024). “Presence of Homologous Recombination Repair Gene Mutations and Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving First Line Treatment (CAPTURE Study).” Presented at ONS 2024 (Abstract I36).

Managing AEs in Cabozantinib + Nivolumab for Advanced RCC

KEY TAKEAWAYS

  • The CheckMate 9ER phase 3 trial aimed to investigate the AE management strategies for oncology nurses caring for patients receiving cabozantinib + nivolumab in RCC.
  • Researchers noticed the critical role of oncology nurses in AE management, enhancing tolerability and treatment continuation.

Tyrosine kinase inhibitor (TKI) plus immune checkpoint inhibitor (ICI) combinations have emerged as pivotal therapies for renal cell carcinoma (RCC). The combination of the TKI cabozantinib with the ICI nivolumab has garnered approval as a first-line (1L) treatment for advanced RCC owing to its demonstrated superiority over sunitinib in terms of overall survival (OS), progression-free survival (PFS), and objective response rate(ORR), as evidenced by the phase 3 CheckMate-9ER study (NCT03141177) and supported by the cabozantinib product label. Given the complexity of managing adverse events (AEs) associated with this regimen, oncology nurses play a critical role in ensuring optimal patient care and treatment outcomes.

Virginia Seery and the team aimed to assess the specific AE management strategies tailored for oncology nurses caring for patients receiving cabozantinib + nivolumab, with the overarching goal of optimizing treatment tolerability and facilitating treatment continuation for patients with advanced RCC.

The management of AEs with cabozantinib plus nivolumab relies on identification of the causative agent, which can be complex given that immune-mediated AEs associated with nivolumab may overlap with cabozantinib AEs (gastrointestinal and dermatologic toxicities, hepatotoxicity, endocrinopathies). AEs observed with cabozantinib plus nivolumab in CheckMate-9ER included diarrhea (64%), hepatotoxicity (44%), palmar-plantar erythrodysesthesia (40%), rash (36%), hypertension (36%), and hypothyroidism (34%). Frequent office visits and laboratory tests are an important part of AE monitoring.

Strategies to manage AEs include prophylaxis, supportive care, dose holds and reductions for cabozantinib, dose holds for nivolumab with immunosuppressive therapy if indicated, and referral to a specialist. Symptomatic therapy is also appropriate for certain AEs, such as adrenal insufficiency. For AEs of unknown etiology, a dose hold of both agents is appropriate. Once the causative agent is identified, dose holds, dose reductions of cabozantinib, immunosuppressive therapy, or treatment discontinuations are appropriate.

Nurses should educate patients about common AEs, develop a communication process with the healthcare team that addresses any potential barriers to care, monitor for signs and symptoms of AEs, implement prophylaxis and supportive care (eg, lotions for skin-related AEs, use of antihypertensives for hypertension, dietary changes for diarrhea), and help oversee dose modification and initiation of immunosuppressive therapy.

The study concluded that oncology nurses play a crucial role in ensuring comprehensive AE management for patients undergoing cabozantinib plus nivolumab treatment for advanced RCC. Their involvement significantly contributes to enhancing treatment tolerability and facilitating patients’ ability to remain on therapy.

The trial was sponsored by Bristol-Myers Squibb.

Source: https://ons.confex.com/ons/2024/meetingapp.cgi/Paper/15378

Clinical Trial: https://clinicaltrials.gov/study/NCT03141177

Seery V, Andresen D, Martone B, et al. (2024). “Management of adverse events associated with cabozantinib plus nivolumab in advanced renal cell carcinoma.” Presented at ONS 2024 (Abstract I37).

Benefit-Risk Profile: NIRA+AAP in BRCA1/2-altered mCRPC

KEY TAKEAWAYS

  • The MAGNITUDE phase 3 trial aimed to present PRO results from the BRCA1/2 cohort, focusing on pain, HRQoL, and side effects.
  • The results revealed that NIRA+AAP delays pain worsening and minimizes treatment-associated side effects, supporting its benefit-risk profile.

In the Phase 3 MAGNITUDE study, niraparib (NIRA) alongside first-line abiraterone acetate plus prednisone (AAP) versus placebo (PBO) + AAP notably enhanced radiographic progression-free survival in metastatic castration-resistant prostate cancer (mCRPC).

