-
European Urology Focus Jan 2023Two recent randomized controlled trials (RCTs) reported overall survival benefit of triplet therapy (androgen receptor axis-targeted therapy agent [ARAT], docetaxel, and... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
Two recent randomized controlled trials (RCTs) reported overall survival benefit of triplet therapy (androgen receptor axis-targeted therapy agent [ARAT], docetaxel, and androgen deprivation therapy [ADT]) over that of doublet therapy (docetaxel and ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Ranking of therapy options and comparisons between triplet therapy and doublet ARAT and ADT therapy are scarce.
OBJECTIVE
To rank therapy options (triplet vs doublet [docetaxel and ADT] vs doublet [ARAT and ADT]) and address them within formal network meta-analyses (NMAs); subsequently, NMAs were refitted following stratification according to (1) low- and high-volume tumor burden and (2) doublet versus triplet therapy.
EVIDENCE ACQUISITION
A systematic literature review (PubMed, MEDLINE, Embase, Web of Science, Scopus, and Cochrane database) of RCT trials that investigated the overall survival efficacy of systemic treatment in the setting of mHSPC was conducted. The study search and inclusion criteria were in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.
EVIDENCE SYNTHESIS
Ten RCTs (n = 9702) were identified. The NMA focusing on the overall cohort of mHSPC demonstrated that triplet therapies (darolutamide, docetaxel, and ADT, and abiraterone, docetaxel, and ADT) were ranked first and second (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.44-0.66; HR: 0.60; 95% CI: 0.46-0.78), followed by doublet therapy (ARAT and ADT) and lastly docetaxel and ADT. Owing to missing data within one RCT, the NMA for low- and high-volume mHSPC focused on nine trials. In high-volume disease, triplet therapy (abiraterone, docetaxel, and ADT) was ranked first (HR: 0.52, 95% CI: 0.38-0.71).
CONCLUSIONS
Triplet therapy, consisting of an ARAT, docetaxel, and ADT, ranked first in systematic treatment in mHSPC. Moreover, triplet therapy might result in more pronounced overall survival benefit than doublet ARAT and ADT therapy in high-volume mHSPC.
PATIENT SUMMARY
We compared different systemic therapy options for metastatic hormone-sensitive prostate cancer and concluded that triplet therapy, consisting of androgen receptor axis-targeted therapy agent, docetaxel, and androgen deprivation therapy, seems to be most beneficial for overall survival. Back to top.
Topics: Male; Humans; Docetaxel; Network Meta-Analysis; Androgens; Receptors, Androgen; Androgen Antagonists; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Prostatic Neoplasms
PubMed: 36058809
DOI: 10.1016/j.euf.2022.08.007 -
European Urology Oncology Dec 2022Multiple treatments for metastatic, hormone-sensitive prostate cancer (mHSPC) are available, but their effects on health-related quality of life (HRQoL) and benefit-harm... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
Multiple treatments for metastatic, hormone-sensitive prostate cancer (mHSPC) are available, but their effects on health-related quality of life (HRQoL) and benefit-harm balance remain unclear.
OBJECTIVE
To assess clinical effectiveness regarding survival and HRQoL, safety, and benefit-harm balance of mHSPC treatments.
EVIDENCE ACQUISITION
We searched MEDLINE, EMBASE, CENTRAL, and ClinicalTrials.gov until March 1, 2022. Randomized controlled trials (RCTs) comparing docetaxel, abiraterone, enzalutamide, apalutamide, darolutamide, and radiotherapy combined with androgen deprivation therapy (ADT) mutually or with ADT alone were eligible. Three reviewers independently performed screening, data extraction, and risk of bias assessment in duplicate.
