-
Journal of the National Cancer Institute Nov 2023Recently, several new treatment regimens have been approved for treating metastatic hormone-sensitive prostate cancer, building on androgen deprivation therapy alone.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Recently, several new treatment regimens have been approved for treating metastatic hormone-sensitive prostate cancer, building on androgen deprivation therapy alone. These include docetaxel androgen deprivation therapy, abiraterone acetate-prednisone androgen deprivation therapy, apalutamide androgen deprivation therapy, enzalutamide androgen deprivation therapy, darolutamide-docetaxel androgen deprivation therapy, and abiraterone-prednisone androgen deprivation therapy with docetaxel. There are no validated predictive biomarkers for choosing a specific regimen. The goal of this study was to conduct a health economic outcome evaluation to determine the optimal treatment from the US public sector (Veterans Affairs).
METHODS
We developed a partitioned survival model in which metastatic hormone-sensitive prostate cancer patients transitioned between 3 health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan-Meier curves using a Bayesian network meta-analysis of 7 clinical trials (7208 patients). The effectiveness outcome in our model was quality-adjusted life-years (QALYs). Cost input parameters included initial and subsequent treatment costs and costs for terminal care and for managing grade 3 or higher drug-related adverse events and were obtained from the Federal Supply Schedule and published literature.
RESULTS
Average 10-year costs ranged from $34 349 (androgen deprivation therapy) to $658 928 (darolutamide-docetaxel androgen deprivation therapy) and mean QALYs ranged from 3.25 (androgen deprivation therapy) to 4.57 (enzalutamide androgen deprivation therapy). Treatment strategies docetaxel androgen deprivation therapy, enzalutamide androgen deprivation therapy docetaxel, apalutamide androgen deprivation therapy, and darolutamide-docetaxel androgen deprivation therapy were eliminated because of dominance (ie, they were more costly and less effective than other strategies). Of the remaining strategies, abiraterone acetate-prednisone androgen deprivation therapy was the most cost-effective strategy at a willingness-to-pay threshold of $100 000/QALY (incremental cost-effectiveness ratios = $21 247/QALY).
CONCLUSIONS
Our simulation model found abiraterone acetate-prednisone androgen deprivation therapy to be an optimal first-line treatment for metastatic hormone-sensitive prostate cancer from a public (Veterans Affairs) payer perspective.
Topics: Male; Humans; Prostatic Neoplasms; Docetaxel; Abiraterone Acetate; Prednisone; Cost-Effectiveness Analysis; Androgen Antagonists; Androgens; Bayes Theorem; Treatment Outcome; Prostatic Neoplasms, Castration-Resistant
PubMed: 37436697
DOI: 10.1093/jnci/djad135 -
Cancer Sep 2023There have been significant advances in the treatment of urology cancers, with a number of practice-changing treatments. There is now greater clarity on the role of the...
There have been significant advances in the treatment of urology cancers, with a number of practice-changing treatments. There is now greater clarity on the role of the use of immunotherapies in renal cell carcinoma. The use of triplet combinations with immune checkpoint inhibition with anti-vascular endothelial growth factor tyrosine kinase inhibitors in the front-line setting for metastatic disease (COSMIC313) has been explored. The use of adjuvant therapy has been complicated by a series of negative immune therapy trials. Promising results with the HIF-2α transcription factor inhibitor, belzutifan, alone or in combination with other agents, have been reported. Antibody drug conjugates, including enfortumab vedotin and sacituzumab govitecan, have continued to show activity in urothelial cancer with promising clinical outcomes. This has led to further exploration of the combination of these novel agents with immunotherapy and accelerated Food and Drug Administration approvals. Data are also discussed regarding intensification for front-line therapy of metastatic castrate sensitive prostate cancer. The combination of androgen-signaling inhibitors, docetaxel, and androgen deprivation therapy (PEACE-1, ARASENS), as well as the use of abiraterone acetate for adjuvant therapy in high-risk disease (STAMPEDE), is included. There is also growing evidence for the use of the radioligand therapy Lu-PSMA-617 in metastatic castrate resistant disease, with an established overall survival benefit in this patient population (VISION, TheraP). PLAIN LANGUAGE SUMMARY: There have been many advancements in the treatment of cancers of the kidney, bladder, and prostate in the past year. Several studies using new therapies or new combinations of therapies have improved the chances of patients living longer with these cancers, especially those with advanced disease. Here, we discuss a selection of the most compelling recently published data that have changed the way these cancers are treated, as well as those that are expected to change treatment in the near future.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Kidney Neoplasms
PubMed: 37378532
DOI: 10.1002/cncr.34907 -
Current Urology Reports Oct 2023Metastatic prostate cancer remains universally lethal. Although de-novo metastatic prostate cancer was historically managed with systemic therapy alone, local therapies... (Review)
Review
PURPOSE OF REVIEW
Metastatic prostate cancer remains universally lethal. Although de-novo metastatic prostate cancer was historically managed with systemic therapy alone, local therapies are increasingly utilized in the early treatment of the disease, particularly in patients with oligometastatic prostate cancer (OMPC). OMPC represents an intermediate stage between clinically localized and widespread metastatic disease. Diseases classified within this stage present an opportunity for localized targeting of the disease prior to progression to widespread metastases. The purpose of this review is to discuss the contemporary and emerging local therapies for the treatment of OMPC.
