Enzalutamide in metastatic hormone-sensitive prostate cancer: results from the international, multicentre, real-world ARON-3 study.

Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches.

ContextRecent randomized controlled trials (RCTs) examined the role of adding androgen receptor signaling inhibitors (ARSIs), including abiraterone acetate (ABI), apalutamide, darolutamide (DAR), and enzalutamide (ENZ), to docetaxel (DOC) and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). ObjectiveTo analyze the oncologic benefit of triplet combination therapies using ARSI + DOC + ADT, and comparing them with available treatment regimens in patients with mHSPC. Evidence acquisitionThree databases and meetings abstracts were queried in April 2022 for RCTs analyzing patients treated with first-line combination systemic therapy for mHSPC. The primary interests of measure were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were conducted to assess the differential outcomes in patients with low- and high-volume disease as well as de novo and metachronous metastasis. Evidence synthesisOverall, 11 RCTs were included for meta-analyses and network meta-analyses (NMAs). We found that the triplet combinations outperformed DOC + ADT in terms of OS (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65–0.84) and PFS (pooled HR: 0.49, 95% CI: 0.42–0.58). There was no statistically significant difference between patients with low- and high-volume disease in terms of an OS benefit from adding an ARSI to DOC +ADT (both HR: 0.79; p = 1). Based on NMAs, triplet therapy also outperformed ARSI + ADT in terms of OS (DAR + DOC + ADT: pooled HR: 0.74, 95% CI: 0.55–0.99) and PFS (ABI + DOC + ADT: HR: 0.68, 95% CI: 0.51–0.91, and ENZ + DOC + ADT: HR: 0.70, 95% CI: 0.53–0.93). An analysis of treatment ranking among de novo mHSPC patients showed that triplet therapy had the highest likelihood of improved OS in patients with high-volume disease; however, doublet therapy using ARSI + ADT had the highest likelihood of improved OS in patients with low-volume disease. ConclusionsWe found that the triplet combination therapy improves survival endpoints in mHSPC patients compared with currently available doublet treatment regimens. Our findings need to be confirmed in further head-to-head trials with longer follow-up and among various patient populations. Patient summaryOur study suggests that triplet therapy with androgen receptor signaling inhibitor, docetaxel, androgen deprivation therapy prolongs survival in patients with metastatic hormone-sensitive prostate cancer compared with the current standard doublet therapy.

The present retrospective, single-centre study investigated the efficacy and toxicity of upfront docetaxel chemotherapy in patients with hormone-sensitive metastatic prostate cancer and evaluated the impact in high and low-volume disease. Data from 167 patients with hormone-sensitive metastatic prostate cancer treated between January 2016 and December 2019 were analysed. The data cut-off was February 2024; the median follow-up time was 37 months and the median age was 66 years. The cohort consisted of varying Gleason scores, with the majority scoring 9 (n=86; 51.1%). Surgical castration was performed in the majority of cases (n=136; 81.4%). Overall, 66 (39.5 %) of the patients had low-volume disease (≤5 sites of metastasis, no visceral metastasis), while 101 (60.5%) patients had high-volume disease. Disease progression occurred in 100 patients (59.9%), with a median progression-free survival (PFS) of 47 months (95% CI, 37.503-56.497). The median overall survival (OS) was 71 months. In the comparison of low-volume vs. high-volume disease groups, the median PFS was 57 vs. 47 months respectively (P=0.276) and the corresponding median OS was not reached vs. 57 months respectively (P=0.192). Among the 100 patients with disease progression, 20 received second-line therapy. The median OS for untreated patients was 9.88 months, while those treated with antiandrogens was 15.14 months and those with re-challenge chemotherapy was 12.46 months (P=0.496; 95% CI, -6.47-11.83). Grade 3-4 treatment-related toxicities were observed in ~37.8% of patients, while one death was associated with chemotherapy-related neutropenic sepsis. The most common toxicities were mucositis (n=53; 31.7%), febrile neutropenia (n=44; 26.3%) and sepsis (n=29; 17.4%). The present study demonstrated that upfront docetaxel chemotherapy may be an effective and tolerable treatment for hormone-sensitive metastatic prostate cancer, particularly in settings where access to novel antiandrogens is limited, thus potentially offering a viable management strategy amidst resource constraints.

1. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. Testosterone suppression (TS) is the backbone of treatment for metastatic hormone-sensitive prostate cancer (mHSPC). Overall survival is improved by the addition of early docetaxel (DOC) or abiraterone to TS. The randomised phase 3 ENZAMET trial assessed the effects of enzalutamide (ENZA), a potent androgen receptor (AR) inhibitor, versus a nonsteroidal anti-androgen (NSAA: bicalutamide, nilutamide, or flutamide) in addition to SOC in mHSPC. Men (1125) with mHSPC were randomly assigned 1:1 to receive TS plus either ENZA (160 mg daily, by mouth, until clinical disease progression or prohibitive toxicity) or NSAA (conventional NSAA, by mouth until clinical disease progression or prohibitive toxicity). All participants were to receive standard background therapy with a LHRHA or surgical castration, as per standard of care. The choice of the LHRHA or surgical castration was at the discretion of the treating clinician. Randomization was stratified by: volume of disease (high vs low, according to CHAARTED); planned early DOC; planned anti-resorptive therapy, comorbidity score (ACE-27), and study site. The primary endpoint was overall survival. Subgroup analyses to assess possible modulation of the treatment effect were specified a priori and included planned early docetaxel (yes vs no) and volume of disease (high vs low). After a median follow-up of 33 months. Overall survival was prolonged by ENZA. At 3 years, 36% NSAA vs 64% ENZA were still on their assigned study treatment. Serious adverse events (regardless of attribution) within 30 days of study treatment occurred in 42% ENZA vs 34% NSAA, commensurate with the different durations of study treatment. ENZA significantly improved OS when added to SOC in mHSPC while the benefits appeared lower in those planned to receive early DOC.

Purpose: The purpose of this study is to investigate the clinical oncological outcomes and prognostic factors of high-volume disease (HVD) in the Asian population with metastatic hormone-sensitive prostate cancer. Methods: We retrospectively analyzed 503 patients with newly diagnosed metastatic prostate cancer. Patients were classified as HVD if visceral metastases were present and/or ≥4 bone lesions with ≥1 lesion beyond the vertebral bodies and pelvis. Overall survival (OS) and cancer-specific survival were investigated based on the disease burden. The Cox proportional hazards regression model was used to evaluate the prognostic factors. Results: About 50.7% patients were classified as low-volume disease (LVD) and 49.3% were HVD at diagnosis. The medians of OS and cancer-specific survival were 64 and 116 months, respectively, for patients with LVD and 26 and 46 months, respectively, for men with HVD (both P < 0.001). Among patients with HVD, 76.6% had both high-volume bone disease (HBD) (≥4 bone metastases) and appendicular bone involvement. There was no significant difference in both OS and cancer-specific survival between patients with visceral metastases and those with HBD combined with appendicular bone involvement. In the multivariable analysis, presence of Gleason score ≥8, HBD, or HVD may predict poorer OS and cancer-specific survival outcomes (all P < 0.05). Conclusions: Asian patients with high-volume metastatic prostate cancer had a larger proportion of HBD with appendicular bone involvement, who had a comparably poor prognosis to those with visceral metastases. Patients with HBD or HVD had reduced survival outcomes.

Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer by Pattern of Metastatic Spread: ARCHES Post Hoc Analyses.

