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BACKGROUND AND OBJECTIVE: The CABASTY study showed that more frequent administration of a lower dose of cabazitaxel (CBZ) reduced toxicity in older men with metastatic castration-resistant prostate cancer (mCRPC), without compromising efficacy. Here, we investigated the impact of a biweekly CBZ schedule on patient-reported pain and health-related quality of life (HRQoL). METHODS: We randomized 196 patients from 25 centers (1:1, stratified by age and G8 score) to the biweekly CBZ16 (CBZ 16 mg/m2) experimental arm or the triweekly CBZ25 (CBZ 25 mg/m2) control arm (CABASTY study, NCT02961257). We assessed pain using the Numeric Pain Rating Scale and HRQoL using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. KEY FINDINGS AND LIMITATIONS: A total of 141 patients were available for a pain and 160 for an HRQoL analysis. Median time to pain progression (stratified hazard ratio [HR]: 1.7, confidence interval [CI]: 0.67-4.22, p = 0.3) and median time to first opiate use (stratified HR: 1.05, CI: 0.44-2.55, p = 0.9) did not differ between arms. We did not see a significant difference in median time to deterioration of FACT-P total score between treatments (stratified HR: 0.88, CI: 0.47-1.7, p = 0.7). Interestingly, the time to onset of several adverse events was significantly longer in the biweekly CBZ16 group. CONCLUSIONS AND CLINICAL IMPLICATIONS: HRQoL did not significantly differ between the biweekly CBZ16 and the standard schedule. Additionally, onset of some adverse events was delayed. These results may increase health care providers' confidence in using CBZ in older patients with mCRPC who are denied chemotherapy. PATIENT SUMMARY: Androgen receptor pathway inhibitors are often preferred to taxane chemotherapy as a treatment of second or subsequent line in older metastatic castration-resistant prostate cancer patients due to more frequent treatment-related toxicities. Here, we showed that quality of life and pain did not differ significantly with an adapted schedule of cabazitaxel (CBZ), compared with the standard regimen. This CBZ schedule could increase eligibility of older patients for chemotherapy.
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BACKGROUND: Prostate cancer is regulated by steroid hormones, even in castration-resistant disease. ODM-208, a novel inhibitor of cytochrome P450 11A1 (which catalyzes the first step of steroid-hormone biosynthesis), was investigated in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). METHODS: CYPIDES is a first-in-human phase 1 (3 + 3 design) and phase 2 study. We administered ODM-208 twice daily with glucocorticoid/mineralocorticoid replacement and ongoing androgen deprivation therapy to adults with previously treated mCRPC, regardless of androgen receptor gene (AR) ligand-binding domain mutations (phase 1) and with activating AR ligand-binding domain mutations (ARmut; phase 2). Safety, pharmacokinetics, steroid-hormone pharmacodynamics, and preliminary efficacy were the key outcomes. RESULTS: Ninety-two patients received one or more doses of ODM-208: 47 in phase 1 (20 [42.6%] with ARmut) and 45 in phase 2 (all ARmut). A dose of ODM-208 of 5 mg twice a day with dexamethasone 1 mg/fludrocortisone 0.1 mg provided a balance between decreased steroidogenesis and toxicity. Treatment-related adrenal insufficiency was the most common toxicity in phase 1 (n=17, 36.2%; necessitating ODM-208 discontinuation in one patient); this toxicity occurred in six patients (13.3%) at 5 mg twice a day in phase 2. Median circulating testosterone levels declined from 3.0 ng/dl (interquartile range, 1.3 to 6.2 ng/dl) at baseline to undetectable levels within the first week of ODM-208 5 mg twice a day treatment in 46 of 53 (87%) patients. A decrease in prostate-specific antigen levels of 50% or more occurred in 14 of 19 (73.7%) patients with ARmut and 2 of 23 (8.7%) patients with AR wild type in phase 1 and in 24 of 45 (53.3%) patients with ARmut in phase 2. CONCLUSIONS: ODM-208 potently inhibited steroid-hormone biosynthesis with the expected toxicity of adrenal insufficiency. Evidence of antitumor activity was observed in this heavily pretreated mCRPC population, especially in those with ARmut. (Funded by Orion Pharma; ClinicalTrials.gov number, NCT03436485.)