Notably, the NIRA+AAP combination exhibited favorable overall survival and clinically relevant enhancements in time to symptomatic progression and cytotoxic chemotherapy, particularly in patients with a BRCA1/2 mutation. Patient-reported outcomes (PROs) were pivotal in assessing study outcomes.

Celine Nguyen and the team aimed to share the final analysis of PROs from the BRCA1/2 cohort in the MAGNITUDE study, covering pain, health-related quality of life (HRQoL), and side effect burden.

Eligible patients with mCRPC had Eastern Cooperative Oncology Group performance status of ≤1 and a Brief Pain Inventory–Short Form (BPI-SF) worst pain score of ≤3 on a scale of 0–10. Patients were randomized 1:1 to receive either NIRA+AAP or PBO+AAP.

Pain assessments (BPI-SF) and HRQoL evaluations (Functional Assessment of Cancer Therapy–Prostate [FACT-P]) were conducted on day 1 of specified cycles and during follow-up. Time to deterioration (TTD) in pain (BPI-SF worst, average, and pain interference) and FACT-P pain-related scale (PRS) were compared between treatment arms using proportional hazards regression models. Changes in HRQoL from baseline (FACT-P total score, range 0–156) were assessed using repeated measures analysis. Side effect bother was evaluated using FACT-P item GP5 in both treatment arms.

The results revealed that compliance with BPI-SF and FACT-P assessments exceeded 85% in 225 patients. At baseline, mean BPI-SF pain scores were 1.09 (SD, 1.57) in the NIRA+AAP arm and 1.35 (SD, 1.98) in the PBO+AAP arm. Mean FACT-P total scores were 116.33 (SD, 18.42) and 114.8 (SD, 18.9), respectively.

Regarding TTD, NIRA+AAP showed a numerically longer median TTD than PBO+AAP across pain measures (BPI-SF worst pain, pain interference, average pain) and FACT-P PRS.

The HRQoL remained stable during treatment, with no significant differences observed over time or between treatment arms for FACT-P total score. Across treatment cycles, 87% of NIRA+AAP and 92% of PBO+AAP subjects rated FACT-P item GP5, assessing the overall impact of treatment toxicity as “not at all” or “a little bit.”

The study concluded that NIRA+AAP effectively delayed pain worsening and resulted in minimal treatment-associated side effects. These findings provided additional evidence supporting the benefit-risk profile of NIRA+AAP for treating BRCA1/2-altered mCRPC.

The trial was sponsored by Janssen Research & Development, LLC.

Source: https://ons.confex.com/ons/2024/meetingapp.cgi/Paper/15603

Clinical Trial: https://clinicaltrials.gov/study/NCT03748641

Nguyen C, Rathkopf DE, N. Kim, et al. (2024). “Patient-Reported Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer and BRCA1/2 Mutations Receiving First-Line Niraparib with Abiraterone Acetate plus Prednisone (MAGNITUDE Study).” Presented at ONS 2024 (I34)

Impact of Annual PSA Screening on PC Mortality in Medicare

Impact of Annual PSA Screening on PC Mortality in Medicare

KEY TAKEAWAYS

  • The study aimed to assess the impact of annual PSA screening on PC mortality in elderly Medicare beneficiaries.
  • Results showed that annual PSA screening may reduce PC deaths in men aged 67-74.

There is no consensus among clinical guidelines regarding the effectiveness of prostate-specific antigen (PSA) screening, particularly for elderly patients with prostate cancer (PC). Previous randomized trials have produced varied results, partly due to differences in adherence, and new trials are unlikely to be conducted.

Xabier García-Albéniz and the team aimed to estimate the impact of annual PSA screening on PC mortality among Medicare beneficiaries aged 67 to 84 years.

Researchers examined 2 approaches: annual PSA screening vs no screening, using data from 537,599 U.S. Medicare beneficiaries aged 67-84 between 2001 and 2008 with good life expectancy and no prior PC or PSA tests in the 2 years before the study.

They estimated the 8-year PC mortality, incidence, treatments, and treatment complications linked to PSA screening. This large-scale observational study aimed to understand the impact of annual PSA screening on patient outcomes.

The results indicated that in men aged 67-74, the 8 year risk of dying from PC was reduced by 2.3 deaths per 1,000 men with PSA screening compared to no screening (95% CI, -4.1 to -1.1), indicating a benefit of screening. However, PSA screening led to more treatment complications than no screening. In men aged 75-84, the difference in risk between screening and no screening was minimal, suggesting less benefit in this order group.