RECENT FINDINGS
To date, there are three utilized forms of local therapy for OMPC: cryoablation, radiation therapy, and cytoreductive prostatectomy. Cryoablation can be utilized for the total ablation of the prostate and has shown promising results in patients with OMPC either in combination with ADT or with ADT and systemic chemotherapy. Radiation therapy along with ADT has demonstrated improvement in progression-free survival. The STAMPEDE Arm G, PEACE-1, and the HORRAD clinical trials have investigated radiation therapy for mPCa compared to standard of care versus systemic therapy with varying results. Cytoreductive radical prostatectomy (CRP) in conjunction with ADT has also been proposed in the management of OPMC with promising results from case-control and retrospective studies. Currently there are larger controlled trials investigating CRP for OPMC including the SIMCAP, LoMP, TRoMbone, SWOG 1802, IP2-ATLANTA, g-RAMPP, and FUSCC-OMPCa trials. Given the novel nature of local treatments for OPMC, treatment selection is still controversial and requires long-term follow-up and randomized clinical trials to aid patient and clinician decision making.
Topics: Male; Humans; Retrospective Studies; Prostatic Neoplasms; Prostate; Prostatectomy; Cytoreduction Surgical Procedures; Androgen Antagonists; Neoplasm Metastasis
PubMed: 37369828
DOI: 10.1007/s11934-023-01173-6 -
Cancer Research Sep 2023Prostate cancer is a common malignancy driven by the androgen receptor (AR) pathway, with androgen deprivation therapy (ADT) being a standard treatment. However, the...
Prostate cancer is a common malignancy driven by the androgen receptor (AR) pathway, with androgen deprivation therapy (ADT) being a standard treatment. However, the development of castration-resistant prostate cancer (CRPC) poses a significant challenge. CRPC is characterized by significantly increased tumor heterogeneity and lineage plasticity. Current research has primarily emphasized intrinsic tumor mechanisms, paying less attention to the role of the tumor microenvironment in cancer recurrence and drug resistance. In their recent study published in Cancer Cell, Wang and colleagues used single-cell RNA sequencing in genetically engineered mouse models with prostate tumors at different stages. They revealed that SPP1+ myofibroblastic cancer-associated fibroblasts (myCAF), induced by ADT, play an instrumental role in CRPC development. Their work also underscores the association between therapy-induced phenotypic alterations of CAFs and disease progression. This discovery highlights the potential for stromal compartment targeting as a means to mitigate CRPC development and overcome treatment resistance.
Topics: Humans; Male; Animals; Mice; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Neoplasm Recurrence, Local; Receptors, Androgen; Disease Progression; Drug Resistance, Neoplasm; Tumor Microenvironment
PubMed: 37504898
DOI: 10.1158/0008-5472.CAN-23-2260 -
International Journal of Molecular... Dec 2023Breast cancer subtypes expressing hormone receptors (HR+ BCa) have a good prognosis and respond to first-line endocrine therapy (ET). However, the majority of HR+ BCa... (Review)
Review
Breast cancer subtypes expressing hormone receptors (HR+ BCa) have a good prognosis and respond to first-line endocrine therapy (ET). However, the majority of HR+ BCa patients exhibit intrinsic or acquired ET resistance (ET-R) and rapid onset of incurable metastatic BCa. With the failure of conventional ET, limited targeted therapy exists for ET-R HR+ BCa patients. The androgen receptor (AR) in HR-negative BCa subtypes is emerging as an attractive alternative target for therapy. The AR drives Luminal AR (LAR) triple-negative breast cancer progression, and LAR patients consistently exhibit positive clinical benefits with AR antagonists in clinical trials. In contrast, the function of the AR in HR+ BCa is more conflicting. AR in HR+ BCa correlates with a favorable prognosis, and yet, the AR supports the development of ET-R BCa. While AR antagonists were ineffective, ongoing clinical trials with a selective AR modulator have shown promise for HR+ BCa patients. To understand the incongruent actions of ARs in HR+ BCa, the current review discusses how the structure and post-translational modification impact AR function. Additionally, completed and ongoing clinical trials with FDA-approved AR-targeting agents for BCa are presented. Finally, we identify promising investigational small molecules and chimera drugs for future HR+ BCa therapy.