EVIDENCE SYNTHESIS
Across ten RCTs, we found relevant survival benefits for ADT + docetaxel (high certainty according to the Grading of Recommendations, Assessment, Development and Evaluation [GRADE]), ADT + abiraterone (moderate certainty), ADT + enzalutamide (low certainty), ADT + apalutamide (high certainty), and ADT + docetaxel + darolutamide (high certainty) compared with ADT alone. ADT + radiotherapy appeared effective only in low-volume de novo mHSPC. We found a short-term HRQoL decrease lasting 3-6 mo for ADT + docetaxel (moderate certainty) and a potential HRQoL benefit for ADT + abiraterone up to 24 mo of follow-up (moderate certainty) compared with ADT alone. There was no difference in HRQoL for ADT + enzalutamide, ADT + apalutamide, or ADT + radiotherapy over ADT alone (low-high certainty). Grade 3-5 adverse effect rates were increased with all systemic combination treatments. A benefit-harm assessment showed high probabilities (>60%) for a net clinical benefit with ADT + abiraterone, ADT + enzalutamide, and ADT + apalutamide, while ADT + docetaxel and ADT + docetaxel + darolutamide appeared unlikely (<40%) to be beneficial.
CONCLUSIONS
Despite substantial survival benefits, no systemic combination treatment showed a clear HRQoL improvement compared with ADT alone. We found evidence for a short-term HRQoL decline with ADT + docetaxel and a higher net clinical benefit with ADT + abiraterone, ADT + apalutamide and ADT + enzalutamide. While individualized decision-making remains important and economic factors need to be considered, the evidence may support a general preference for the combination of ADT with androgen receptor axis-targeted therapies over docetaxel-containing strategies.
PATIENT SUMMARY
We assessed different combination treatments for metastatic hormone-sensitive prostate cancer. While survival was better with all systemic combination treatments, there was no clear improvement in health-related quality of life compared with androgen deprivation therapy alone. Novel hormonal combination treatments had a more favorable benefit-harm balance than combination treatments that include chemotherapy.
Topics: Male; Humans; Docetaxel; Network Meta-Analysis; Androgens; Prostatic Neoplasms
PubMed: 35599144
DOI: 10.1016/j.euo.2022.04.007 -
Theranostics 2022Prostate cancer is usually considered as immune "cold" tumor with poor immunogenic response and low density of tumor-infiltrating immune cells, highlighting the need to...
Prostate cancer is usually considered as immune "cold" tumor with poor immunogenic response and low density of tumor-infiltrating immune cells, highlighting the need to explore clinically actionable strategies to sensitize prostate cancer to immunotherapy. In this study, we investigated whether docetaxel-based chemohormonal therapy induces immunologic changes and potentiates checkpoint blockade immunotherapy in prostate cancer. We performed transcriptome and histopathology analysis to characterize the changes of prostate cancer immune microenvironment before and after docetaxel-based chemohormonal therapy. Furthermore, we investigated the therapeutic benefits and underlying mechanisms of chemohormonal therapy combined with anti-PD1 blockade using cellular experiments and xenograft prostate cancer models. Finally, we performed a retrospective cohort analysis to evaluate the antitumor efficacy of anti-PD1 blockade alone or in combination with docetaxel-based chemotherapy. Histopathology assessments on patient samples confirmed the enrichment of tumor-infiltrating T cells after chemohormonal therapy. Moreover, we found that docetaxel activated the cGAS/STING pathway in prostate cancer, subsequently induced IFN signaling, resulting in lymphocytes infiltration. In a xenograft mouse model, docetaxel-based chemohormonal therapy prompted the intratumoral infiltration of T cells and upregulated the abundance of PD1 and PD-L1, thereby sensitizing mouse tumors to the anti-PD1 blockade. To determine the clinical significance of these results, we retrospectively analyzed a cohort of 30 metastatic castration-resistant prostate cancer patients and found that docetaxel combined with anti-PD1 blockade resulted in better prostate-specific antigen progression-free survival when compared with anti-PD1 blockade alone. Our study demonstrates that docetaxel activates the antitumoral immune response and facilitates T cell infiltration in a cGAS/STING-dependent manner, providing a combination immunotherapy strategy that would improve the clinical benefits of immunotherapy.
Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Docetaxel; Humans; Immunologic Factors; Immunotherapy; Male; Mice; Nucleotidyltransferases; Prostatic Neoplasms; Retrospective Studies; Tumor Microenvironment
PubMed: 35836810
DOI: 10.7150/thno.73152 -
BJU International Apr 2022To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available treatments for the management of metastatic... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available treatments for the management of metastatic hormone-sensitive prostate cancer (mHSPC), as there has been a paradigm shift with the use of next-generation androgen receptor inhibitors (ARIs) and docetaxel.
METHODS
Multiple databases were searched for articles published before May 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analysis extension statement for network meta-analysis. Studies comparing overall/progression-free survival (OS/PFS) and/or adverse events (AEs) in patients with mHSPC were eligible.
RESULTS
Nine studies (N = 9960) were selected, and formal network meta-analyses were conducted. Abiraterone (hazard ratio [HR] 0.83, 95% credible interval [CrI] 0.76-0.90), docetaxel (HR 0.90, 95% CrI 0.82-0.98), and enzalutamide (HR 0.85, 95% CrI 0.73-0.99) were associated with significantly better OS than androgen-deprivation therapy (ADT), and abiraterone emerged as the best option. Abiraterone (HR 0.71, 95% CrI 0.67-0.76), apalutamide (HR 0.73, 95% CrI 0.65-0.81), docetaxel (HR 0.84, 95% CrI 0.78-0.90), and enzalutamide (HR 0.67, 95% CrI 0.63-0.71) were associated with significantly better PFS than ADT, and enzalutamide emerged as the best option. Abiraterone (HR 0.85, 95% CrI 0.78-0.93), apalutamide (HR 0.87, 95% CrI 0.77-0.98), and enzalutamide (HR 0.80, 95% CrI 0.73-0.88) were significantly more effective than docetaxel. Regarding AEs, apalutamide was the likely best option among the three ARIs. In patients with low-volume mHSPC, enzalutamide was the best option in terms of OS and PFS.
CONCLUSIONS
All three ARIs are effective therapies for mHSPC; apalutamide was the best tolerated. All three seemed more effective than docetaxel. These findings may facilitate individualised treatment strategies and inform future comparative trials.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Docetaxel; Hormones; Humans; Male; Network Meta-Analysis; Prostatic Neoplasms
PubMed: 34171173
DOI: 10.1111/bju.15507 -
Journal of Thoracic Oncology : Official... Jan 2023The phase 3 RATIONALE-303 trial (NCT03358875) investigated the efficacy and safety of tislelizumab versus docetaxel in pretreated patients with advanced NSCLC. Here, we... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
The phase 3 RATIONALE-303 trial (NCT03358875) investigated the efficacy and safety of tislelizumab versus docetaxel in pretreated patients with advanced NSCLC. Here, we report the efficacy and safety results and describe the exploratory biomarker analyses.
METHODS
A total of 805 patients aged more than or equal to 18 years with locally advanced or metastatic squamous or nonsquamous NSCLC were randomized 2:1 to intravenous tislelizumab 200 mg or docetaxel 75 mg/m every 3 weeks. Co-primary end points were overall survival (OS) in the intent-to-treat (ITT) and programmed death-ligand 1 (PD-L1) tumor cell expression greater than or equal to 25% populations. The exploratory biomarker analyses included PD-L1 expression, tumor mutation burden, and gene expression profile.
RESULTS
At the prespecified interim analysis (August 10, 2020), the co-primary end point of OS in the ITT population was met, with a statistically significant and clinically meaningful improvement in OS with tislelizumab versus docetaxel (median 17.2 versus 11.9 mo, respectively; hazard ratio [HR] = 0.64, p < 0.0001). At the final analysis (July 15, 2021), the other co-primary end point of OS in the PD-L1 tumor cell greater than or equal to 25% population was further met (median 19.3 versus 11.5 mo, respectively; HR = 0.53, p < 0.0001), and OS continued to improve in the ITT population (median 16.9 versus 11.9 mo, respectively, HR = 0.66). Exploratory biomarker analyses revealed the potential association of NOTCH1-4 mutations with improved tislelizumab efficacy for both OS and progression-free survival, whereas tissue tumor mutation burden correlated with progression-free survival benefit, but not OS benefit. No new safety signals were identified.
