Prior Local Therapy Research Articles

Prior Local Therapy and First-Line Apalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

Preclinical studies suggest that exposure to prostate-directed local therapy (LT) may influence the efficacy of subsequent systemic therapy including androgen receptor pathway inhibitors. However, there is insufficient clinical evidence to support this premise in patients with nonmetastatic castrate-resistant prostate cancer (nmCRPC). To determine whether exposure to prior prostate-directed LT (radical prostatectomy [RP], radiation therapy [RT], or both) played any effect-modifying role in the treatment effect of apalutamide on metastasis-free survival (MFS) and overall survival (OS) in patients with nmCRPC. This post hoc secondary analysis used individual patient data from SPARTAN (Study of Apalutamide [ARN-509] in Men With Non-Metastatic Castration-Resistant Prostate Cancer), a phase 3, double-blinded, placebo-controlled randomized clinical trial conducted at 332 sites in 26 countries. Between October 14, 2013, and December 15, 2016, patients with nmCRPC and a prostate-specific antigen doubling time of 10 months or less were randomly assigned to apalutamide vs placebo; all patients received androgen deprivation therapy. The final data analysis was performed on December 31, 2023. Prior prostate-directed LT. Separate Cox proportional hazards regression models were constructed for OS and MFS, which included prior LT, treatment group, and an interaction term, in addition to a minimally sufficient set of confounders. Adjusted hazard ratios (HRs) with 95% CIs for MFS and OS were determined for the apalutamide groups with or without prior LT. Among the 1179 evaluable patients included in this analysis, 795 received prior LT and 384 did not. The median age of patients with and without prior LT was 70 (IQR, 45-90) years and 75 (IQR, 50-95) years, respectively. The median follow-up was 52.0 (IQR, 51.5-52.8) months. A differential treatment effect of apalutamide on MFS was observed between patients with and without prior LT (P for interaction = .009), with greater benefits for those with prior LT (adjusted HR, 0.22 [95% CI, 0.17-0.27]) compared with those without prior LT (adjusted HR, 0.35 [95% CI, 0.25-0.51]). However, there was insufficient evidence of a differential treatment effect on OS among subgroups stratified by exposure to prior LT (P for interaction = .23), with improved OS in the subgroup with prior LT (adjusted HR, 0.72 [95% CI, 0.57-0.92]) but no significant difference in OS in the subgroup without prior LT (adjusted HR, 0.92 [95% CI, 0.64-1.31]). This post hoc analysis of the SPARTAN trial provides evidence of an interaction between prior LT and apalutamide in patients with nmCRPC, with a clinically significant and more favorable treatment effect from apalutamide on MFS among patients with prior LT. Further studies are needed to validate these findings. ClinicalTrials.gov Identifier: NCT01946204.

Impact of Previous Surgery and/or Radiation Therapy on Endoscopic Reconstruction Outcomes.

The impact of prior local therapies, including radiation and surgery, on reconstruction outcomes after endonasal surgery is currently not well known. Reconstruction nuances in the preoperative setting merit further evaluation to avoid potential postoperative complications that can hinder overall tumor management and negatively impact patient outcome. We sought to determine whether prior treatments increase risk of reconstruction-related postoperative morbidity and to evaluate the effectiveness of our current treatment paradigm for skull base reconstruction. A retrospective review of all endonasal surgeries for tumor resection between March 2000 and March 2022 was performed. Patients were grouped based on treatment history. Patient demographics, operative, and postoperative reconstruction-related morbidity data were collected, including cerebrospinal fluid leak, sinonasal morbidity, and infectious complications. Variables significantly associated with postoperative complications in the univariate analysis were included in the multivariate Cox proportional hazards regression model. Complication-free survival curves were generated, and the log-rank test evaluated the relationship between complication-free survival and the different clinical, surgical, and treatment parameters. All statistical analyses were performed with SPSS 26 (IBM Corp) and Graph Pad 9.0 (GraphPad Software). A total of 418 patients were included. 291 patients had no prior treatments, 49 patients had previously received radiation, and 78 patients had prior surgeries. Of the 49 patients who had prior radiation, 27% underwent reconstruction with tunneled pericranial flaps vs 16% of treatment-naïve patients. On multivariate analysis, prior treatment was not significantly associated with reconstruction-related complications. Negative smoking history, no leak or small intraoperative leak, and use of vascularized flap in reconstruction were protective factors. In patients undergoing endonasal surgery, prior radiation and/or surgery does not appear to significantly increase the risk of immediate or delayed reconstruction complications using our current reconstructive management plan, which incorporates an upfront regional flap for high-risk cases.

Abstract PO2-04-05: FINAL OUTCOME ANALYSIS FROM THE PHASE II TUXEDO-1 TRIAL OF TRASTUZUMAB-DERUXTECAN IN HER2-POSITIVE BREAST CANCER PATIENTS WITH ACTIVE BRAIN METASTASES