853P - ARCHES - The role of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): Post hoc analyses of high and low disease volume and risk groups

146 Background: The CHAARTED study showed that adding docetaxel (Doc) to androgen deprivation therapy (ADT) in men initiating treatment for mHSPC prolongs survival, particularly in high-volume disease. Androgens are known drivers of both mHSPC and metastatic castration resistant prostate cancer (mCRPC). Lower nadir testosterone (T) is associated with better outcomes in men treated with ADT for biochemical relapse, while higher androgens at mCRPC are associated with better prognosis and increased benefit from abiraterone. Methods: We evaluated the association of serum steroid levels at 24 weeks with overall survival (OS) and time to CRPC (TTCRPC) in 588 men with available samples from the CHAARTED study. Steroid levels were measured using mass spectrometry. Results: The median (med) T level at 24 weeks was 8 ng/dl and did not differ in the ADT alone vs ADT plus Doc arms. Achieving a nadir T below 20ng/dl was not associated with OS or TTCRPC in either arm. In the ADT arm pregnenolone (preg) and T levels > med associated with longer OS (HR 0.62; p = 0.017 for both), as did AED and T levels in the highest 3 quartiles (HR 0.61 p = 0.025; HR 0.67, p = 0.069). OS did not differ by steroid levels in high volume patients. In low volume patients OS was longer for those in the highest 3 quartiles of progesterone (HR 0.52 p = 0.10), DHEA (HR 0.41 p = 0.03), AED (HR 0.39 p = 0.027), T (HR 0.36 p = 0.006) and estrone (HR 0.52 p = 0.10). In the ADT + Doc arm estrone levels < med associated with longer OS (HR 0.68; p = 0.05) as did AED levels in the lowest quartile (HR 0.67 p = 0.063). Estrone levels < med also associated with longer TTCRPC (HR 0.75; p = 0.097), as did AED and estrone in the lowest quartiles (HR 0.60 p = 0.009; HR 0.65 p = 0.05). There was no difference in OS in either the high or low volume patients based on steroid levels. In high volume patients, OS was particularly longer with ADT + Doc vs ADT in those with estradiol or estrone levels in the highest 3 quartiles (p = 0.018; 0.029) and in those with pregnenolone, AED, T, and DHT in the lowest quartile (p = 0.046, p = 0.018, p = 0.095; p = 0.066). In low volume patients, OS was also longer with ADT + Doc vs ADT in those with T levels in the lowest quartile (p = 0.055), but shorter with ADT + Doc vs ADT among those with progesterone, DHEA, AED, T and estrone levels in the top 3 quartiles (p = 0.095; p = 0.071; p = 0.091; p = 0.031; and p = 0.031). Conclusions: In men with mHNPC treated with ADT alone higher steroid levels at 24 weeks associate with longer OS (primarily in low volume disease), consistent with findings in the mCRPC setting (Mostaghel et al CCR 2021). In men treated with ADT + Doc lower levels of estrone and AED associate with longer OS and TTCRPC. The findings overall highlight that serum steroid levels associate with different patient outcomes depending on whether treated with ADT alone or with Doc, as well as the prognostic variable of high vs low volume disease. Clinical trial information: NCT00309985.

687 Background: ENZA, a potent androgen receptor inhibitor, has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). Efficacy of ENZA with ADT in men with mHSPC is unknown. Methods: ARCHES is a multinational, double-blind, phase 3 study (NCT02677896). Patients (pts) with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume (CHAARTED criteria) and prior docetaxel therapy. Primary endpoint was radiographic progression-free survival (rPFS) assessed centrally or death within 24 weeks of treatment discontinuation. Secondary endpoints included time to prostate-specific antigen (PSA) progression, PSA and radiographic responses and overall survival (OS). Treatment continued until disease progression or unacceptable toxicity. Results: 1150 men were randomized to ENZA (n=574) or PBO (n=576); baseline characteristics were balanced between groups. Overall, 67% had distant metastasis at initial diagnosis; 63% had high volume disease, 18% had prior docetaxel. Median follow-up was 14.4 mo. ENZA + ADT significantly improved rPFS (Table); similar significant improvements in rPFS were reported in prespecified subgroups of disease volume, pattern of spread, region and prior docetaxel (HRs 0.24–0.53). Secondary endpoints improved with ENZA + ADT (Table); OS data are immature. Grade 3–4 adverse events (AEs) were reported in 23.6% of ENZA pts vs 24.7% of PBO pts with no unexpected AEs. Conclusions: ENZA + ADT significantly improved rPFS and other efficacy endpoints vs PBO + ADT in men with mHSPC, with a preliminary safety analysis that appears consistent with the safety profile of ENZA in previous CRPC clinical trials. Acknowledgements: Medical writing and editing assistance was provided by Stephanie Rippon, MBio, and Lauren Smith from Complete HealthVizion, funded by the study sponsors. This study was funded by Astellas Pharma Inc. and Medivation LLC, a Pfizer Company, the co-developers of enzalutamide. Clinical trial information: NCT02677896. [Table: see text]