Topics: Humans; Receptors, Androgen; Androgens; Triple Negative Breast Neoplasms; Androgen Antagonists; Androgen Receptor Antagonists
PubMed: 38203649
DOI: 10.3390/ijms25010476 -
Acta Oncologica (Stockholm, Sweden) Sep 2023We compared the effectiveness of currently available systemic therapies for high-volume metastatic hormone-sensitive prostate cancer (mHSPC) and aimed to establish the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
We compared the effectiveness of currently available systemic therapies for high-volume metastatic hormone-sensitive prostate cancer (mHSPC) and aimed to establish the optimal treatment regimen.
MATERIAL AND METHODS
We searched multiple databases for randomized controlled trials (RCTs) that evaluated the efficacy of systemic therapy in patients with high-volume mHSPC. Bayesian network meta-analysis was used to indirectly compare overall survival (OS) and progression-free survival (PFS) of various systemic therapies.
RESULTS
Eleven RCTs (6708 participants) finally met the eligibility criteria. Compared with androgen deprivation therapy (ADT) alone, rezvilutamide (REZ) [hazard ratio (HR) = 0.58, 95% confidence interval (CI): 0.44-0.77], abiraterone (ABI) (HR = 0.61, 95% CI: 0.53-0.71), apalutamide (APA) (HR = 0.70, 95% CI: 0.56-0.88), enzalutamide (ENZ) (HR = 0.65, 95% CI: 0.53-0.80), docetaxel (DOC) (HR = 0.72, 95% CI: 0.63-0.84), darolutamide (DAR) + DOC (HR = 0.49, 95% CI: 0.39-0.62), and ABI + DOC (HR = 0.52, 95% CI: 0.38-0.71) significantly improved OS in patients with high-volume mHSPC. Compared with DOC, no advantages were observed for doublet therapies, including REZ, ABI, APA, and ENZ on the basis of ADT, whereas DAR + DOC (HR = 0.68, 95% CI: 0.57-0.82) and ABI + DOC (HR = 0.72, 95% CI: 0.55-0.95) was associated with better OS. The ranking analysis showed that triplet therapy (DAR + DOC + ADT and ABI + DOC + ADT) had the greatest improvement in OS, followed by REZ + ADT. All the regimens showed improved PFS in patients with high-volume mHSPC. Compared with DOC, significant differences were detected for DAR + DOC, ABI + DOC, ENZ + DOC, REZ, and ENZ. According to the ranking analysis, triplet therapy ranked first, followed by ENZ and REZ.
CONCLUSIONS
REZ + ADT were the highest ranked doublet therapy for improvement in OS of patients with high-volume mHSPC, second only to triplet therapy (DAR + DOC + ADT and ABI + DOC + ADT).
Topics: Male; Humans; Network Meta-Analysis; Treatment Outcome; Prostatic Neoplasms; Docetaxel; Androgen Antagonists; Hormones; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37548225
DOI: 10.1080/0284186X.2023.2241985 -
Journal of Nuclear Medicine : Official... Oct 2023For patients with advanced-stage metastatic castration-resistant prostate cancer (mCRPC) who do not respond to [Lu]Lu-PSMA therapy, there are limited treatment options....
For patients with advanced-stage metastatic castration-resistant prostate cancer (mCRPC) who do not respond to [Lu]Lu-PSMA therapy, there are limited treatment options. Clinical results obtained with [Ac]Ac-PSMA are promising. We retrospectively analyzed the outcomes of patients treated with [Ac]Ac-PSMA between December 2018 and October 2022. We evaluated the treatment results of 23 patients (mean age, 70.3 ± 8.8 y) with mCRPC who were refractory to treatment with [Lu]Lu-PSMA (2-9 cycles). The safety profile was assessed according to Common Technology Criteria for Adverse Events version 5.0. Treatment efficacy was assessed using prostate-specific membrane antigen PET progression criteria and prostate-specific antigen (PSA) response according to Prostate Cancer Working Group 2 criteria after the first cycle of [Ac]Ac-PSMA treatment. All patients received androgen-deprivation therapy, whereas 22 (96%) and 19 (83%) patients received chemotherapy and second-generation antiandrogen therapy, respectively. One patient received 4 cycles, 2 received 3 cycles, 8 received 2 cycles, and 12 received 1 cycle of [Ac]Ac-PSMA. The median interval between cycles was 13 wk (range, 8-28 wk). [Ac]Ac-PSMA was administered with a mean activity of 7.6 MBq (range, 6.2-10.0 MBq) in each cycle. Patients were at an advanced stage of disease, and tumor burden was very high. Although the best PSA response was observed in 5 patients (26%) after [Ac]Ac-PSMA treatment, there was at least some level of decline in PSA observed in 11 patients (58%; = 19). Treatment response was assessed in patients who underwent [Ga]Ga-PSMA PET/CT imaging. After the first cycle of treatment ( = 18), 50% of patients ( = 9) showed disease progression according to prostate-specific membrane antigen PET progression criteria, and the disease control rate was calculated to be 50%. Median progression-free survival was 3.1 mo, and median overall survival was 7.7 mo. Grade 3 hematologic toxicity occurred in 1 patient, and grade 3 nephrotoxicity was observed in another patient. Parotid SUV decreased by 33%, although all patients complained of dry mouth before treatment. We observed that [Ac]Ac-PSMA therapy was safe and showed potential even in cases with advanced-stage mCRPC in which all other treatment options were completed.