CONCLUSIONS
Tislelizumab was found to have a significantly improved and long-term clinical benefit in OS versus docetaxel in pretreated patients with advanced NSCLC, regardless of PD-L1 expression.
Topics: Humans; Docetaxel; B7-H1 Antigen; Lung Neoplasms; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Biomarkers
PubMed: 36184068
DOI: 10.1016/j.jtho.2022.09.217 -
Journal For Immunotherapy of Cancer May 2022Although the antitumor efficacy of docetaxel (DTX) has long been attributed to the antimitotic activities, its impact on the tumor microenvironment (TME) has recently...
BACKGROUND
Although the antitumor efficacy of docetaxel (DTX) has long been attributed to the antimitotic activities, its impact on the tumor microenvironment (TME) has recently gained more attention. Macrophages are a major component of the TME and play a critical role in DTX efficacy; however, the underlying action mechanisms remain unclear.
METHODS
DTX chemotherapeutic efficacy was demonstrated via both macrophage depletion and C-C motif chemokine ligand 3 (Ccl3)-knockout transgenic allograft mouse model. Ccl3-knockdown and Ccl3-overexpressing breast cancer cell allografts were used for the in vivo study. Combination therapy was used to evaluate the effect of Ccl3 induction on DTX chemosensitivity. Vital regulatory molecules and pathways were identified using RNA sequencing. Macrophage phagocytosis of cancer cells and its influence on cancer cell proliferation under DTX treatment were assessed using an in vitro coculture assay. Serum and tumor samples from patients with breast cancer were used to demonstrate the clinical relevance of our study.
RESULTS
Our study revealed that Ccl3 induced by DTX in macrophages and cancer cells was indispensable for the chemotherapeutic efficacy of DTX. DTX-induced Ccl3 promoted proinflammatory macrophage polarization and subsequently facilitated phagocytosis of breast cancer cells and cancer stem cells. Ccl3 overexpression in cancer cells promoted proinflammatory macrophage polarization to suppress tumor progression and increase DTX chemosensitivity. Mechanistically, DTX induced Ccl3 by relieving the inhibition of cAMP-response element binding protein on Ccl3 via reactive oxygen species accumulation, and Ccl3 then promoted proinflammatory macrophage polarization via activation of the Ccl3-C-C motif chemokine receptor 5-p38/interferon regulatory factor 5 pathway. High CCL3 expression predicted better prognosis, and high CCL3 induction revealed better DTX chemosensitivity in patients with breast cancer. Furthermore, both the Creb inhibitor and recombinant mouse Ccl3 significantly enhanced DTX chemosensitivity.
CONCLUSIONS
Our results indicate that Ccl3 induced by DTX triggers proinflammatory macrophage polarization and subsequently facilitates phagocytosis of cancer cells. Ccl3 induction in combination with DTX may provide a promising therapeutic rationale for increasing DTX chemosensitivity in breast cancer.
Topics: Animals; Breast Neoplasms; Cell Proliferation; Chemokine CCL3; Docetaxel; Female; Humans; Macrophage Activation; Macrophages; Mice; Tumor Microenvironment
PubMed: 35613826
DOI: 10.1136/jitc-2021-003793 -
FASEB Journal : Official Publication of... Sep 2023Cuproptosis, a newly discovered programmed cell death induced by copper ions, is associated with the progression and drug resistance of various tumors. Docetaxel plays a...
