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Cancer Biology & Therapy Dec 2022In the last decade, many life-prolonging therapeutic options have emerged for metastatic castration-resistant prostate cancer (mCRPC). The recent VISION trial is the...
In the last decade, many life-prolonging therapeutic options have emerged for metastatic castration-resistant prostate cancer (mCRPC). The recent VISION trial is the first to demonstrate a survival benefit of Lutetium-177[Lu]Lu-PSMA-617 in post-chemotherapy mCRPC. This journal club reviews the VISION trial in the context of the earlier TheraP trial of [Lu]Lu-PSMA-617 in mCRPC post docetaxel and androgen pathway inhibition, to provide direction for the real-world application of [Lu]Lu-PSMA-617. Treatment in the control groups differed significantly between both trials and may have influenced outcomes: TheraP mandated cabazitaxel whereas VISION's design could not allow it. In both trials, [Lu]Lu-PSMA-617 had a good safety profile, with common adverse events being fatigue, nausea, dry mouth, marrow suppression and diarrhea. Given its efficacy and favorable safety even in heavily pre-treated patients, [Lu]Lu-PSMA-617 provides hope to mCRPC patients and may be applied to earlier disease stages in future investigations.
Topics: Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radiopharmaceuticals; Treatment Outcome
PubMed: 35220877
DOI: 10.1080/15384047.2022.2037985 -
Research and Reports in Urology 2022Metastatic castration resistant prostate cancer (CRPC) is an inevitably fatal disease. However, in recent years, several treatments have been shown to improve the... (Review)
Review
Metastatic castration resistant prostate cancer (CRPC) is an inevitably fatal disease. However, in recent years, several treatments have been shown to improve the outcome of CRPC patients both in the non-metastatic (nmCRPC) as well as the metastatic setting (mCRPC). In nmCRPC patients with a PSA doubling time <10 months, the addition of enzalutamide, apalutamide and darolutamide to androgen deprivation therapy (ADT) compared to ADT alone resulted in improved metastases free (MFS) and overall survival (OS). For mCRPC patients, several treatment options have been shown to be effective: two taxane based chemotherapies (docetaxel and cabazitaxel), two androgen-receptor pathway inhibitors (ARPI) (abiraterone and enzalutamide), two radiopharmaceutical agents (radium 223 and 177Lutetium-PSMA-617), one immunotherapy treatment (sipuleucel-T) and two poly ADP-ribose polymerase (PARP) inhibitors (olaparib and rucaparib). Pembrolizumab is US Food and Drug Administration (FDA) approved in all MSI high solid tumors, although a very small proportion of prostate cancer patients harboring this characteristic will benefit. Despite having a broad variety of treatments available, there are still several unmet clinical needs for CRPC. The objective of this review was to describe the therapeutic landscape in CRPC patients, to identify criteria for selecting patients for specific treatments currently available, and to address the current challenges in this setting.
PubMed: 36199275
DOI: 10.2147/RRU.S360444 -
The World Journal of Men's Health Oct 2023The introduction of novel therapeutic agents for advanced prostate cancer has led to a wide range of treatment options for patients with metastatic castration-resistant... (Review)
Review
The introduction of novel therapeutic agents for advanced prostate cancer has led to a wide range of treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC). In the past decade, new treatment options for mCRPC, including abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, radium-223, Lu-PSMA-617, and Olaparib, have demonstrated a survival benefit in phase 3 trials. Bone-modifying agents have become part of the overall treatment strategy for mCRPC, in which denosumab and zoledronic acid reduce skeletal-related events. Recently, androgen receptor-signaling inhibitors (ARSIs) and docetaxel have been used upfront against metastatic castration-sensitive prostate cancer. Further, triplet therapy with ARSI, docetaxel, and androgen deprivation therapy is emerging. However, cross-resistance may occur between these treatments, and the optimal treatment sequence must be considered. The sequential administration of ARSIs, such as abiraterone and enzalutamide, is associated with limited efficacy; however, cabazitaxel is effective for patients with mCRPC who were previously treated with docetaxel and had disease progression during treatment with ARSI. Radioligand therapy with Lu-PSMA-617 is a new effective class of therapy for patients with advanced PSMA-positive mCRPC. Tumors with gene alterations that affect homologous recombination repair, such as and alterations, are sensitive to poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors in mCRPC. This review sought to highlight recent advances in systemic therapy for mCRPC and strategies to support patient selection and treatment sequencing.
