The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains controversial.In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomly assigned 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (composite of death, myocardial infarction, or stroke) through 12 months.Because of slower-than-projected enrollment and fewer-than-projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From May 3, 2016, to April 16, 2020, a total of 545 patients from 113 sites across 12 countries were randomly selected. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease, and 20.4% had metastatic disease. A major adverse cardiovascular event occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) patients assigned to leuprolide (hazard ratio, 1.28 [95% CI, 0.59-2.79]; P=0.53).PRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease) is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely because of the smaller than planned number of participants and events, and no difference in major adverse cardiovascular events at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02663908.
Perirectal spacing, whereby biomaterials are placed between the prostate and rectum, shows promise in reducing rectal dose during prostate cancer radiation therapy. A prospective multicenter randomized controlled pivotal trial was performed to assess outcomes following absorbable spacer (SpaceOAR system) implantation.Overall, 222 patients with clinical stage T1 or T2 prostate cancer underwent computed tomography (CT) and magnetic resonance imaging (MRI) scans for treatment planning, followed with fiducial marker placement, and were randomized to receive spacer injection or no injection (control). Patients received postprocedure CT and MRI planning scans and underwent image guided intensity modulated radiation therapy (79.2 Gy in 1.8-Gy fractions). Spacer safety and impact on rectal irradiation, toxicity, and quality of life were assessed throughout 15 months.Spacer application was rated as "easy" or "very easy" 98.7% of the time, with a 99% hydrogel placement success rate. Perirectal spaces were 12.6 ± 3.9 mm and 1.6 ± 2.0 mm in the spacer and control groups, respectively. There were no device-related adverse events, rectal perforations, serious bleeding, or infections within either group. Pre-to postspacer plans had a significant reduction in mean rectal V70 (12.4% to 3.3%, P<.0001). Overall acute rectal adverse event rates were similar between groups, with fewer spacer patients experiencing rectal pain (P=.02). A significant reduction in late (3-15 months) rectal toxicity severity in the spacer group was observed (P=.04), with a 2.0% and 7.0% late rectal toxicity incidence in the spacer and control groups, respectively. There was no late rectal toxicity greater than grade 1 in the spacer group. At 15 months 11.6% and 21.4% of spacer and control patients, respectively, experienced 10-point declines in bowel quality of life. MRI scans at 12 months verified spacer absorption.Spacer application was well tolerated. Increased perirectal space reduced rectal irradiation, reduced rectal toxicity severity, and decreased rates of patients experiencing declines in bowel quality of life. The spacer appears to be an effective tool, potentially enabling advanced prostate RT protocols.
Abstract Background Androgen receptor pathway inhibitors (apalutamide [APA], enzalutamide [ENZ], abiraterone acetate plus prednisone [AAP]) combined with androgen-deprivation therapy (ADT) are effective life-prolonging treatment options for metastatic hormone-sensitive prostate cancer (mHSPC). We evaluated the impact of upfront therapy for mHSPC on outcomes in real-world clinical practice in the United States. Methods This retrospective, observational cohort study used electronic healthcare records from the ConcertAI RWD 360 Prostate Cancer Dataset. All patients with newly diagnosed mHSPC from January 2018 to June 2023 were enrolled and followed-up until death, end of follow-up, or January 2024, whichever occurred first. Kaplan-Meier methods were used to estimate overall survival (OS), time to PSA50/PSA90 (50%/90% decline in PSA from baseline, respectively), time to undetectable PSA ( ≤ 0.2 ng/ml), and time to castration resistance (TTCR). Adjusted hazard ratios (aHR) were estimated using inverse probability of treatment weighted multivariate Cox proportional models adjusted for age, comorbidities, BMI, and baseline PSA. Results 4937 patients with mHSPC were included in the analysis: 315 received upfront APA + ADT, 1181 ENZ + ADT, 1760 AAP + ADT, 432 docetaxel (DTX) + ADT, and 1249 ADT alone. Percentages of patients reaching PSA50, PSA90, and undetectable PSA at 3 months were significantly higher for APA + ADT (70%/49%/44%, respectively) compared to ENZ + ADT (60%/38%/32%), AAP + ADT (59%/37%/33%) and ADT alone (32%/15%/32%). OS and TTCR were also significantly longer for APA + ADT (66%/77% respectively at 24 months) vs ENZ + ADT (55%/63%) AAP + ADT (59%/67%) and ADT alone (54%/57%). Starting treatment with APA + ADT was associated with a significantly reduced risk of death compared with ENZ + ADT (aHR, 95%CI) (0.66, 0.51–0.87), AAP + ADT (0.72, 0.55–0.94), and ADT alone (0.64, 0.49–0.84). Conclusions Numerous patients were not treated with intensified therapies despite their increased effectiveness. First-line APA + ADT in mHSPC was associated with statistically significantly longer OS, longer TTCR, and faster and deeper PSA responses than other life-prolonging treatments in real-world clinical practice in the US.
Purpose Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd-IFNα/Syn3 (randomly assigned 1:1 to 1 × 1011 viral particles (vp)/mL or 3 × 1011 vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd-IFNα/Syn3 (1 × 1011 vp/mL, n = 21; 3 × 1011 vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd-IFNα/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd-IFNα/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy.