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Receptors, Androgen , Male , Humans , Receptors, Androgen/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Cholesterol Side-Chain Cleavage Enzyme , Prostate-Specific Antigen/therapeutic use , Treatment Outcome , Androgen Receptor Antagonists/pharmacologyABSTRACT
Importance: Many patients 65 years or older with metastatic castration-resistant prostate cancer (mCRPC) are denied taxane chemotherapy because this treatment is considered unsuitable. Objective: To determine whether biweekly cabazitaxel (CBZ), 16 mg/m2 (biweekly CBZ16), plus prophylactic granulocyte colony-stimulating factor (G-CSF) at each cycle reduces the risk of grade 3 or higher neutropenia and/or neutropenic complications (eg, febrile neutropenia, neutropenic infection, or sepsis) compared with triweekly CBZ, 25 mg/m2 (triweekly CBZ25), plus G-CSF (standard regimen). Design, Setting, and Participants: A total of 196 patients 65 years or older with progressive mCRPC were enrolled in this prospective phase 3 randomized clinical trial conducted in France (18 centers) and Germany (7 centers) between May 5, 2017, and January 7, 2021. All patients had received docetaxel and at least 1 novel androgen receptor-targeted agent. Interventions: Patients were randomly assigned 1:1 to receive biweekly CBZ16 plus G-CSF and daily prednisolone (experimental group) or triweekly CBZ25 plus G-CSF and daily prednisolone (control group). Main Outcome and Measures: The primary end point was the occurrence of grade 3 or higher neutropenia measured at nadir and/or neutropenic complications. Results: Among 196 patients (97 in the triweekly CBZ25 group and 99 in the biweekly CBZ16 group), the median (IQR) age was 74.6 (70.4-79.3) years, and 181 (92.3%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median (IQR) follow-up duration was 31.3 (22.5-37.5) months. Relative dose intensities were comparable between groups (median [IQR], 92.7% [83.7%-98.9%] in the triweekly CBZ25 group vs 92.8% [87.0%-98.9%] in the biweekly CBZ16 group). The rate of grade 3 or higher neutropenia and/or neutropenic complications was significantly higher with triweekly CBZ25 vs biweekly CBZ16 (60 of 96 [62.5%] vs 5 of 98 [5.1%]; odds ratio, 0.03; 95% CI, 0.01-0.08; P < .001). Grade 3 or higher adverse events were more common with triweekly CBZ25 (70 of 96 [72.9%]) vs biweekly CBZ16 (55 of 98 [56.1%]). One patient (triweekly CBZ25 group) died of a neutropenic complication. Conclusions and Relevance: In this randomized clinical trial, compared with the standard regimen, biweekly CBZ16 plus G-CSF significantly reduced by 12-fold the occurrence of grade 3 or higher neutropenia and/or neutropenic complications, with comparable clinical outcomes. The findings suggest that biweekly CBZ16 regimen should be offered to patients 65 years or older with mCRPC for whom the standard regimen is unsuitable. Trial Registration: ClinicalTrials.gov Identifier: NCT02961257.