Abstract Background Brain metastases (BM) are a severe complication of HER2-positive metastatic breast cancer. In the absence of any immediate indication for local therapy, the tyrosine-kinase inhibitor tucatinib combined with trastuzumab and capecitabine (TTC) is regarded as the preferred systemic treatment option for active BM, while data on the activity of antibody-drug conjugates (ADC) is limited. In the primary outcome analysis of TUXEDO-1, an intracranial response rate (RR) of 73.3% was reported with the ADC trastuzumab-deruxtecan (T-DXd). Here, we report final progression-free survival (PFS) and overall survival (OS) results of this study. Patients and Methods: TUXEDO-1 is a prospective, single-centre, single-arm phase 2 trial. Adult patients with HER2-positive BC and active BM (newly diagnosed untreated or progressing after prior local therapy), prior treatment with trastuzumab and pertuzumab, ECOG performance status 0 or 1 without indication for immediate local therapy were accrued and received T-DXd until progression, inacceptable toxicity, or withdrawal for any other reason. The primary endpoint was intracranial RR centrally assessed by Response Assessment in Neuro-Oncology (RANO)-BM criteria in the intention-to-treat population; secondary endpoints included PFS, OS, safety, quality-of-life (QoL), and neurocognitive function. PFS and OS were estimated with the Kaplan-Meier method and analysed in the per-protocol population (PPP). Results A total number of 15 patients were accrued; one patient was found to have dural metastases only upon restaging, resulting in a PPP of 14 patients. Patients had received a median number of two prior treatment lines (range, 1-5), 60% had progressive brain metastases and 60% had received prior T-DM1. At 26.5 months median follow-up, median PFS was 21 months (95% CI 13.3-n.r.) and median OS was not reached (95% CI 22.2-n.r.). A total of 238 cycles of T-DXd were administered (median 11.5 cycles; range 4-42). With longer follow-up, no new safety signals were observed. The most common grade 3 adverse event (AE) was fatigue (n=3; 20%). A total of 8 serious AEs were reported in 8 patients. Grade 2 interstitial lung disease and a grade 3 symptomatic drop of left-ventricular ejection fraction were observed in one patient each. QoL and neurocognitive functioning were maintained over the entire treatment duration and a significant deterioration of global QoL was observed upon progression (p=0.036). Most patients received TTC (n=5) or local therapy (n=4) as next subsequent treatment line. Ancillary biomarker studies are ongoing, and results will be presented at the meeting. Discussion In TUXEDO-1, T-DXd yielded prolonged intra- and extracranial disease control in patients with active HER2-positive breast cancer BM. The safety profile was consistent with previous reports. T-DXd did not impair QoL and neurocognitive functioning was maintained. Results therefore support the concept of ADCs as systemic therapy for active BM. Citation Format: Rupert Bartsch, Anna Sophie Berghoff, Julia Furtner, Maximilian Marhold, Elisabeth Sophie Bergen, Sophie Roider-Schur, Angelika Maria Starzer, Maximilian Mair, Heidrun Forstner, Beate Rottenmanner, Marie-Bernadette Aretin, Karin Dieckmann, Zsuzsanna Bago-Horvath, Helmuth Haslacher, Georg Widhalm, Aysegül Ilhan-Mutlu, Christoph Minichsdorfer, Thorsten Fuereder, Thomas Szekeres, Leopold Oehler, Birgit Gruenberger, Georg Pfeiler, Christian F. Singer, Ansgar Weltermann, Luzia Berchtold, Matthias Preusser. FINAL OUTCOME ANALYSIS FROM THE PHASE II TUXEDO-1 TRIAL OF TRASTUZUMAB-DERUXTECAN IN HER2-POSITIVE BREAST CANCER PATIENTS WITH ACTIVE BRAIN METASTASES [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-05.

Abstract CT157: Phase 1 trial of MEK1 inhibitor E6201 plus dabrafenib in patients (pts) with BRAF V600-mutated metastatic melanoma (MM) with central nervous system (CNS) metastases (mets)

Abstract Background: The prognosis of patients with MM with CNS mets is poor. E6201 is an intravenous (IV) MEK inhibitor with activity against BRAF V600-mutated MM cell lines, including MAPK resistance alteration. A previous phase I trial demonstrated activity of E6201 in BRAF V600E mutated MM with a Maximal Tolerated Dose of 320mg/m2 given IV once a week x 3 weeks q 28 days. 2/23 (8.7%) of patients had a PR, 8/23 (34.8%) had SD. Two patients with MM and brain mets achieved near-CR which led to preclinical studies that demonstrated E6201 is unaffected by P-gp and BCRP transport and achieved higher brain to blood concentration (266%).In this trial, patients with BRAF mutation + MM with brain mets, single agent E6201 given at 320mg/m2 twice weekly x 3 weeks q 28 days was determined to be safe. One patient had CNS SD and a PR in lung mets, and a second patient achieved CNS stable disease and CR in a leg melanotic lesion. The drug was well-tolerated with one reversible AE thrombocytopenia (Gr 2). The final review showed intracranial response of SD in 2/4 (50%) patients and systemic SD in 3/4 (75%) patients. Methods: We are currently accruing to the dose escalation cohort of E6201 with dabrafenib 150 mg twice daily orally (n=up to 22 evaluable patients). E6201 is administered IV at 320mg/m2 twice weekly for 3 weeks every 28 days. Patients must have stage IV melanoma with BRAF mutation with at least one active lesion in the brain. Prior local therapy is allowed if done at least 3 weeks prior to cycle 1. Participants must be on a stable dose of steroids for at least 7 days and have an ECOG <!–=2. The study allows one prior BRAF/MEK inhibitor therapy. The primary objectives are to determine the MTD of E6201 when combined with dabrafenib and the response rate of brain mets. The secondary objectives include duration of response, extracranial response, progression free survival, overall survival, and impact of BRAF mutation subtype and safety of the combination. Clinicaltrials.gov: NCT05388877

A real-world observational study characterizing patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) treated with or without androgen receptor pathway inhibitors (ARPIs).

59 Background: mCSPC treatment is rapidly evolving with androgen deprivation therapy (ADT) plus ARPIs viewed as the standard of care for most pts. Data are needed to understand the real-world characteristics and treatment patterns of mCSPC (PC) pts in this dynamic field. This study aimed to define clinical features of mCSPC pts, estimate the proportion of pts receiving ARPIs, and evaluate clinical and demographic features associated with ARPI use. Methods: This retrospective cohort study used data from electronic health records and administrative databases in the province of Alberta, Canada. All newly diagnosed metastatic PC pts between 2017-2020 were identified. Pts were considered to have mCSPC if they initiated ADT within 30 days prior to, or at any time after diagnosis. ARPI exposure was defined as receiving ARPI within 180 days of initiating ADT. ARPI-naïve pts may have received ADT alone or other non-ARPI therapy (i.e., docetaxel) within 180 days of initiating ADT. Multivariable logistic regression was used to evaluate pt characteristics related to the receipt of ARPI. Overall survival (OS) was defined as the date of diagnosis to death from any cause or last known contact. Results: Of the 976 mCSPC pts identified, 33.5% received an ARPI. In ARPI exposed pts, the median time from ADT to ARPI start was 7.9 weeks and median time on ARPI was 13.1 months (mos). In multivariable analyses, ARPI use was associated with younger pt age, more recent diagnosis, fewer comorbidities, a higher metastatic burden, treatment centre, referral to a medical oncologist, and prior local therapy (all p<0.05). The median time to next therapy was 24.6 mos (95%CI=19.5-33.0) vs. 18.5 mos (95%CI+16.9-21.1), and median OS was 38.5 mos (95%CI=32.8-NA) vs. 34.2 mos (95%CI=33.3-38.8) for APRI exposed vs. ARPI-naive pts, respectively (p=0.03). Conclusions: This study identified factors associated with ARPI use in mCSPC, potentially allowing targeted efforts to improve ARPI uptake for pts in whom use is low. These findings are important as they reflect outcomes seen in real world pts.