PubMed: 36792090
DOI: 10.5534/wjmh.220200 -
The Lancet. Oncology Oct 2019Taxane-platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Taxane-platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised trials. Distinct biological subsets of the disease might derive the greatest benefit from the addition of platinum. We aimed to determine whether adding carboplatin to cabazitaxel would improve the outcomes of men with metastatic castration-resistant prostate cancer.
METHODS
We did a phase 1-2, open label, randomised study at two centres in men with progressive metastatic castration-resistant prostate cancer. In phase 1, patients received intravenous cabazitaxel 20-25 mg/m and intravenous carboplatin area under the curve (AUC) 3-4 mg/mL per min every 21 days. The maximum tolerated dose was defined as the highest dose cohort studied in which one of six or fewer patients experienced a dose-limiting toxicity. In phase 2, patients were randomly assigned (1:1) centrally by a computerised algorithm to intravenous cabazitaxel 25 mg/m with or without intravenous carboplatin AUC 4 mg/mL per min. All patients received growth factor support and oral prednisone 10 mg daily. The primary endpoints were the maximum tolerated dose of the combination in phase 1 and investigator-assessed progression-free survival in phase 2. This trial is registered at ClinicalTrials.gov, number NCT01505868.
FINDINGS
Between Aug 17, 2012, and May 11, 2015, nine patients completed phase 1 as planned, and 160 were randomly assigned to cabazitaxel (n=79) or cabazitaxel plus carboplatin (n=81) in phase 2. During phase I, grade 3 adverse events were anaemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesaemia (n=1), diarrhoea (n=1), hypokalaemia (n=1), anorexia (n=1), and dehydration (n=1), and no grade 4 adverse events occurred. No dose-limiting toxicities were observed, therefore, a maximum tolerated dose of cabazitaxel of 25 mg/m and carboplatin of AUC 4 mg/mL per min was selected for phase 2. At a median follow-up of 31·0 months (IQR 20·5-37·1), the combination improved the median progression-free survival from 4·5 months (95% CI 3·5-5·7) to 7·3 months (95% CI 5·5-8·2; hazard ratio 0·69, 95% CI 0·50-0·95, p=0·018). In the phase 2 study, the most common grade 3-5 adverse events were fatigue (7 [9%] of 79 in the cabazitaxel group vs 16 [20%] of 81 in the combination group), anaemia (3 [4%] vs 19 [23%]), neutropenia (3 [4%] vs 13 [16%]), and thrombocytopenia (1 [1%] vs 11 [14%]). There were no treatment-related deaths.
INTERPRETATION
Carboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane-platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned.
FUNDING
Sanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, and Solon Scott III Prostate Cancer Research Fund.
Topics: Aged; Anemia; Anorexia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Dehydration; Diarrhea; Fatigue; Humans; Hypokalemia; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neutropenia; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Taxoids; Thrombocytopenia
PubMed: 31515154
DOI: 10.1016/S1470-2045(19)30408-5 -
Ultrasound in Medicine & Biology May 2021Delivery of drugs and nanomedicines to tumors is often heterogeneous and insufficient and, thus, of limited efficacy. Microbubbles in combination with ultrasound have...
Delivery of drugs and nanomedicines to tumors is often heterogeneous and insufficient and, thus, of limited efficacy. Microbubbles in combination with ultrasound have been found to improve delivery to tumors, enhancing accumulation and penetration. We used a subcutaneous prostate cancer xenograft model in mice to investigate the effect of free and nanoparticle-encapsulated cabazitaxel in combination with ultrasound and microbubbles with a lipid shell or a shell of nanoparticles. Sonopermeation reduced tumor growth and prolonged survival (26%-100%), whether the free drug was co-injected with lipid-shelled microbubbles or the nanoformulation was co-injected with lipid-shelled or nanoparticle-shelled microbubbles. Coherently with the improved therapeutic response, we found enhanced uptake of nanoparticles directly after ultrasound treatment that lasted several weeks (2.3 × -15.8 × increase). Neither cavitation dose nor total accumulation of nanoparticles could explain the variation within treatment groups, emphasizing the need for a better understanding of the tumor biology and mechanisms involved in ultrasound-mediated treatment.