Topics: Male; Humans; Middle Aged; Aged; Prostatic Neoplasms, Castration-Resistant; Prostate-Specific Antigen; Positron Emission Tomography Computed Tomography; Retrospective Studies; Androgen Antagonists; Radiopharmaceuticals; Dipeptides; Treatment Outcome; Heterocyclic Compounds, 1-Ring; Lutetium
PubMed: 37620050
DOI: 10.2967/jnumed.123.265546 -
Current Oncology Reports Sep 2023There have been increasing reports of cardiovascular complications of androgen deprivation therapy (ADT) leading to worse outcomes among patients with prostate cancer.... (Review)
Review
PURPOSE OF THE REVIEW
There have been increasing reports of cardiovascular complications of androgen deprivation therapy (ADT) leading to worse outcomes among patients with prostate cancer. While this may result from the direct effects of androgen suppression in the cardiovascular systems, there are ADT-type-specific distinct cardiovascular complications suggestive of mechanisms beyond androgen-mediated. Thus, it is critical to understand the biological and clinical impact of ADT on the cardiovascular system.
RECENT FINDINGS
Gonadotropin-releasing hormone (GnRH) agonists cause increased cardiovascular events compared to GnRH antagonists. Androgen receptor antagonists are linked to an increased risk of long QT syndrome, torsades de pointes, and sudden cardiac death. Androgen synthesis inhibitors are associated with increased rates of hypertension, atrial tachyarrhythmia, and, in rare incidences, heart failure. ADT increases the risk of cardiovascular disease. The risk among ADT drugs differs and must be evaluated to develop a medically optimal plan for prostate cancer patients.
Topics: Male; Humans; Prostatic Neoplasms; Androgens; Androgen Antagonists; Gonadotropin-Releasing Hormone; Cardiovascular System; Biology
PubMed: 37273124
DOI: 10.1007/s11912-023-01424-2 -
Journal of Clinical Oncology : Official... Apr 2024Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide,... (Randomized Controlled Trial)
Randomized Controlled Trial
PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in Patients With High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19).
PURPOSE
Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC.
PATIENTS AND METHODS
PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion.
RESULTS
Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; = .00047; median, 26.0 months for ADT + apalutamide + AAP 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively).
CONCLUSION
Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.
Topics: Humans; Male; Abiraterone Acetate; Androgen Antagonists; Androgens; Castration; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Testosterone
PubMed: 38261983
DOI: 10.1200/JCO.23.01157 -
Prostate Cancer and Prostatic Diseases Dec 2023Oligometastatic prostate cancer (OMPCa) is emerging as a transitional disease state between localized and polymetastatic disease. This review will assess the current... (Review)
Review
BACKGROUND
Oligometastatic prostate cancer (OMPCa) is emerging as a transitional disease state between localized and polymetastatic disease. This review will assess the current knowledge of castrate-sensitive OMPCa.
METHODS
A review of the current literature was performed to summarize the definition and classification of OMPCa, assess the diagnostic methods and imaging modalities utilized, and to review the treatment options and outcomes. We further identify gaps in knowledge and areas for future research.
RESULTS
Currently there is no unified definition of OMPCa. National guidelines mostly recommend systemic therapies without distinguishing oligometastatic and polymetastatic disease. Next generation imaging is more sensitive than conventional imaging and has led to early detection of metastases at initial diagnosis or recurrence. While mostly retrospective in nature, recent studies suggest that treatment (surgical or radiation) of the primary tumor and/or metastatic sites might delay initiation of androgen deprivation therapy while increasing survival in selected patients.
CONCLUSIONS
Prospective data are required to better assess the incremental improvement in survival and quality of life achieved with various treatment strategies in patients with OMPCa.
Topics: Male; Humans; Prostatic Neoplasms; Prospective Studies; Quality of Life; Androgen Antagonists; Retrospective Studies
PubMed: 37422523
DOI: 10.1038/s41391-023-00688-w