Cuproptosis, a newly discovered programmed cell death induced by copper ions, is associated with the progression and drug resistance of various tumors. Docetaxel plays a vital role as a first-line chemotherapeutic agent for advanced prostate cancer; however, most patients end up with prostate cancer progression because of inherent or acquired resistance. Herein, we examined the role of cuproptosis in the chemotherapeutic resistance of prostate cancer to docetaxel. We treated prostate cancer cell lines with elesclomol-CuCl , as well as with docetaxel. We performed analyses of CCK8, colony formation tests, cell cycle flow assay, transmission electron microscopy, and mTOR signaling in treated cells, and treated a xenograft prostate cancer model with elesclomol-CuCl and docetaxel in vivo, and performed immunohistochemistry and Western blotting analysis in treated tumors. We found that elesclomol-CuCl could promote cell death and enhance chemosensitivity to docetaxel. Elesclomol-CuCl induced cell death and inhibited the growth of prostate cancer cells relying on copper ions-induced cuproptosis, not elesclomol. In addition, dihydrolipoamide S-acetyltransferase (DLAT) was involved in cuproptosis-enhanced drug sensitivity to docetaxel. Mechanistically, upregulated DLAT by cuproptosis inhibited autophagy, promoted G2/M phase retention of cells, and enhanced the sensitivity to docetaxel chemotherapy in vitro and in vivo via the mTOR signaling pathway. Our findings demonstrated that the cuproptosis-regulated DLAT/mTOR pathway inhibited autophagy and promoted cells in G2/M phase retention, thus enhancing the chemosensitivity to docetaxel. This discovery may provide an effective therapeutic option for treating advanced prostate cancer by inhibiting the chemotherapeutic resistance to docetaxel.
Topics: Male; Humans; Docetaxel; Dihydrolipoyllysine-Residue Acetyltransferase; Copper; Taxoids; Prostatic Neoplasms; TOR Serine-Threonine Kinases; Apoptosis; Autophagy; Cell Line, Tumor
PubMed: 37584654
DOI: 10.1096/fj.202300980R -
JAMA Network Open Feb 2023Due to the ongoing bacillus Calmette-Guérin (BCG) shortage, sequential intravesical gemcitabine and docetaxel has been increasingly used as first-line therapy for... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparison of Sequential Intravesical Gemcitabine and Docetaxel vs Bacillus Calmette-Guérin for the Treatment of Patients With High-Risk Non-Muscle-Invasive Bladder Cancer.
IMPORTANCE
Due to the ongoing bacillus Calmette-Guérin (BCG) shortage, sequential intravesical gemcitabine and docetaxel has been increasingly used as first-line therapy for high-risk non-muscle-invasive bladder cancer (NMIBC). However, data directly comparing these 2 therapies are lacking.
OBJECTIVE
To compare the outcomes of patients with high-risk NMIBC treated with gemcitabine and docetaxel vs BCG.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study was conducted from January 1, 2011, to December 31, 2021. The median (IQR) duration of follow-up was 23 (12-33) months for patients receiving gemcitabine and docetaxel and 49 (27-79) months for patients receiving BCG. All patients were treated at the University of Iowa tertiary care center. A total of 312 patients with high-risk treatment-naive NMIBC were included; 174 patients were treated with BCG therapy and 138 were treated with gemcitabine and docetaxel therapy.
EXPOSURES
After undergoing complete transurethral resection of bladder tumor, patients received either sequential intravesical gemcitabine, 1 g, and docetaxel, 37.5 mg, or 1 vial of BCG. Induction treatments were administered once per week for 6 weeks. Maintenance regimens were initiated if the patient was disease free at the first follow-up visit.
MAIN OUTCOMES AND MEASURES
The primary outcome was high-grade recurrence-free survival (RFS). Survival probabilities were estimated using the Kaplan-Meier method. Cox regression models were used to evaluate the association of covariates with outcomes. Adverse events were reported using the Common Terminology Criteria for Adverse Events, version 5.