Subject(s)
Neutropenia , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Aged , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Prospective Studies , Treatment Outcome , Taxoids/administration & dosage , Neutropenia/chemically induced , Prednisolone/administration & dosage , Prednisolone/adverse effects , Granulocyte Colony-Stimulating Factor/adverse effectsABSTRACT
Few prognostic factors have been identified in patients with metastatic urothelial carcinoma (mUC) treated with immune checkpoint inhibitors (ICIs). The Lung Immune Prognostic Index (LIPI) was associated with clinical outcomes for ICIs in several tumor types. We aim to assess the value of the LIPI in patients with mUC treated with ICIs. A retrospective ICI cohort and a validation cohort (SAUL cohort) included, respectively, patients with mUC treated with ICI in 8 European centers (any line) and patients treated with atezolizumab in a second or further line. A chemotherapy-only cohort was also analyzed. The LIPI score was based on 2 factors, derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) > 3 and lactate dehydrogenase > upper limit of normal, and defined 3 prognostic groups. The association of LIPI with progression-free survival (PFS) and overall survival (OS) was assessed. In the ICI and SAUL cohorts, 137 and 541 patients were respectively analyzed. In the ICI cohort, mPFS and mOS were 3.6 mo (95% CI; 2.6-6.0) and 13.8 mo (95% CI; 11.5-23.2) whereas in the SAUL cohort the mPFS and mOS were 2.2 mo (95% CI; 2.1-2.3) and 8.7 mo (95% CI; 7.8-9.9) respectively. The LIPI classified the population of these cohorts in good (56%; 52%), intermediate (35%; 36%) and poor (9%; 12%) prognostic groups (values for the ICI and SAUL cohorts respectively). Poor LIPI was associated with a poorer OS in both cohorts: hazard ratio (HR) for the ICI cohort = 2.69 (95% CI; 1.24-5.84, p = 0.035); HR = 2. 89 for the SAUL cohort (CI 95%: 1.93-4.32, p < 0.0001). Similar results were found in the chemo cohort. The LIPI score allows to identify different subgroups in patients with good prognostis according to the Bellmunt score criteria, with a subset of patients with poorer outcomes having an mOS of 3.7 mo compared to the good and intermediate LIPI subgroups with mOS of 17.9 and 7.4 mo, respectively. The LIPI score was associated with survival in mUC patients treated by ICIs. Future prospective studies will be required to test the combination of Bellmunt score and the LIPI score as a more accurate prognosis tool.
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BACKGROUND: Immune checkpoint inhibitor-based combination therapy (ICI-based combination) is a new standard of care for metastatic clear cell renal cell carcinoma (mRCC) in the frontline setting. Patients with poor performance status (PS) (≥2) were excluded from pivotal trials. Hence, the activity and safety of ICI-based combination therapy in this group of patients is still unknown. METHODS: We performed a multicentre retrospective study of PS ≥2 mRCC patients who received frontline ICI-based combination, either nivolumab-ipilimumab (NI) or pembrolizumab-axitinib (AP). Patients' characteristics, clinical outcomes, and toxicity were collected. We analysed overall response rate (ORR), median progression-free survival (mPFS), median overall survival (mOS) and grade ≥3 adverse events (G ≥ 3AEs). The association between the predictive biomarker IPI (immune prognostic index) and ORR/PFS/OS was also evaluated. RESULTS: We identified 70 mRCC patients with PS ≥2 treated with ICI-based combination across 14 institutions between October 2017 and December 2021, including 45 and 25 patients were treated with NI and AP, respectively. Median age at diagnosis was 63 years, 51 (73%) were male, only 17 (24%) had prior nephrectomy, 50 (71%) had synchronous metastatic disease at diagnosis, and 16 (23%) had brain metastases. Sixty-one (87%) and 9 (13%) patients had ECOG (Eastern Cooperative Oncology Group) PS 2 and 3, respectively, and 25 (36%) and 45 (64%) patients were intermediate and poor International Metastatic RCC Database Consortium (IMDC) risk, respectively. Among all, 91% were clear cell RCC, 7 patients had sarcomatoid features. At the time of the analysis (median follow-up 11.1 months), 41% patients were dead. Median PFS and mOS in the entire cohort were 5.4 months and 16.0 months, respectively; ORR was 31%. No significant differences in ORR, PFS, OS, or G ≥3AEs were seen between NI and AP. The intermediate and poor IPI groups were significantly associated with reduced ORR and shorter PFS. CONCLUSION: We report the first cohort of PS ≥2 mRCC patients treated with frontline ICI-based combination therapy. The survival outcomes in our cohort were inferior to that reported in pivotal trials. No significant differences in ORR, PFS, OS or toxicity were seen between NI and AP. Prospective real-world studies are needed to confirm these results.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Male , Female , Carcinoma, Renal Cell/pathology , Immune Checkpoint Inhibitors/adverse effects , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Retrospective Studies , Prospective StudiesABSTRACT