Racial/ethnic disparities in the effectiveness of atezolizumab plus bevacizumab (A+B) vs. tyrosine kinase inhibitors (TKIs) among veterans with unresectable hepatocellular carcinoma (uHCC).

448 Background: The etiology of liver disease and HCC often differs by race and ethnicity, which may lead to potential differential effectiveness of immunotherapy (IO) by race/ethnicity. However, clinical trials for HCC have historically had limited racial diversity. Emerging data has characterized the real-world effectiveness of A+B, the standard of care for first-line (1L) uHCC. This study assessed whether there is racial/ethnic difference in the effectiveness of A+B compared to TKIs, including sorafenib (S) or lenvatinib (L). Methods: A population-based retrospective analysis was conducted using data from the Veterans Health Administration (VHA) Data Warehouse. Non-Hispanic White, African American (AA), and Hispanic patients diagnosed with uHCC between 2017 and 2022 who initiated 1L A+B (on or after 2020), S, or L were selected. Kaplan-Meier analyses and multivariable Cox regression analysis with race/ethnicity as a treatment modifier (adjusting for age, region, extrahepatic metastases, etiology, presence of cirrhosis, comorbidity index, prior local therapies, Child-Pugh [CP] class, and Albumin-Bilirubin [ABLI] grades) were conducted to investigate the racial/ethnic differences in the effectiveness of A+B vs S or L. Results: Of 1,738 patients, 1,140 were White (20% A+B, 56% S, 24% L), 437 were AA (25% A+B, 50% S, 25% L), and 161 were Hispanic (22% A+B, 57% S, 21% L). Compared to Whites, a significantly higher proportion of AAs had underlying hepatitis C (87% vs 56%, p<0.05). There was a trend towards a lower proportion of CP B and C and less ascites in AAs compared to Whites. Table shows median OS (mOS) by race and regimen, along with hazard ratios (HRs) from the multivariate analysis. The survival benefit associated with A+B compared with S or L was numerically greater in AA patients versus White patients, although the difference did not achieve statistical significance. Conclusions: In this real-world cohort of 1L uHCC patients, A+B demonstrated a significant survival advantage over TKIs across racial/ethnic groups. Understanding the factors contributing to the effectiveness of A+B across racial/ethnic groups could provide valuable insights for guiding future trials and initiatives aimed at addressing racial disparities in HCC. [Table: see text]

Real-world correlation of RFS and OS in early-stage hepatocellular carcinoma treated with curative intent: A retrospective analysis of SEER-Medicare data.

451 Background: Curative intent therapy with resection or ablation for early-stage HCC is associated with high incidence of recurrence. Effective adjuvant therapy is needed to improve outcomes. While OS is the preferred endpoint for demonstrating efficacy of new adjuvant therapies, recurrence-free survival (RFS) may better reflect the benefits associated with adjuvant therapy due to being independent of subsequent therapies upon recurrence. Additionally, RFS may provide insights into patient (pt) outcomes while OS data are immature. We assessed the correlation between OS and RFS in pts with early-stage HCC after treatment with curative intent. Methods: This study used the SEER-Medicare database (2007–2017). RFS was defined as time from curative intent therapy, by local ablation or surgical resection, until death or disease recurrence (first of: new HCC treatment, liver transplant, metastatic disease). OS was defined as time from curative intent therapy until death. Kaplan-Meier analyses were used, censoring on end of Medicare Parts A/B/D continuous eligibility or end of data availability. RFS/OS were summarized overall and by type of prior local therapy and risk of recurrence. Pts with a solitary tumor with histologic grade 3 or 4, solitary tumor >3cm, or multiple tumors were classified as high to very high risk. Pts with a solitary tumor not histologic grade 3 or 4 or a solitary tumor ≤3 cm were classified as low to intermediate risk. Correlation between RFS and OS was assessed using the Kendall’s τ rank correlation. Results: 611 HCC pts met the inclusion criteria (mean follow-up 3.3 years; mean age 73.3 years). Average (median) primary tumor size at diagnosis was 4.8 (4) cm. 91.6% of pts had a solitary tumor at diagnosis. 66.1% of pts experienced death or recurrence (Table). Median [IQR] OS and RFS post-curative intent therapy were 4.6 [1.8, NR] and 1.8 [0.8, 6.3] years, respectively. OS and RFS were poorer for those in the ablation (median OS 3.2 years; RFS 1.2 years) and high to very high risk of recurrence group (median OS 4.3 years; RFS 1.4 years). Kendall’s τ rank correlation model in the overall group demonstrated a statistically significant positive correlation between RFS and OS (τ = 0.66; 95% CI: 0.60–0.70; P < 0.001). Conclusions: Based on real-world data, a significant positive correlation between RFS and OS supports RFS as an efficacy marker and appropriate endpoint for pts in adjuvant HCC setting when OS data are immature. [Table: see text]

Toxicity profile, palliative care and hospice utilization of geriatric patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab in the veteran health administration.