RESULTS
Among 312 patients, the median (IQR) age was 73 (66-79) years; 255 patients (81.7%) were male and 292 (93.6%) were White. Baseline clinicopathological characteristics such as sex, smoking status, and pretreatment tumor pathology were similar between treatment groups. High-grade RFS estimates were 76% (95% CI, 69%-82%) at 6 months, 71% (95% CI, 64%-78%) at 12 months, and 69% (95% CI, 62%-76%) at 24 months in the BCG group and 92% (95% CI, 86%-95%) at 6 months, 85% (95% CI, 78%-91%) at 12 months, and 81% (95% CI, 72%-87%) at 24 months in the gemcitabine and docetaxel group. Multivariable Cox regression analyses controlled for age, sex, treatment year, and presence of carcinoma in situ revealed that treatment with gemcitabine and docetaxel was associated with better high-grade RFS (hazard ratio, 0.57; 95% CI, 0.33-0.97; P = .04) and RFS (hazard ratio, 0.56; 95% CI, 0.34-0.92; P = .02) than treatment with BCG. Induction therapy for BCG was associated with greater treatment discontinuation than induction therapy for gemcitabine and docetaxel (9.2% vs 2.9%; P = .02).
CONCLUSIONS AND RELEVANCE
In this cohort study, gemcitabine and docetaxel therapy was associated with less high-grade disease recurrence and treatment discontinuation than BCG therapy. These findings suggest that, while awaiting results from an ongoing randomized clinical trial during the current BCG shortage, use of gemcitabine and docetaxel can be considered for recommendation in updated practice guidelines.
Topics: Humans; Male; Aged; Female; BCG Vaccine; Docetaxel; Gemcitabine; Cohort Studies; Non-Muscle Invasive Bladder Neoplasms; Retrospective Studies
PubMed: 36853609
DOI: 10.1001/jamanetworkopen.2023.0849 -
European Urology Focus Sep 2023Two randomized controlled trials recently demonstrated an overall survival benefit with triplet therapy (androgen receptor axis-targeted agent... (Meta-Analysis)
Meta-Analysis
Two randomized controlled trials recently demonstrated an overall survival benefit with triplet therapy (androgen receptor axis-targeted agent [ARAT] + docetaxel + androgen deprivation therapy [ADT]) over doublet therapy (docetaxel + ADT) in metastatic hormone-sensitive prostate cancer (mHSPC), broadening the treatment options. In our previous systematic review and network meta-analysis on the role of triplet versus doublet therapy, we focused on ARAT + ADT, as this is the actual standard of care in many countries for mHSPC. However, survival data by disease volume were only available for one triplet therapy regimen (PEACE-1). Survival data stratified by disease volume for a second triplet regimen (ARASENS) are now available, hence we updated our meta-analysis for low- and high-volume mHSPC. Consistent with previous findings, ADT alone no longer represents a valid treatment option for mHSPC. Similar considerations apply to doublet therapy with docetaxel + ADT. For low-volume mHSPC, in comparison to ADT, the benefit of combination therapies other than ARAT + ADT was not substantial. For high-volume mHSPC, darolutamide + docetaxel + ADT ranked first (P score 0.92), followed by abiraterone + docetaxel + ADT (P score 0.85) and then ARAT + ADT combination therapies. In high-volume mHSPC, only darolutamide + docetaxel + ADT demonstrated superior overall survival (hazard ratio 0.76, 95% confidence interval 0.59-0.97) versus (pooled) ARAT + ADT, confirming the importance of triplet therapy in (high-volume) mHSPC. PATIENT SUMMARY: We performed an updated comparison of double and triple therapy options for metastatic prostate cancer that still responds to hormone treatment. For patients with low-volume cancer, there was no significant survival benefit from addition of a third drug. For patients with high-volume cancer, the best survival was obtained with darolutamide + docetaxel + androgen deprivation therapy.
Topics: Male; Humans; Prostatic Neoplasms; Docetaxel; Androgen Antagonists; Network Meta-Analysis; Androgens; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37055323
DOI: 10.1016/j.euf.2023.03.024 -
Biological & Pharmaceutical Bulletin 2020
Topics: Docetaxel; Drug Discovery; Drug Repositioning; Humans; Selenoproteins
PubMed: 32115496
DOI: 10.1248/bpb.b20-ctf4303