Olaparib for Chinese Metastatic Castration-resistant Prostate Cancer: A Real-World Study of Efficacy and Gene Predictive Analysis

Objective: To evaluate the real-world effectiveness and gene predictive analysis of olaparib in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) .Methods: A multicenter, retrospective, real-world study was conducted by involving Chinese patients with mCRPC from December 2017 to June 2021. Homologous Recombination repair (HRR)gene mutation (HRRm) status was identified using targeted next-generation sequencing (NGS). The primary endpoint includes prostate-specific antigen (PSA) response rate (PSA50). Secondary end points include PSA progression-free survival (PSA-PFS), exploratory endpoints include PSA50, and PSA-PFS in HRRm-negative patients with variants of unknown significance (VUS). Survival rates were analyzed using Kaplan–Meier (KM) plot.Results: A total of 39 eligible patients with a median age of 65 (interquartile range [IQR]: 59.5-69.5) years were included in the study. Overall, 40% (12/30) of the patients with mCRPC achieved PSA50 and the median PSA-PFS was 3.1 months (95% Confidence interval [CI]: 2.4-7). Furthermore, higher PSA50 rate and longer PSA-PFS were observed in HRRm-positive patients (PSA50: 50% [7/14]; median PSA-PFS: 5.3 months, 95% CI: 3.73–10). Among the HRRm-positive patients, those harboring the BRCA2 aberrations experienced best clinical efficacy (PSA50: 55.5% [5/9] and median PSA-PFS [95% CI]: 9.5 months [4.3, NA]). Clinical benefit was also observed in HRRm-negative patients (PSA50: 31.3% [5/16]; median PSA-PFS [95% CI]:2.05 months [1.5,8]), wherein most patients with a PSA50 response were carrying VUS mutations (PSA50: 50% [4/8]; median PSA-PFS [95% CI]: 2.75 months [1.27, NA]). In one patients with mutation in the ATR gene, the PSA level decreased by 62%. Conclusion: Olaparib improved PSA response and prolonged PSA-PFS in Chinese mCRPC patients especially in those carrying HRR mutation. Among the HRR genes, patients with BRCA2 mutation showed the best clinical benefit. Besides, some patients carrying HRR VUS alternations and other DNA damage response (DDR) gene mutations also showed response to olaparib treatment, indicating that the clinical benefits observed in HRR negative group were driven by VUS and other DDR gene mutation. However, this should be further explored in the future, and more molecular functional studies are needed to reclassify VUS mutations for better clinical treatment decision-making and management of mCRPC.

A prospective phase-II trial of biweekly docetaxel plus androgen deprivation therapy in patients with previously-untreated metastatic castration-naïve prostate cancer

Introduction The aim of this prospective phase II study was to evaluate the efficacy and safety of biweekly docetaxel plus androgen-deprivation therapy (ADT) in patients with metastatic castration-naïve prostate cancer (mCNPC). Patients and methods Patients with histologically-proven, previously-untreated mCNPC received ADT plus docetaxel, 40 mg/m2. Docetaxel was repeated every 2 weeks, up to 12 cycles. Endpoints included castration-resistant prostate cancer (CRPC)-free survival, prostate-specific antigen (PSA) response, and safety. Results A total of 42 patients were registered and analyzed for final outcomes. Of the 42 patients, 36 (86%) completed the 12 planned cycles of docetaxel plus ADT. During a median follow up of 25 months, all but two patients (95%) achieved a PSA response with a nadir PSA level of 0.42 ng/ml (range 0.01–1280.87). The median CRPC-free survival was 26.4 months (95% confidence interval [CI] 20.9–32.0) with a one-year CRPC-free rate of 79% (33 patients, 95% CI 66–91). Multivariable analysis revealed that the performance status of the Eastern Cooperative Oncology Group 0 was independently associated with longer CRPC-free survival (hazard ratio [HR] 0.27, 95% CI 0.07–0.99). The most common adverse events of any grade were anemia (95%), followed by nail changes (33%), fatigue (29%), and oral mucositis (26%). Severe (grade 3 or higher) adverse events were infrequent: pneumonitis (n = 2), diarrhea (n = 1), and neutropenia (n = 1). Conclusion Our results suggest that biweekly docetaxel plus ADT is feasible, and clinical efficacy does not seem to be compromised compared to a standard triweekly docetaxel 75 mg/m2 plus ADT regimen.