e24022 Background: Over the last decade, the incidence of Hepatocellular carcinoma (HCC) has increased in the geriatric population. Atezolizumab plus Bevacizumab (A+B) has become an established systemic therapy for patients with HCC. Even with the aging population and elevated prevalence of HCC amongst Veterans, limited studies have explored the safety of A+B in geriatric patients. This study aims to investigate the toxicity profile of A+B in the geriatric population as well as Palliative Care and Hospice utilization within the Veteran Health Administration (VHA). Methods: Data were extracted from the electronic medical records (EMR) for adults (deceased and living) with ICD9 and ICD10 HCC codes that received 1st line systemic therapy with A+B within the VHA between December 1, 2019, and March 1, 2023. Descriptive statistics were used to summarize baseline characteristics, toxicity profile and Palliative Care and Hospice enrollment between 3 populations aged < 65, 65-69, and > 70 years. A significant p-value of ≤0.05 was used. Results: In total, 332 patients were included in the study; 206 were deceased. Approximately 70% of patients were > 65 years. The majority in each age group were non-Hispanic white males, ECOG ≥1, CPS class A and BCLC score of C. Veterans > 70, significantly had less cirrhosis caused by viral hepatitis(p < 0.0001) and no prior local therapy (p = 0.002). There was no significant difference in either median A+B doses, cessation of therapy due to toxicities or median reported toxicities of any grade, as reported in Table 1. Most common toxicities in all age groups were fatigue, decreased appetite, proteinuria and transaminitis. There was a significant difference in Hospice enrollment in deceased patients (p = 0.027), with Veterans > 70 years more likely to enroll in Hospice. Conclusions: This is the first known study that reports geriatric advanced HCC patients with A+Z toxicities in VHA patients. This study demonstrates that A+Z can be used safely in geriatric patients. Further quality improvements projects need to be implemented to improve number and timing Hospice utilization.[Table: see text]

Real-world data: Clinical characteristics and outcomes of patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab in Veteran Health Administration.

2651 Background: Advanced Hepatocellular carcinoma (HCC) is an aggressive tumor, and most patients have a poor prognosis. Recent clinical trials have demonstrated improved survival with molecularly targeted treatment and immunotherapy. Atezolizumab plus Bevacizumab (A+B ) is the recommended first-line treatment for advanced HCC based on the phase 3 IMbrave 150 trial. However, in a real-life setting, many patients do not meet the inclusion criteria of this landmark trial. This study proposes a retrospective review of outcomes of advanced HCC patients receiving A + B in Veterans Health Administration (VHA). Methods: Patients with advanced HCC receiving 1st line systemic therapy with A+ B at the VHA between Dec 1, 2019, to Mar 1, 2022, were selected from the electronic medical records (EMR) using ICD-9 and ICD-10 codes. Abstractors reviewed EMR and followed from their index date of A+ B initiation until death or their last VHA visit, with the study period ending on Jan 31, 2023. The Chi-Squared test was used to compare rates, and the Mann-Whitney test was used to compare medians. Results: A total of 332 patients met the study criteria. The median age was 67 yrs., 99% were males, 63% non-Hispanic White, 26% were Black, 66 % had ECOG ≥ 1, 84% had CPS class A, 16% had CPS class B and C, 62% had grade 2 ALBI score, 56% had viral hepatitis-caused HCC, 80 % had cirrhosis, and 67% had prior local therapies. The outcomes are shown. Conclusions: In our real world, despite having similar PFS as the phase 3 IMbrave 150 trial, our OS at 12 months was lower (52% vs. 67%), given that we had more elderly patients with moderate liver dysfunction and 40% were non-white. This study provides actual outcomes in clinical practice where patients do not match the study population of the pivotal trial. [Table: see text]

A randomized phase 2 trial of encorafenib + binimetinib + nivolumab vs ipilimumab + nivolumab in BRAFV600-mutant melanoma brain metastases: SWOG S2000.

TPS9603 Background: While anti-PD-1 and anti-CTLA4 immunotherapies are widely used in the treatment of metastatic melanoma, including melanoma brain metastases (MBM), their efficacy in patients with symptomatic MBM is very limited. In the Checkmate-204 trial of ipilimumab with nivolumab in MBM, the 6-month progression free survival (PFS) rate was 19% with a median PFS of only 1.2 months in symptomatic participants (those with neurological symptoms including steroids up to 4 mg/day of dexamethasone, n=18). (Tawbi, Lancet et al., 2021) In the COMBI-MB study of BRAF/MEK-inhibitors in BRAF-V600 mutant MBM, median PFS was 5.5 months in those with symptomatic metastases (n=17). (Davies et al., Lancet Oncol, 2017) The combination of anti-PD-1/PD-L1 therapy with BRAF/MEK inhibitors has been tested in various trials. The single-arm phase 2 TRICOTEL study explored the triplet regimen of vemurafenib + cobimetinib + atezolizumab in MBM; in the symptomatic brain met cohort, 6-month PFS was 57% (n=24). (Dummer et al., Lancet Oncol 2022). Methods: SWOG S2000 is a randomized phase 2 trial exploring the efficacy of a triplet regimen of BRAF/MEK inhibitors with PD-1 therapy (encorafenib 450 mg qday + binimetinib 30 mg BID + nivolumab 480 mg IV q4 weeks) versus ipilimumab 3 mg/kg + nivolumab 1 mg/kg q3 weeks in patients with symptomatic BRAF-mutant MBM. (The study was amended to exclude patients with asymptomatic MBM.) Eligible patients are ≥18 years old, ECOG 0-2, and prior neoadjuvant or adjuvant anti-PD-1, CTLA-4, or BRAF/MEK-inhibitors is permitted. Steroids up to 8 mg of dexamethasone/day (or equivalent), leptomeningeal spread, and prior local therapy (radiation or surgery) for brain mets are permitted, if a patient has at least one measurable, progressing brain met ≥0.5 cm in size. Primary objective is to compare PFS per (RECIST 1.1) between the two study arms. Secondary objectives include overall survival, toxicity profile, objective tumor response, intracranial response and duration per modified RECIST 1.1, modified RANO-BM, and iRANO criteria, and evaluation of radiographic response criteria by centralized review of banked images. This study is powered to detect an increase in estimated 6-month PFS from 20% to 52% with 80% power and type I error rate of 10%, with 24 eligible patients required. Total sample size is 28 to account for ineligible patients. Available blood, tissue, CSF and stool samples are banked for future correlative studies. The study is currently enrolling patients through SWOG, ECOG and NRG centers. Funding: NIH/NCI grants U10CA180888, U10CA180819, U10CA180820 U10CA180868; and in part by Pfizer, Inc. Clinical trial information: NCT04511013 .

Application of the albumin-bilirubin (ALBI) grade as predictive marker of atezolizumab plus bevacizumab (A+B) treatment outcomes for patients with advanced hepatocellular carcinoma (HCC): Real-world retrospective analysis at Veterans Health Administration (VHA).