PurposeNo currently available phase III trial compared docetaxel vs. androgen receptor pathway inhibitors (ARPI) regarding cancer-control outcomes in metastatic hormone-sensitive prostate cancer (mHSPC). Moreover, few is known about the effect of sequential therapies in mHSPC and subsequent metastatic castration resistant prostate cancer (mCRPC).MethodsWe relied on the FRAMCAP database and compared docetaxel vs. ARPI in mHSPC patients regarding time to mCRPC (ttCRPC) and overall survival (OS). Sensitivity analyses addressed high volume mHSPC patients. Finally, sequential therapies were compared regarding progression-free survival (PFS) and OS in first-line mCRPC.ResultsOf 419 included mHSPC patients, 25% received docetaxel vs. 75% ARPI. ARPI patients were significantly older (71 vs. 66 years), and harbored lower baseline PSA (38 vs. 183 ng/ml, both p ≤ 0.002). Median ttCRPC was significantly longer for ARPI than for docetaxel-treated patients (30 vs. 17 months, hazard ratio [HR]: 0.49, p < 0.001). In OS analyses, ARPI patients also exhibited significantly longer OS, relative to docetaxel patients (96 vs. 50 months, HR: 0.67, p = 0.03). After multivariable adjustment in Cox regression models, no difference between both treatments remained in both analyses (all p > 0.05). In sensitivity analyses of high volume mHSPC patients only, also no ttCRPC or OS differences were observed for ARPI vs. docetaxel (all p > 0.05). Regarding sequential therapies, no PFS and OS differences were observed for all and specifically high volume mHSPC patients, when ARPI-ARPI vs. ARPI-docetaxel vs. docetaxel-ARPI treatments were compared (all p > 0.05).ConclusionIn real-world setting, ARPI treatment performs comparable to docetaxel chemotherapy in mHSPC. Therefore, docetaxel should only be used in triplet therapy. Moreover, no differences for sequential therapies of ARPI/docetaxel combinations in first-line mCRPC were observed.

115 Background: In ARCHES (NCT02677896), ENZA + ADT improved radiographic progression-free survival, OS, and other key secondary endpoints vs placebo (PBO) + ADT for pts with mHSPC (also known as metastatic castration-sensitive prostate cancer). Final OS results confirmed a long-term survival benefit with ENZA + ADT (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.53, 0.81; p&lt;0.0001). We present post hoc analyses of OS by disease volume and progression to M1 HSPC after initial diagnosis with localized disease (M0) or presentation of de novo mHSPC at initial diagnosis (M1). Methods: Pts with mHSPC (N=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT (n=574) or PBO + ADT (n=576), stratified by disease volume and prior docetaxel use. After unblinding, 180 (31.3%) PBO + ADT-treated pts crossed over to open-label ENZA + ADT. High disease volume was defined per CHAARTED criteria. Medical profiles of pts assessed as MX/unknown metastasis at initial diagnosis (n=213) were further reviewed centrally and adjudicated as having either M0 or M1 disease. Median OS and HRs were estimated by Kaplan-Meier methods and Cox proportional hazards, respectively. Results: Median treatment duration was 40.2 months (mo) for ENZA + ADT and 13.8 mo for PBO + ADT. Inclusive of crossover, 401 (69.6%) PBO + ADT pts had subsequent life-prolonging therapy. OS benefits with ENZA + ADT were seen in all disease volume and M0/M1 populations at a similar magnitude to the overall population (Table). Median OS was not reached in most populations except PBO + ADT pts with high disease volume (45.9 mo; 95% CI 40.1, not estimable [NE]) or high disease volume and M1 disease (43.4 mo; 95% CI 36.4, 49.7) and ENZA + ADT pts with high disease volume and M0 disease (54.2 mo; 95% CI 54.2, NE). Conclusions: Our post hoc analysis demonstrates consistent long-term survival benefit with ENZA + ADT vs PBO + ADT across pts with mHSPC with high and low disease volumes and M0 or M1 disease at initial diagnosis, despite substantial treatment crossover and subsequent therapy use in PBO + ADT pts.[Table: see text]