The study concluded that annual PSA screening over 8 years likely reduces PC mortality by 1 to 4 deaths per 1,000 men aged 67-74. However, results may be influenced by residual confounding in real-world data.

The study was funded by Steven and Christine Burd-Safeway Distinguished Professorship.

Source: https://pubmed.ncbi.nlm.nih.gov/39159422/

García-Albéniz X., Hsu J., Etzioni R., et al. (2024). “Prostate-Specific Antigen Screening and Prostate Cancer Mortality: An Emulation of Target Trials in US Medicare.” JCO clinical cancer informatics, 8, e2400094. https://doi.org/10.1200/CCI.24.00094

Docetaxel Pre-treatment Impact in mCSPC: TITAN Insights

KEY TAKEAWAYS

  • The TITAN phase 3 trial aimed to assess patient outcomes based on prior docetaxel chemotherapy before Apa+ADT.
  • The results revealed no added benefit from docetaxel before Apa+ADT in patients with mCSPC, citing limited data and analysis.

In the Phase 3 TITAN study, the inclusion of apalutamide (Apa) with androgen deprivation therapy (ADT) notably enhanced overall survival (OS) and other clinical parameters compared to placebo in patients with metastatic castration-sensitive prostate cancer (mCSPC).

Julia Batten and the team aimed to examine patient outcomes based on prior docetaxel chemotherapy before Apa+ADT administration.

Patients received either Apa or placebo alongside ongoing ADT, with some having prior docetaxel with ADT before randomization. The analysis evaluated the influence of prior docetaxel exposure on radiographic progression-free survival (rPFS) at the first interim analysis (median follow-up: 23 months).

At the final analysis (median follow-up: 44 months), the impact of prior docetaxel on OS and time to prostate-specific antigen (PSA) progression was examined. Furthermore, the study analyzed the effect of disease volume at baseline according to adapted CHAARTED criteria, along with matching baseline characteristics.

The results revealed that among 525 patients receiving Apa+ADT in TITAN, 58 (11%) had prior docetaxel treatment in which 76% had high-volume disease, 62% had bone-only metastases, 16% had visceral metastases, and 59% had >10 bone lesions. Analysis showed no significant difference in OS, rPFS, or time to PSA progression with Apa+ADT, regardless of prior docetaxel receipt. This held for both high-volume and low-volume disease subgroups and when baseline characteristics were matched, including PSA levels and time from initial diagnosis to randomization. Safety profiles of Apa were unaffected by prior docetaxel exposure.

The study concluded that prior docetaxel treatment did not enhance the clinical advantages of Apa+ADT in patients with mCSPC patients in TITAN. However, limitations include the small proportion of patients who received prior docetaxel (only 11% of TITAN participants) and the absence of tumor volume data. Additionally, since docetaxel was administered as a prior therapy, information regarding disease characteristics before docetaxel initiation was unavailable.

The trial was sponsored by Aragon Pharmaceuticals, Inc.

Source: https://ons.confex.com/ons/2024/meetingapp.cgi/Paper/15604

Clinical Trial: https://clinicaltrials.gov/study/NCT02489318

Batten J, Chi KN, Given R, et al. (2024). “The Effect of Prior Docetaxel Treatment in Patients with Metastatic Castration-Sensitive Prostate Cancer Receiving Apalutamide plus Androgen Deprivation Therapy (TITAN Study).” Presented at ONS 2024 (I20)

CBX2 and ASPH Prognostic Significance in KIRP

KEY TAKEAWAYS

  • The study aimed to investigate the role of cancer stem cells and SRGs in the carcinogenesis and metastasis of KIRP.
  • Researchers noticed the potential of CBX2 to regulate ASPH via Notch signaling, implicating its association with KIRP carcinogenesis, progression, and poor prognosis.

Kidney renal papillary cell carcinoma (KIRP) is the second most common malignancy arising from renal epithelium, with cancer stem cells and stemness-related genes (SRGs) implicated in tumor development and metastasis across various cancers. Understanding the mechanisms of SRGs in KIRP is crucial for targeted therapies.

Yifan Liu and the team aimed to assess the regulatory roles of SRGs in KIRP progression and identify potential therapeutic targets for improved patient outcomes.