4107 Background: Most clinical trials use Child-Pugh (CP) for patient selection; this subjective scale was originally developed to assess liver function in cirrhosis, thus cannot be applied to HCC patients with non-cirrhotic background. Alternatively, ALBI grade is an objective and validated prognostic system that has demonstrated improved accuracy to predict survival and liver function decline in HCC patients. Our real-world study aims to assess the ALBI grade as a predictive marker of treatment response in patients with advanced HCC who received (A+B) within the VHA. Methods: VHA patients with HCC receiving 1st line therapy with A+B were identified through EMR using ICD-9 or ICD-10 codes between 1 Jan 2007 and 31 Dec 2021. Patients were followed from their A+B initiation date through the earliest of the last VHA visit, loss to follow up, death, or end of study on Jan 31, 2023. Structured electronic health record and chart review data were retrospectively collected to determine patient baseline characteristics, treatment response, overall survival (OS), and progression-free survival. Survival rates were based on patients with at least 6 months or 1 year of time (as indicated) from A+B initiation until the chart was reviewed; patients without a scan or known date of scan were excluded from PFS calculations. The Chi-Squared test was used to compare rates. Results: 332 patients were included in the study. The median age was 67 yrs, 99% were males, 63% non-Hispanic White, 26% Black, 86% with ECOG < 1, 84% had CPS class A, 16% had CPS class B and C, 56% had viral hepatitis-caused HCC, 20% had no cirrhosis present, and 60% had prior local therapies. There was a statistically significant difference in progression free survival (PFS) and over survival (OS) amongst different ALBI grades as shown. Conclusions: In our retrospective cohort, it was clear that patients with ALBI grade 1 had improved PFS and OS compared to ALBI score grade 3. Patients with ALBI score grade 2 also had a moderate response to treatment with modest OS and PFS compared to patients with ALBI score grade 3. Utilizing stratification ability ALBI grade in future clinical trials may improve prognostic power facilitating ideal patient selection. [Table: see text]

Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer.

We performed a secondary analysis of ACIS study to determine if synchronous versus metachronous metastatic presentation has any association with survival and treatment response to dual androgen receptor axis-targeted therapy (ARAT) in docetaxel naïve metastatic castrate resistant prostate cancer (mCRPC). In this phase III randomized controlled trial, docetaxel naïve mCRPC patients were randomized to either apalutamide or placebo combined with abiraterone and prednisone. Multivariable Cox regression models were applied to determine the adjusted association of M-stage with radiographic progression-free survival (rPFS) and overall survival (OS). To determine the heterogeneity of treatment effect based on metastatic stage (M-stage) at presentation, Cox regression was applied with interaction terms between M-stage and treatment. Among 972 patients, 432 had M0, 334 had M1, while M-stage at presentation was unknown in 206. There was no association of M-stage at presentation with rPFS in patients with prior local therapy (LT) (hazard ratio for M1-stage: 1.22 [95% confidence interval: 0.82-1.82]; unknown: 1.03 [0.77-1.38]) or without prior LT (M1-stage: 0.87 [0.64-1.19]; unknown: 1.15 [0.77-1.72]) with no significant heterogeneity. Similarly, there was no association of M-stage with OS in patients with prior LT (M1-stage: 1.04 [0.81-1.33]; unknown: 0.98 [0.79-1.21]) or without prior LT (M1-stage: 0.95 [0.70-1.29]; unknown: 1.17 [0.80-1.71]) with no significant heterogeneity. Based on M-stage at presentation, we did not find any significant heterogeneity in treatment effect on rPFS (interaction p = 0.13), and OS (interaction p = 0.87). M-stage at presentation had no association with survival in chemotherapy-naïve mCRPC. We did not find any statistically significant heterogeneity in efficacy of dual ARAT based on synchronous versus metachronous presentation.

Abstract 2105: Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer

Abstract Background: Studies on metastatic hormone sensitive prostate cancer have shown that metachronous presentation has a better prognosis compared to synchronous disease. However, it remains unknown if such association is pertinent in metastatic castrate resistant prostate cancer (mCRPC). We performed a secondary analysis of ACIS study to determine if the response to dual androgen receptor axis-targeted therapy (ARAT) in in docetaxel naïve metastatic castrate resistant prostate cancer (mCRPC) varies based on M-stage at diagnosis and if prior local therapy plays an effect modifying role in the association of M-stage at presentation with survival. Patients and Methods: In this phase III randomized controlled trial, mCRPC patients with no prior exposure to androgen biosynthesis signaling inhibitors were randomly assigned to either apalutamide or placebo combined with abiraterone and prednisone. Cox regression models were applied for radiographic progression-free survival (rPFS), overall survival (OS) with interaction terms between M-stage and treatment regimen. Multivariable Cox regression analyses were performed to determine the adjusted association of M-stage with rPFS and OS after considering the effect modification by prior local therapy (LT). Results: Among 972 evaluable patients -432 had M0, 334 had M1 at diagnosis while M-stage was unknown in 206. We did not find any statistically significant heterogeneity of treatment effect on rPFS (interaction p=0.13; HR for placebo in M0 group: 1.42 [1.13-1.79]; M1/unknown group: 1.11 [0.90-1.37]), and OS (interaction p=0.87; HR for placebo in M0 group: 1.02 [0.81-1.29], and M1/unknown group: 1.00 [0.82-1.23]) based on M-stage at diagnosis. There was no significant association of M-stage with rPFS (HR for LT group: 1.08 [0.84-1.40], HR for no LT: 0.91 [0.67-1.24]) and OS (HR for LT: 1.04 [0.81-1.33] and no LT: 0.95 [0.70-1.29]) with no significant heterogeneity depending on receipt of LT (interaction p-value of 0.94 and 0.93, respectively). Conclusion: We did not find a statistically significant heterogeneity in efficacy of dual ARAT based on synchronous versus metachronous presentation. M-stage was not found to be a predictor for rPFS and OS after considering effect modification by prior LT. Citation Format: Shawn Malone, Christopher Wallis, Scott Morgan, Amar Kishan, Amy Tu Trinh Le, Julia Malone, Yilun Sun, Daniel Spratt, Fred Saad, Soumyajit Roy. Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2105.