5069 Background: Patients with metastatic prostate cancer aged ≥75 years have a poorer prognosis compared with younger patients. In ARCHES (NCT02677896), ENZA + ADT improved radiographic progression-free survival (rPFS), overall survival (OS), and other key secondary endpoints vs. placebo (PBO) + ADT in patients with mHSPC. Final OS results confirmed a long-term survival benefit with ENZA + ADT. This post hoc analysis of ARCHES data investigated OS and other clinical outcomes in patients aged &lt;75 and ≥75 years. Methods: Patients with mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel use. Subgroup analysis was performed in patients aged &lt;75 and ≥75 years. Efficacy and safety outcomes were compared across treatment arms. Results: Of the ARCHES population, 339 patients (29.5%) were aged ≥75 years (ENZA + ADT, n=170; PBO + ADT, n=169); PBO patients crossing over to ENZA were aged: &lt;75 years, n=133; ≥75 years, n=47. Some differences in baseline characteristics were observed between age groups, such as higher prior docetaxel use in patients aged &lt;75 years (ENZA + ADT, 21.0%; PBO + ADT, 20.4%) vs. those aged ≥75 years (ENZA + ADT, 10.6%; PBO + ADT, 11.2%). When compared to PBO + ADT, ENZA + ADT improved OS and other secondary efficacy endpoints in both age groups without evidence of statistical heterogeneity (Table); however, 95% confidence intervals for OS and rPFS hazard ratios spanned 1 in the older age group. The safety profile of treatment arms was generally similar in both age groups, with a higher incidence of falls, cognitive impairment, and cardiovascular events among elderly patients receiving ENZA + ADT vs. PBO + ADT. Conclusions: This post hoc analysis of ARCHES data demonstrated that ENZA + ADT provides clinical benefit and is generally well-tolerated in patients with mHSPC aged ≥75 years, supporting the therapeutic role of ENZA in these patients. Clinical trial information: NCT02677896. [Table: see text]

5074 Background: DDR alterations are associated with poorer prognosis, including shorter overall survival (OS), in patients with mHSPC. In ARCHES (NCT02677896), patients with mHSPC treated with ENZA + ADT had a reduced risk of radiographic progression or death and improved OS versus PBO + ADT. This post hoc analysis assessed the prevalence of DDR alterations and associated baseline characteristics in patients with mHSPC in ARCHES. Methods: Patients with mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT. Germline DDR alteration testing was performed in blood using Ambry Genetics CustomNext-Cancer panel; 16 DDR-related genes were reported in the subset of patients who consented to participate in a pharmacogenomic study (n=664; Table). Descriptive analyses of baseline demographics and disease characteristics by DDR status were performed. Results: Of 664 patient samples tested, 652 were evaluable for analysis (ENZA + ADT, n=326; PBO + ADT, n=326). Baseline characteristics of these patients were similar to the ARCHES intent-to-treat population. The prevalence of DDR+ patients was lower than expected (n=34/652, 5.2%; Table). Of DDR+ patients, 13 (38.2%) had low-volume disease, compared with 228 (36.9%) of DDR− patients. High-volume disease was present in 21 (61.8%) DDR+ and 390 (63.1%) DDR− patients. Of DDR+ patients, 6 (17.6%) had localized disease at initial diagnosis (M0), compared with 145 (23.5%) DDR− patients. De novo metastatic disease at initial diagnosis (M1) was present in 28 (82.4%) DDR+ patients and 465 (75.2%) DDR− patients. Of DDR+ patients, 29 (85.3%) were from Europe, four (11.8%) were from North America, and one (2.9%) was from the Asia-Pacific region. Conclusions: This post hoc analysis found a lower prevalence of DDR alterations in patients with mHSPC in ARCHES, compared with the 7–12% previously reported in patients with metastatic castration-resistant prostate cancer (Lozano et al. Br J Cancer 2021; Pritchard et al. N Engl J Med 2016). We did not identify differences in baseline disease characteristics based on DDR status. Clinical trial information: NCT02677896. [Table: see text]