Background Bladder EpiCheck (BE) is a novel methylation-based PCR urine test for the detection of non-muscle invasive bladder cancer (NMIBC) recurrences. Objective We present the results of a North American study evaluating BE and meta-analysis of literature. Methods A prospective, blinded, multicenter study was conducted in North America. Voided urine was collected from NMIBC patients prior to cystoscopic surveillance. BE testing was performed centrally. For the meta-analysis, a PUBMED search was performed to identify all published peer-reviewed clinical studies of BE for NMIBC surveillance. Results In this study, 674 patients were enrolled of which 449 were included. Overall sensitivity was 67% (95%CI 58%-74%), specificity was 84% (80%-88%), PPV was 65% (57%-73%) and NPV was 85% (81%-89%). For high-grade (HG) recurrence, sensitivity was 77% (65%-85%) and NPV was 95% (92%-97%). In patients with negative cystoscopy and cytology at the first study visit, risk of subsequent recurrence in 12 months was 5.3 (2.7–10.3) times higher in patients with positive BE vs. negative BE (p < 0.0001). In patients with negative cystoscopy and equivocal cytology, BE was positive in 75–89% of those with later HG recurrence, with PPV of 42% (15%-72%)-63% (38%-84%). The meta-analysis included 7 studies and 1564 patients. Overall sensitivity was 82% (66–92%), HG sensitivity was 91% (82–95%), specificity was 85% (80–88%), PPV was 60% (55–64%) and HG NPV was 98% (97–99%). Conclusions The consistently strong performance of BE indicate that a positive test could improve timely disease recurrence detection and a negative test could rule-out HG disease. Furthermore, the low rate of false positive results, potentially minimizes unnecessary downstream procedures and patient anxiety.
Abstract Background: In TALAPRO-2 (NCT03395197), pts unselected for homologous recombination repair (HRR) gene mutations (muts) received TALA + ENZA or PBO + ENZA in 1L mCRPC. TALA + ENZA significantly improved radiographic progression-free survival (rPFS). Previous analyses focused on the association of tumor HRR gene muts with outcome; here, we examined TALA + ENZA efficacy in pts with ≥1 non-HRR gene mut with/without HRR gene muts. Methods: This is a post-hoc exploratory agnostic analysis of a TALAPRO-2 dataset of prospectively collected/retrospectively analyzed plasma ctDNA (FoundationOne®Liquid CDx). Response was assessed per RECIST v1.1. Results: Overall, 616 pts in the intent-to-treat population had non-HRR gene muts with/without HRR gene muts; 98 (16%) pts had TMPRSS2-ERG fusions. In these 616 pts, TALA + ENZA improved rPFS vs PBO + ENZA (Table). TALA + ENZA improved rPFS in pts with TMPRSS2-ERG, RB1, or MLL2 muts, and objective response rates (ORR) in pts with TMPRSS2-ERG or RB1 muts and measurable disease at baseline (the association of MLL2 with enhanced rPFS was lost without TMPRSS2-ERG, not shown). In pts with non-HRR gene muts and no HRR gene muts (n=427), TALA + ENZA showed improvement in rPFS vs PBO + ENZA. Enhanced rPFS benefit with TALA + ENZA vs PBO + ENZA was noted in pts with TMPRSS2-ERG, RB1, or MLL2 muts, but TMPRSS2-ERG ORRs were similar across treatment arms. Conclusions: TALA + ENZA improved outcomes compared with PBO + ENZA in patients with muts in specific non-HRR genes (regardless of HRR gene muts). TMPRSS2-ERG and RB1 emerged as candidate predictive biomarkers for differential efficacy favoring TALA + ENZA vs PBO + ENZA. PARP inhibitors may induce a synthetically lethal interaction with TMPRSS2-ERG-mediated inhibition of non-homologous end joining and help overcome RB1-mediated ENZA resistance. ≥1 non-HRR gene muts ≥1 non-HRR gene muts with no HRR gene muts Median rPFS, mo HR (95% CI) Median rPFS, mo HR (95% CI) Gene mutation TALA + ENZA (N=310) PBO + ENZA (N=306) TALA + ENZA (N=218) PBO + ENZA (N=209) Any non-HRR NR 19.3 0.63 (0.50–0.80) NR 22.5 0.66 (0.49–0.89) TMPRSS2-ERG, [n] 25.9 [n=43] 11.0 [n=55] 0.36 (0.20–0.64) 19.4 [n=32] 11.0 [n=44] 0.40 (0.20–0.76) MLL2, [n] 18.2 [n=20] 13.8 [n=20] 0.43 (0.19–0.98) NR [n=8] 17.2 [n=11] 0.50 (0.14–1.74) RB1, [n] 9.8 [n=14] 1.9 [n=8] 0.22 (0.07–0.73) 10.8 [n=6] 1.8 [n=3] 0.40 (0.05–2.92) ORR, % (n/N)a OR (95% CI) ORR, % (n/N)a OR (95% CI) TALA + ENZA (N=96) PBO + ENZA (N=105) TALA + ENZA (N=62) PBO + ENZA (N=75) TMPRSS2-ERG 56 (13/23) 41 (7/17) 0.54 (0.12–2.27) 53 (9/17) 47 (7/15) 0.78 (0.16–3.85) MLL2 64 (7/11) 70 (7/10) 1.33 (0.15–12.60) ND ND ND RB1 62 (5/8) 0 (0/6) 0.00 (0.00–0.75) ND ND ND CI, confidence interval; HR, hazard ratio; mo, months; ND, not displayed (combined prevalence <10 pts); NR, not reached; OR, odds ratio. aMeasurable disease at baseline Citation Format: Josep M. Piulats, Arun A. Azad, A. Douglas Laird, Nobuaki Matsubara, Karim Fizazi, Neal D. Shore, Lawrence Karsh, Glenn Liu, Andre P. Fay, Joan Carles, Robert J. Jones, Eric Voog, Stefanie Zschäbitz, Ugo De Giorgi, Steven M. Yip, Xinmeng Jasmine Mu, Xun Lin, Arne Engelsberg, Neeraj Agarwal. TMPRSS2-ERG and RB1 as candidate predictive biomarkers for efficacy in TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT018.