Effect of docetaxel added to bicalutamide in Hormone-Naïve non-metastatic prostate cancer with rising PSA, a randomized clinical trial (SPCG-14)

Background Historically, endocrine therapy was used in a range of scenarios in patients with rising PSA, both as a treatment for locally advanced non-metastatic prostate cancer and PSA recurrence following curative intended therapy. In the present study the objective was to investigate if chemotherapy added to endocrine therapy could improve progression-free survival (PFS). Materials and Methods Patients with hormone-naïve, non-metastatic prostate cancer and rising prostate-specific antigen (PSA), enrolled from Sweden, Denmark, the Netherlands, and Finland, were randomized to long-term bicalutamide (150 mg daily) or plus docetaxel (75 mg/m2, q3w, 8–10 cycles) without prednisone, after stratification for the site, prior local therapy or not, and PSA doubling time. The primary endpoint was 5-year PFS analyzed with a stratified Cox proportional hazards regression model on intention to treat basis. Results Between 2009 and 2018, a total of 348 patients were randomized; 315 patients had PSA relapse after radical treatment, 33 patients had no prior local therapy. Median follow-up was 4.9 years (IQR 4.0–5.1). Adding docetaxel improved PFS (HR 0.68, 95% CI 0.50–0.93; p = 0.015). Docetaxel showed an advantage for patients with PSA relapse after prior local therapy (HR 0.67, 95% CI 0.49–0.94; p = 0.019). One event of neutropenic infection/fever occurred in 27% of the patients receiving docetaxel. Limitations were slow recruitment, lack of enrolling patients without radical local treatment, and too short follow-up for evaluation of overall survival in patients with PSA relapse. Conclusion Docetaxel improved PFS in patients starting bicalutamide due to PSA relapse after local therapy or localized disease without local therapy. Confirmatory studies of the efficacy of docetaxel in the setting of PSA-only relapse in addition to endocrine therapies may be justified if longer follow-up will show increased metastatic-free survival.

Effect of Prior Local Therapy on Response to First-line Androgen Receptor Axis Targeted Therapy in Metastatic Castrate-resistant Prostate Cancer: A Secondary Analysis of the COU-AA-302 Trial

BackgroundMen with localized prostate cancer are often treated with local therapy (LT). However, a proportion of these patients will eventually develop recurrence and progression requiring systemic therapy. Whether primary LT affects the response to this subsequent systemic treatment is unclear. ObjectiveWe investigated whether the receipt of prior prostate-directed LT influenced the response to first-line systemic therapy and survival in docetaxel-naïve metastatic castrate-resistant prostate cancer (mCRPC) patients. Design, setting, and participantsThis is an exploratory analysis of the COU-AA-302 trial, a multicentric double-blinded phase 3 randomized controlled trial in which mCRPC patients with no to mild symptoms were randomized to receive abiraterone plus prednisone or placebo plus prednisone. Outcome measurements and statistical analysisWe compared the time-varying effects of first-line abiraterone in patients with and without prior LT using a Cox proportional hazard model. The cut points were chosen using grid search, and were 6 and 36 mo for radiographic progression-free survival (rPFS) and overall survival (OS), respectively. We also investigated whether there was any difference in treatment effect on score change (relative to baseline) in various patient-reported outcomes (measured by Functional Assessment of Cancer Therapy—Prostate [FACT-P]) over time depending on the receipt of prior LT. The adjusted association of prior LT with survival was determined using weighted Cox regression models. Results and limitationsAmong 1053 eligible patients, 64% (n = 669) received prior LT. We did not find any statistically significant heterogeneity of time-dependent treatment effect from abiraterone on rPFS in patients with (hazard ratio [HR]: 0.36 [95% confidence interval: 0.27–0.49] at ≤6 mo; 0.64 [0.49–0.83] at >6 mo) or without (HR: 0.37 [0.26–0.55] at ≤6 mo; 0.72 [0.50–1.03] at >6 mo) prior LT. Similarly, there was no significant heterogeneity in time-dependent treatment effect on OS with (HR: 0.88 [0.71–1.10] at ≤36 mo; 0.76 [0.52–1.11] at >36 mo) or without (0.78 [0.60–1.01] at ≤36 mo; 0.55 [0.30–0.99] at >36 mo) prior LT. We did not find sufficient evidence of a difference in treatment effect from abiraterone on score change over time in prostate cancer subscale (interaction p = 0.4), trial outcome index (interaction p = 0.8), and FACT-P total score (interaction p = 0.6) depending on the receipt of prior LT. Receipt of prior LT was associated with a significant improvement in OS (average HR: 0.72 [0.59–0.89]). ConclusionsThis study demonstrates that the efficacy of first-line abiraterone and prednisone in docetaxel-naïve mCRPC do not vary significantly based on the receipt of prior prostate-directed LT. Further studies are needed to explore the plausible mechanisms of the association of prior LT with superior OS. Patient summaryThis secondary analysis of the COU-AA-302 trial suggests that survival benefits and temporal changes in quality of life with first-line abiraterone in docetaxel-naïve mCRPC do not differ significantly among patients who received versus those who did not receive prior prostate-directed local therapy.

Abstract PD7-03: Translational Breast Cancer Research Consortium Trial 022: Neratinib and Trastuzumab-Emtansine for HER2+ Breast Cancer Brain Metastases (BCBM)