Topics: Animals; Combined Modality Therapy; Drug Delivery Systems; Heterografts; Male; Mice; Mice, Inbred BALB C; Microbubbles; Nanoparticles; Prostatic Neoplasms; Taxoids; Treatment Outcome; Ultrasonic Therapy
PubMed: 33549379
DOI: 10.1016/j.ultrasmedbio.2020.12.026 -
BJU International Nov 2019To assess the activity and safety of cabazitaxel chemotherapy vs that of treatment with Lu-PSMA-617, a novel radiolabelled small molecule that binds with high affinity... (Randomized Controlled Trial)
Randomized Controlled Trial
TheraP: a randomized phase 2 trial of Lu-PSMA-617 theranostic treatment vs cabazitaxel in progressive metastatic castration-resistant prostate cancer (Clinical Trial Protocol ANZUP 1603).
OBJECTIVE
To assess the activity and safety of cabazitaxel chemotherapy vs that of treatment with Lu-PSMA-617, a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), in men with metastatic castration-resistant prostate cancer (mCRPC) who have received prior docetaxel treatment.
PATIENTS AND METHODS
The TheraP trial (ANZUP 1603) is an open-label, randomized, stratified, two-arm multicentre phase 2 trial comparing the activity and safety of cabazitaxel chemotherapy vs Lu-PSMA-617 therapy in the treatment of men with mCRPC. Key eligibility criteria include prior docetaxel chemotherapy, rising prostate-specific antigen (PSA) level, sufficient PSMA avidity, as defined by centrally reviewed Ga-PSMA-11 and fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) with no discordant FDG-avid PSMA-negative sites of disease. Patients in the control group receive standard treatment with cabazitaxel (20 mg/m ) i.v. every 3 weeks with prednisolone 10 mg daily orally, for a maximum of 10 cycles. Patients in the experimental group receive Lu-PSMA-617 (8.5 GBq decreasing by 0.5 GBq per cycle) i.v. every 6 weeks, for up to a maximum of six cycles. In the event of an exceptional response as defined on centrally reviewed post-therapy single-photon emission CT imaging, treatment will be suspended but can recommence on progression. The trial aims to include 200 patients who will be centrally randomized to one of the two treatment groups, in a 1:1 ratio. The primary endpoint is PSA response. Secondary endpoints are overall survival, progression-free survival (PFS), radiographic PFS, PSA PFS, objective tumour response, pain response, pain PFS, health-related quality of life, and frequency and severity of adverse events. The treatment and outcomes of patients excluded on the basis of low PSMA avidity or discordant FDG-avid disease on screening Ga-PSMA-11 and Fluorine-18 ( F)-FDG-PET/CT scan will also be assessed. Enrolment in the study commenced on 29 January 2018.
RESULTS AND CONCLUSIONS
Lu-PSMA-617 offers a potential additional life-prolonging treatment option for men with mCRPC. The results of this trial will determine, for the first time in a randomized design, the activity and safety of Lu-PSMA-617, as compared with cabazitaxel chemotherapy in men with progressive mCRPC.
Topics: Dipeptides; Disease-Free Survival; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Positron Emission Tomography Computed Tomography; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Radiopharmaceuticals; Radiotherapy Dosage; Taxoids; Theranostic Nanomedicine; Treatment Outcome
PubMed: 31638341
DOI: 10.1111/bju.14876 -
British Journal of Pharmacology Jul 2020Taxane-derived drugs are antineoplastic agents used for the treatment of highly common malignancies. Paclitaxel and docetaxel are the most commonly used taxanes;... (Review)
Review
Taxane-derived drugs are antineoplastic agents used for the treatment of highly common malignancies. Paclitaxel and docetaxel are the most commonly used taxanes; however, other drugs and formulations have been used, such as cabazitaxel and nab-paclitaxel. Taxane treatment is associated with neurotoxicity, a well-known and relevant side effect, very prevalent amongst patients undergoing chemotherapy. Painful peripheral neuropathy is the most dose-limiting side effect of taxanes, affecting up to 97% of paclitaxel-treated patients. Central neurotoxicity is an emerging side effect of taxanes and it is characterized by cognitive impairment and encephalopathy. Besides impairing compliance to chemotherapy treatment, taxane-induced neurotoxicity (TIN) can adversely affect the patient's life quality on a long-term basis. Despite the clinical relevance, not many reviews have comprehensively addressed taxane-induced neurotoxicity when they are used therapeutically. This article provides an up-to-date review on the pathophysiology of TIN and the novel potential therapies to prevent or treat this side effect.
Topics: Antineoplastic Agents; Bridged-Ring Compounds; Docetaxel; Humans; Paclitaxel; Taxoids
PubMed: 32352155
DOI: 10.1111/bph.15086