Her2 Expression in Circulating Tumor Cells Is Associated with Poor Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer

HER2−dependent signaling may support the development of metastatic castration-resistant prostate cancer (mCRPC) by activating androgen receptor signaling through ligand–independent mechanisms. From 41 mCRPC patients (including 31 treated with Androgen Receptor Signaling Inhibitors [ARSI]), Circulating Tumor Cells (CTCs) were prospectively enriched with AdnaTest platform and analyzed with a multiplexed assay for HER2 and AR-V7 mRNA expression. Then, we evaluated the impact of HER2 expression on PSA-response, Progression Free Survival (PFS) and Overall Survival (OS). HER2 expression was detected in CTCs of 26 patients (63%). Although PSA response was similar regardless of HER2 status, patients with HER2 positive CTCs had shorter PSA-PFS (median: 6.2 months versus 13.0 months, p = 0.034) and radiological-PFS (6.8 months versus 25.6 months, p = 0.022) than patients without HER2 expression. HER2 expression was also associated with a shorter OS (22.7 months versus not reached, p = 0.05). In patients treated with ARSI, multivariate analyses revealed that the prognostic impact of HER2 status on PSA-PFS was independent of AR-V7 expression and of the detection of CTCs by an AdnaTest. We showed for the first time the poor prognostic value of HER2 expression in CTCs from patients with mCRPC. The therapeutic interest of targeting this actionable pathway remains to be explored.

Impact of Serum γ-Glutamyltransferase on Overall Survival in Men with Metastatic Castration-Resistant Prostate Cancer Treated with Docetaxel

Background: Reports on the prognostic significance of serum γ-glutamyltransferase (GGT) in men with metastatic castration-resistant prostate cancer (mCRPC) are limited. In addition, GGT expression status in cancer tissues has not been well characterized regardless of cancer types. Methods: This retrospective study included 107 consecutive men with mCRPC receiving docetaxel therapy. The primary endpoints were associations of serum GGT with overall survival (OS) and prostate-specific antigen (PSA) response. The secondary endpoint was an association of serum GGT with progression-free survival (PFS). Additionally, GGT expression status was immunohistochemically semi-quantified using tissue microarrays. Results: A total of 67 (63%) men died during follow-up periods (median 22.5 months for survivors). On multivariable analysis, high Log GGT was independently associated with adverse OS (HR 1.49, p = 0.006) as were low hemoglobin (HR 0.79, p = 0.002) and high PSA (HR 1.40, p < 0.001). In contrast, serum GGT was not significantly associated with PSA response or PFS. Moreover, incorporation of serum GGT into established prognostic models (i.e., Halabi and Smaletz models) increased their C-indices for predicting OS from 0.772 to 0.787 (p = 0.066) and from 0.777 to 0.785 (p = 0.118), respectively. Furthermore, there was a positive correlation between serum and tissue GGT levels (ρ = 0.53, p = 0.003). Conclusions: Serum GGT may be a prognostic biomarker in men with mCRPC receiving docetaxel therapy. GGT overexpression by prostate cancer cells appears to be responsible for the elevation of GGT in the serum.

347 KEYNOTE-365 cohort C: pembrolizumab + enzalutamide in patients with abiraterone acetate–pretreated metastatic castration-resistant prostate cancer (mCRPC)—data after minimum of 22 months of follow-up