Abstract PURPOSE: Treatment options for patients (pts) with HER2+ BCBM remain limited. We previously reported that neratinib monotherapy is associated with a volumetric central nervous system objective response rate (CNS ORR) of 8%, whereas the combination of neratinib and capecitabine resulted in a volumetric CNS ORR of 49% (in lapatinib-naïve pts). Preclinical data suggest that neratinib may overcome resistance to trastuzumab-emtansine (T-DM1) and that the combination has potential CNS efficacy. Here, we report results of neratinib plus T-DM1 in pts with HER2+ BCBM. PATIENTS AND METHODS: In this prospective, multicenter, phase II study, pts with measurable HER2+ BCBM received neratinib 160 mg orally once daily plus T-DM1 3.6 mg/kg IV every 21 days in three parallel-enrolling cohorts. Cohort 4A enrolled pts with previously untreated brain metastases. Cohort 4B enrolled pts with BCBM progressing after prior local CNS-directed therapy without prior exposure to T-DM1. Cohort 4C enrolled pts with BCBM progressing after prior local CNS-directed therapy who had previous exposure to T-DM1. Diarrhea prophylaxis with colestipol and loperamide was required during cycle 1. Cohorts 4A and 4B were single-stage with a planned enrollment of 20 patients; cohort 4C had a two-stage design, with a requirement for at least 1 of the first 9 pts to achieve a response in order to enroll a total of 24 patients. The primary endpoint was Response Assessment in Neuro-Oncology-Brain Metastases (RANO BM) in each cohort separately. Correlative studies included patient-reported outcomes (PROs) for gastrointestinal toxicity. RESULTS: We enrolled 6, 17, and 21 patients to cohorts 4A, 4B, and 4C, during 11/07/2018 – 11/01/2021. Enrollment was stopped prematurely due to slow accrual. Across Cohorts 4A-4C, the median number of prior lines of chemotherapy prior to enrollment was 2 (range 1-10); 25% received prior lapatinib and no patients received prior tucatinib. In cohorts 4B and 4C (prior CNS-treated cohorts), 33% had prior CNS surgery and >94% had prior CNS radiation. Among evaluable patients, CNS ORR in cohorts 4A (n=6), 4B (n=16), and 4C (n=21) was 50.0% (95% CI 18.8- 81.2%), 25.0% (95% CI 8.3-52.6%), and 38.1% (95% CI 19.0-61.3%), respectively. Median (range) number of cycles completed for 4A, 4B, and 4C was 4.5 (1-15), 4 (range 0-49+), and 6 (0-23); three patients on Cohort 4B remain on protocol therapy (cycles 14, 45, and 49). The overall survival at 12-months for cohorts 4A, 4B, and 4C was 83.3% (95% CI, 58.3-100%), 86.2% (95% CI 70-100%), and 83.3% (95% CI 67.6-100%). Diarrhea was the most common grade 3 toxicity (19.0–33.3% across cohorts); one grade 4 liver function event occurred in cohort 4B. Updated efficacy results will be reported at the meeting; PRO analyses are ongoing. CONCLUSION: Intracranial activity was observed for the combination of neratinib plus T-DM1 across all three enrolled cohorts, including those with prior T-DM1 exposure, suggesting synergistic effects of this treatment combination. Our data provide additional evidence for consideration of neratinib-based combinations in pts with HER2+ BCBM. Citation Format: Rachel Freedman, Siyang Ren, Nabihah Tayob, Rebecca Gelman, Karen L. Smith, Raechel Davis, Alyssa Pereslete, Victoria Attaya, Christine Cotter, Wendy Y. Chen, Cesar Augusto Santa-Maria, Catherine Van Poznak, Beverly Moy, Adam M. Brufsky, Michelle Melisko, Ciara C. O’Sullivan, Nadia Ashai, Yasmeen Rauf, Julie Nangia, Dario Trapani, Jennifer Savoie, Robyn Burns, Antonio C. Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy U. Lin. Translational Breast Cancer Research Consortium Trial 022: Neratinib and Trastuzumab-Emtansine for HER2+ Breast Cancer Brain Metastases (BCBM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-03.

Abstract P4-01-36: Real World Data for Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases

Abstract Background: Trastuzumab deruxtecan (T-DXd) improves outcomes in HER2-positive metastatic breast cancer (MBC) patients, including patients with previously treated stable brain metastases (BMs). Our objective was to examine the characteristics of HER2-positive MBC patients with BMs prior to T-DXd use. Methods: We performed a retrospective cross-sectional study of T-DXd prior authorization (PA) approvals by OncoHealth for HER2-positive MBC patients between 1/17/2020 – 6/21/2022. Using medical records and utilization management data, we assessed the characteristics of PA approvals for 145 patients requesting T-DXd in Stage 4, HER2-positive, female MBC with BMs. Results: Brain metastases were identified in 41/145 patients with HER2-positive MBC prior to T-DXd authorization. Among the 41 patients The mean age was within the range of 50-59 years, 72% were hormone receptor-positive, and all were HER2 positive. 19/41(46%) had symptomatic BMs, 5/41(12%) had asymptomatic BMs. Prior local therapies for the BMs included craniotomy in 19.5% and brain radiotherapy in 87.8% prior to T-DXd. The median number of prior MBC therapies was 2 (range: 0-8) and 73% (30/41) did not receive tucatinib-based therapy prior to T-DXd. Tucatinib-based therapy was the most common subsequent line of therapy among T-DXd patients with further therapy (5/8). For available data (13 metastatic patients), 8 metastatic patients received tucatinib for an average of 149 days before receiving T-DXd for an average of 238 days, compared to 5 metastatic patients who received T-DXd for an average of 295 days before receiving tucatinib for 240 days, implying improved disease management in the T-DXd-to-tucatinib sequence. Conclusions: In the real world, patients with symptomatic, progressing BMs are more likely to receive T-DXd prior to tucatinib or potential tucatinib-based therapy, with longer duration of stability and treatment. Appropriate sequencing of available treatments with activity on brain metastases such as T-DXd and tucatinib-based therapy needs to be further studied. Citation Format: Andrew Toler, Laura R. Bobolts, Mark Mangurian, Melissa Pozotrigo, Corey Wise, Hiywete Solomon, Nicole Hartung, Rory Makielski, Shika Marur, Meera Ravindranathan, Shanthi Marur. Real World Data for Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-36.

Clinical outcomes of abiraterone acetate (AA) or enzalutamide (E) as first-line therapy (Rx) for men aged ≥75 with metastatic castration-resistant prostate cancer (mCRPC) according to previous use of docetaxel (D) for metastatic castration-sensitive prostate cancer (mCSPC) in a multicenter international registry: A SPARTACUSS – Meet-URO 26 study.