PurposeTo determine prognostic parameters, we extensively examined whether physical, biochemical, and histological factors were associated with clinical outcomes in metastatic hormone sensitive prostate cancer (mHSPC) patients.MethodsA total 822 mHSPC patients were retrospectively investigated and examined the associations between prognosis and clinicopathological parameters including BMI, initial PSA level, TNM classification, Hb, Alb, CRP, AST, ALT, LDH, ALP, Gleason grade group, and EOD score.ResultsAccording to the CHAARTED criteria, 338 (41.1%) and 484 (58.9%) patients were classified into low- and high-volume disease, respectively. In univariate and multivariate analyses, Gleason grade group, Alb, CRP, LDH, and ALP were determined as significant predictors for both PFS and OS. When mHSPC patients were classified into three group including favorable (none of risk factors), intermediate (one or two risk factors) and poor (more than three risk factors) according to these four parameters, the survival curves were significantly stratified according to the risk classification. When the risk classification was applied on the patients with low- or high-volume disease in CHAARTED criteria, worse prognosis was found in poor risk group patients with low-volume disease and favorable prognosis was found in favorable risk group patients with high-volume disease.ConclusionThese results suggested that Gleason grade, CRP, LDH, and ALP were the independent predictors for mHSPC patients regardless of metastatic burden.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00345-025-05862-4.

BackgroundThe best choice of first-line treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is unclear. We aimed to compare the effectiveness and safety determined in randomized clinical trials of doublet and triplet treatments for mHSPC.MethodsMedline, Embase, Cochrane Central and ClinicalTrials.gov were searched from inception through July 01, 2022. Eligible studies were phase III randomized clinical trials evaluating androgen deprivation treatment (ADT) alone, doublet therapies [ADT combined with docetaxel (DOC), novel hormonal agents (NHAs), or radiotherapy (RT)], or triplet therapies (NHA+DOC+ADT) as first-line treatments for mHSPC. Outcomes of interest included overall survival (OS), progression-free survival (PFS) and grades 3-5 adverse events (AEs). Subgroup analyses were performed based on tumor burden. The effects of competing treatments were assessed by Bayesian network meta-analysis using R software.ResultsTen trials with 12,298 patients comparing nine treatments were included. Darolutamide (DARO) +DOC+ADT ranked best in terms of OS benefits (OR 0·52 [95% CI 0·39–0·70]), but its advantages were all statistically insignificant compared with other therapy options except for DOC+ADT (OR 0·68 [95% CI 0·53–0·88]) and RT+ADT (OR 0·57 [95% CI 0·40–0·80]). In terms of PFS, enzalutamide(ENZA)+DOC+ADT (OR 0·32 [95% CI 0·24–0·44]) and abiraterone and prednisone (AAP) +DOC+ADT (OR 0·33 [95% CI 0·25–0·45]) ranked best. For patients with high volume disease (HVD), low volume disease (LVD), and visceral metastases, the optimal therapies were AAP+DOC+ADT (OR 0·52 [95% CI 0·33–0·83]), apalutamide+ADT (OR 0·52 [95% CI 0·26–1·05]) and DARO+DOC+ADT (OR 0·42 [95% CI 0·13–1·34]), respectively. For safety, AAP+DOC+ADT (OR 3·56 [95% CI 1·51–8·43]) ranked worst with the highest risk of grade 3−5 AEs.ConclusionsTriple therapies may further improve OS and PFS but may be associated with a decrease in safety. Triplet therapies could be suggested for HVD patients, while doublet combinations should still be preferred for LVD patients.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPEROFILES/303117_STRATEGY_20220202.pdf, identifier CRD4202303117.