BackgroundPrevious data from cohort C of phase 1b/2 study KEYNOTE-365 (NCT02861573) showed that PD-1 inhibitor pembrolizumab + enzalutamide was well tolerated and showed antitumor activity in patients with abiraterone acetate–pretreated mCRPC. Updated data after a minimum of 22 months of follow-up are presented.MethodsPatients in the prechemotherapy mCRPC state who were intolerant to ≥4 weeks‘ treatment with abiraterone acetate or for whom this treatment failed, had progressive disease ≤6 months before screening, and had ECOG PS 0-2 were enrolled. Patients received pembrolizumab 200 mg IV Q3W + enzalutamide 160 mg orally QD. Primary end points were PSA response rate (decrease ≥50% from baseline), confirmed ORR per RECIST v1.1 by blinded independent central review (BICR), and safety. Secondary end points were time to PSA progression; DCR (CR or PR of any duration + SD or non-CR/non-PD ≥6 months) and DOR per RECIST v1.1 by BICR; rPFS per PCWG3-modified RECIST v1.1 by BICR; and OS.ResultsOf 103 enrolled patients, 102 were treated. Median age was 70.0 years (range, 43–87); 29.4% of patients were PD-L1+; 37.3% had RECIST-measurable disease. Median follow-up (time from enrollment to data cutoff) was 40.2 months (range, 22.3–49.9). Confirmed PSA response rate in patients with baseline PSA measurement (N = 101) was 23.8%. Median time to PSA progression was 4.0 months (95% CI, 3.5–4.4). In 38 patients with measurable disease, ORR was 10.5% (2 CR; 2 PR). Median DOR was 11.8 months (4.3 to 38.3+ months); 1 patient had a response ≥12 months. DCR for the total population was 33.3%. Median (95% CI) rPFS was 6.0 months (4.1–6.3); rPFS at 12 months was 30.1%. Median (95% CI) OS was 20.1 months (16.9–25.2); OS at 12 months was 76.2%. Treatment-related AEs (TRAEs) occurred in 92.2% of patients; most common (≥20%) were fatigue (39.2%), nausea (21.6%), and rash (21.6%). Grade 3–5 TRAEs occurred in 42.2%, most commonly rash (7.8%) and fatigue (5.9%). Four patients died of AEs: 1 death was treatment-related (unknown cause).ConclusionsAfter a minimum follow-up of 22 months, pembrolizumab + enzalutamide continued to show antitumor activity in abiraterone acetate–pretreated mCRPC. The safety profile of pembrolizumab + enzalutamide was generally consistent with individual profiles of each agent. There was a higher incidence than typically reported for the individual agents of all-grade (21.6%) and grade 3 (7.8%) rash, which resolved with standard-of-care treatment. The combination is being further evaluated in the phase 3 study KEYNOTE-641.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicalTrialsgov, identifier: NCT02861573Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

Initial dose reduction of enzalutamide does not decrease the incidence of adverse events in castration-resistant prostate cancer

Background There was no clear evidence whether the initial dose of enzalutamide affects the incidence of adverse events (AEs), and oncological outcome in patients with castration-resistant prostate cancer (CRPC). Methods The clinical charts of 233 patients with CRPC treated with enzalutamide were reviewed retrospectively. After 1:3 propensity score matching (PSM), 124 patients were divided into a reduced dose group and a standard dose group, and the prostate specific antigen (PSA) response and the incidence of AEs were compared. Results 190 patients with CRPC initiated with standard dose enzalutamide were younger and better performance status compared with 43 patients beginning with reduced dose. After PSM, the baseline characteristics were not different between the standard and the reduced dose group. In the PSM cohort, the PSA response rate was significantly lower in the reduced dose group than in the standard dose group (-66.3% and -87.4%, p = 0.02). The incidence rates of AEs were not statistically different between the groups (22.6% and 34.4%, respectively, p = 0.24). Conclusion Initiating treatment with a reduced dose of enzalutamide did not significantly decrease the incidence rate of AEs, and it showed poorer PSA response rate. There is no clear rationale for treating with a reduced initial dose of enzalutamide to reduce the incidence of AEs.

Radium-223 Treatment of Patients with Metastatic Castration Resistant Prostate Cancer: Biomarkers for Stratification and Response Evaluation

Radium-223 dichloride ([223Ra]RaCl2; Ra-223) is a targeted alpha-emitting radiopharmaceutical which results in an overall survival and health related quality of life (HRQoL) benefit in symptomatic patients with metastatic castration resistant prostate cancer (mCRPC) and predominantly bone metastasis. Although effective, options to select patients who will derive treatment benefit and to monitor and predict treatment outcomes are limited. PSA response and radiographic evaluation are commonly used in mCRPC treatment assessment but are not informative in Ra-223 treated patients. Consequently, there is a clear need for predictive and prognostic tools. In this review, we discuss the physiology of bone metastases and the mechanism of action and efficacy of Ra-223 treatment, as well as offering an outline of current innovative prognostic and predictive biomarkers.