They performed an inclusive analysis by downloading RNA-seq profiles of 141 KIRP samples from the TCGA database. They calculated the mRNA expression-based stemness index (mRNAsi) and selected differentially expressed genes (DEGs) between low- and high-mRNAsi groups. Weighted gene correlation network analysis (WGCNA) and univariate Cox analysis were utilized to identify prognostic SRGs.

Subsequently, SRGs were subjected to multivariate Cox regression analysis to establish a prognostic model. Additionally, a regulatory network was constructed through Pearson correlation analysis, incorporating key genes, upstream transcription factors (TFs), and downstream signaling pathways. Finally, Connectivity map analysis was employed to identify potential inhibitors.

About 1124 genes were characterized as DEGs between low- and high-RNAsi groups. A prediction model was established based on 6 prognostic SRGs (CCKBR, GPR50, GDNF, SPOCK3, KC877982.1, and MYO15A), achieving an area under the curve of 0.861. Notably, the CBX2-ASPH-Notch signaling pathway exhibited a significant correlation among TFs, genes, and signaling pathways. Resveratrol emerged as a potential inhibitor for KIRP.

The study concluded that CBX2 potentially regulates ASPH via activation of the Notch signaling pathway, implicating its correlation with the carcinogenesis, development, and unfavorable prognosis of KIRP.

This work was sponsored by the National Natural Science Foundation of China, Leading health talents of Shanghai Municipal Health Commission; Shanghai Rising-Star Program; the Natural Science Foundation of Shanghai; Hospital Funded Clinical Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.

Source: https://pubmed.ncbi.nlm.nih.gov/38702698/

Liu Y, Yao Y, Zhang Y, et al. (2024). “Identification of prognostic stemness-related genes in kidney renal papillary cell carcinoma. BMC Med Genomics.” 2024 May 3;17(1):121. doi: 10.1186/s12920-024-01870-2. PMID: 38702698.

GEMDOCE Shows Promise in BCG-Naïve NMIBC

KEY TAKEAWAYS

  • The GEMDOCE phase 2 trial aimed to investigate the efficacy and safety of GemDoce as a 1L therapy for patients with BCG-naïve NMIBC.
  • The primary endpoint was to determine CR.
  • Researchers noticed favorable tolerability and promising efficacy of GemDoce in patients with BCG-naïve high-risk NMIBC.

A combination of intravesical Gemcitabine and Docetaxel (GemDoce) has shown effectiveness as a second-line therapy for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). Given the widespread shortages of Bacillus Calmette-Guérin (BCG), alternative treatments are crucial.

Sunil H. Patel and the team aimed to conduct a phase 2 prospective trial to evaluate GemDoce for BCG-naïve NMIBC.

They performed an inclusive analysis in a prospective single-arm open-label phase II trial for patients with BCG-naïve high-risk NMIBC. Intravesical gemcitabine and docetaxel were administered weekly for 6 weeks as induction, followed by monthly maintenance therapy for 2 years among responders. The primary endpoint was 3-month complete response (CR), and key secondary endpoints included adverse events (AE) and 12-month CR.

About 25 patients were enrolled between August 2020 and August 2022, with a median follow-up of 19.6 months. Pre-trial pathologic stages included HGT1 with CIS (n=7), HGT1 without CIS (n=6), HGTa (n=9), and CIS alone (n=3). The 3-month and 12-month CR rates were 100% and 88%, respectively. Recurrences of HGT1 occurred in 2 patients at 9 and 12 months.

No progression to T2 disease, radical cystectomy, or radiographic evidence of progressive disease was observed. Grade 1 AE’s were common (23/25 patients) including hematuria, urinary frequency, urgency, and fatigue. 5 patients (20%) experienced Grade 3 AE’s, including hematuria and UTI.

The study concluded that GEMDOCE demonstrated good tolerability and promising efficacy in patients with BCG-naïve high-risk NMIBC.

The trial was sponsored by the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

Source: https://www.auajournals.org/doi/10.1097/01.JU.0001008640.01272.9d.14

Clinical Trial: https://clinicaltrials.gov/study/NCT04386746

Patel S. H., Gabrielson A. T., Chan S, et al. (2024). “A PHASE II TRIAL OF INTRAVESICAL GEMCITABINE AND DOCETAXEL (GEMDOCE) IN THE TREATMENT OF BCG-NAÏVE NON-MUSCLE INVASIVE UROTHELIAL CARCINOMA OF THE BLADDER.” Presented at AUA 2024 (Abstract MP16-14).

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