107 Background: The optimal management of mCRPC in men aged ≥75 is challenging, and there is a paucity of clinical data in the literature. Although AA and E are commonly used as 1st line Rx for mCRPC, it is unclear whether use of upfront D for mCSPC may impact their clinical efficacy or safety in this elderly population. Methods: Patients aged ≥75 who started AA or E as 1st line Rx for mCRPC within January 2015 - April 2019 were identified from the IRB approved databases of 10 institutions in Europe, South and North America. Demographic and clinicopathological data were collected from available medical records, including Gleason, prior local therapy, newly diagnosed metastatic disease, disease volume, ECOG, PSA and sites of metastases. Patients were classified by use of upfront D for mCSPC. The primary endpoints were overall survival (OS) from AA/E onset and OS from ADT start and safety of AA/E. The endpoints distributions including median (95% CI) were estimated by Kaplan-Meier method. Results: Of the 337 patients selected, 24 (7.1%) received ADT+D and 313 (92.9%) ADT alone for mCSPC. Patients with ADT+D tended to be younger (78 vs 81, p=0.022) and, albeit not statistically significant, had higher rates of Gleason score >8 (81.0% vs 62.6%, p=0.10), newly diagnosed (83.3% vs 65.6%, p=0.08) and high volume disease (45.8% vs 34.6%, p=0.28), compared to those with ADT alone. Median follow-up was 18.8 months. No significant difference of OS from ADT start or from AA/E onset was observed between the 2 cohorts (see table). Despite OS from ADT start being longer in those having ADT+D, OS from AA/E start was approximately 2 years in both cohorts. Rates of adverse events (AEs) of any grade (58.3% vs 52.1%, p=0.67) and grade ≥3 (12.5% vs 15.7%, p=1.0) did not significantly differ between the 2 cohorts. Conclusions: While limited by small sample size for ADT+D and retrospective study design, patients aged ≥75 having AA/E as 1st line mCRPC Rx showed similar survival outcomes and tolerability regardless of previous use of D for mCSPC. [Table: see text]

A cohort study evaluating the clinical, environmental and genetic profiles of men with early-onset, aggressive prostate cancer.

266 Background: The frequency of young men with aggressive prostate cancer (PC) at diagnosis is increasing. Clinical, environmental, and genetic drivers of this change have not been well characterized. Methods: This multi-institutional study evaluated two cohorts; Cohort 1 completed enrollment and is reported here. Eligible patients (pts) had early-onset (age ≤ 60 years) PC with metastasis (N+ or M+) at diagnosis, or within 5 years of curative intent local therapy. Data were collected to define clinical, environmental, and genetic profiles, including ctDNA and whole genome and transcriptome sequencing using Tempus xE. Standard descriptive statistics were used. Results: 46 pts were enrolled. Median age at diagnosis was 55 (range 41-60 years); 85% were White, 15% were Black; 4% served in the military and 4% reported biochemical exposure. 85% reported a family history of cancer, 46% had family history of PC. Median PSA at diagnosis was 19 (range 1-534 ng/mL), 56% had a Gleason score of 9-10, and 56% had de novo metastatic PC. 46% had prior local therapy. Genetic data is available for 40 pts. The most frequent clinically significant mutations (≥10% for somatic, ≥2.5% for germline) are summarized. 23 unique germline and over 1,000 unique somatic mutations were identified. Germline mutations associated with hereditary PC were found in 15%, all were associated with DNA damage repair (DDR). Somatic mutations in DDR genes were found in 10%. Co-mutations in TP53 and BRAF were seen in 30%. Interestingly, there were also incidental germline mutations identified that are associated with cardiac ( MYBPC, MYH7) and vascular ( MYH11, ACTA2) conditions, among others. Conclusions: In this cohort study we identified an unexpectedly high frequency of family histories that were positive for cancer (85%), and specifically PC (46%). However, rates of germline mutations associated with hereditary PC were similar to previous studies (15%), suggesting the possibility that other novel hereditary mutations driving increased PC risk may be present. Increased rates of somatic mutations in BRAF (35%) were also seen. The high frequency of BRAF mutations, particularly those that co-occur with TP53 mutations, may be driving more aggressive disease. We also found enrichment of mutations associated with non-cancer hereditary syndromes, including hypertrophic cardiomyopathy. These are not usually included in cancer-focused genetic studies, suggesting broader testing that includes potentially actionable incidental findings should be considered. More work is needed to define characteristics of this high-risk population and optimize management. [Table: see text]

Clinical impact of volume of disease and time of metastatic disease presentation on patients receiving enzalutamide or abiraterone acetate plus prednisone as first-line therapy for metastatic castration-resistant prostate cancer

BackgroundMetastatic castration-resistant prostate cancer remains a challenging condition to treat. Among the available therapeutic options, the androgen receptor signaling inhibitors abiraterone acetate plus prednisone (AA) and enzalutamide (Enza), are currently the most used first-line therapies in clinical practice. However, validated clinical indicators of prognosis in this setting are still lacking. In this study, we aimed to evaluate a prognostic model based on the time of metastatic disease presentation (after prior local therapy [PLT] or de-novo [DN]) and disease burden (low volume [LV] or high-volume [HV]) at AA/Enza onset for mCRPC patients receiving either AA or Enza as first-line.MethodsA cohort of consecutive patients who started AA or Enza as first-line treatment for mCRPC between January 1st, 2015, and April 1st, 2019 was identified from the clinical and electronic registries of the 9 American and European participating centers. Patients were classified into 4 cohorts by the time of metastatic disease presentation (PLT or DN) and volume of disease (LV or HV; per the E3805 trial, HV was defined as the presence of visceral metastases and/or at least 4 bone metastases of which at least 1 out the axial/pelvic skeleton) at AA/Enza onset. The endpoint was overall survival defined as the time from AA or Enza initiation, respectively, to death from any cause or censored at the last follow-up visit, whichever occurred first.ResultsOf the 417 eligible patients identified, 157 (37.6%) had LV/PLT, 87 (20.9%) LV/DN, 64 (15.3%) HV/PLT, and 109 (26.1%) HV/DN. LV cohorts showed improved median overall survival (59.0 months; 95% CI, 51.0–66.9 months) vs. HV cohorts (27.5 months; 95% CI, 22.8–32.2 months; P = 0.0001), regardless of the time of metastatic presentation. In multivariate analysis, HV cohorts were confirmed associated with worse prognosis compared to those with LV (HV/PLT, HR = 1.87; p = 0.029; HV/DN, HR = 2.19; P = 0.002).ConclusionOur analysis suggests that the volume of disease could be a prognostic factor for patients starting AA or Enza as first-line treatment for metastatic castration-resistant prostate cancer, pending prospective clinical trial validation.