Nivolumab and cabozantinib are approved agents in mRCC patients after sunitinib/pazopanib (TKI) failure. However, the optimal sequence, cabozantinib then nivolumab (CN) or nivolumab then cabozantinib (NC), is still unknown. The CABIR study aimed to identify the optimal sequence between CN and NC after frontline VEGFR-TKI. In this multicenter retrospective study, we collected data from mRCC pts receiving CN or NC, after frontline VEGFR-TKI. A propensity score (PrS) was calculated to manage bias selection, and sequence comparisons were carried out with a cox model on a matched sample 1:1. The primary endpoint was progression-free survival (PFS) from the start of second line to progression in third line (PFS2-3 ). Key secondary endpoints included overall survival from second line (OS2 ). Out of 139 included mRCC patients, 38 (27%) and 101 (73%) received CN and NC, respectively. Overlap in PrS allowed 1:1 matching for each CN pts, with characteristics well balanced. For both PFS2-3 and OS2 , NC sequence was superior to CN (PFS2-3 : HR = 0.58 [0.34-0.98], P = .043; OS2 : 0.66 [0.42-1.05], P = .080). Superior PFS2-3 was in patients treated between 6 and 18 months with prior VEGFR-TKI (P = .019) and was driven by a higher PFSL3 with cabozantinib when given after nivolumab (P < .001). The CABIR study shows a prolonged PFS of the NC sequence compared to CN in mRCC after first line VEGFR-TKI failure. The data suggest that cabozantinib may be more effective than nivolumab in the third-line setting, possibly related to an ability of cabozantinib to overcome resistance to PD-1 blockade.
Subject(s)
Antineoplastic Agents , Carcinoma, Renal Cell , Kidney Neoplasms , Anilides/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/pathology , Humans , Kidney Neoplasms/pathology , Nivolumab/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyridines , Retrospective StudiesABSTRACT
INTRODUCTION: Immune checkpoint inhibitors (ICI) have been approved for front-line therapy in metastatic renal cell carcinoma (mRCC). However, progressive disease often occurs and subsequent therapies are needed. ICI rechallenge may be an option, but there is a lack of data regarding efficacy and prognostic factors. We assessed efficacy of ICI rechallenge and factors associated with better outcomes. Patients and Methods. This ambispective multicenter study included 45 mRCC patients rechallenged with nivolumab ± ipilimumab between 2014 and 2020. Primary endpoint was investigator-assessed best objective response rate (ORR) for ICI rechallenge (ICI-2). Factors associated with ICI-2 progression-free survival (PFS) were evaluated with multivariate Cox models. RESULTS: ORR was 51% (n = 23) at first ICI therapy (ICI-1) and 16% (n = 7) for ICI-2. Median PFS was 11.4 months (95% CI, 9.8-23.5) and 3.5 months (95% CI, 2.8-9.7), and median overall survival was not reached (NR) (95% CI, 37.8-NR) and 24 months (95% CI, 9.9-NR) for ICI-1 and ICI-2, respectively. Factors associated with poorer ICI-2 PFS were a high number of metastatic sites, presence of liver metastases, use of an intervening treatment between ICI regimens, Eastern Cooperative Oncology Group performance status ≥2, and poor International Metastatic RCC Database Consortium score at ICI-2 start. Conversely, ICI-1 PFS >6 months was associated with better ICI-2 PFS. In multivariate analysis, there were only statistical trends toward better ICI-2 PFS in patients with ICI-1 PFS >6 months (p=0.07) and toward poorer ICI-2 PFS in patients who received a treatment between ICI regimens (p=0.07). CONCLUSION: Rechallenge with nivolumab-based ICI has some efficacy in mRCC. We identified various prognostic factors in univariate analysis but only statistical trends in multivariate analysis. Our findings bring new evidence on ICI rechallenge and preliminary but unique data that may help clinicians to select patients who will benefit from this strategy.
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BACKGROUND: Pembrolizumab is approved for patients with metastatic urothelial carcinoma (UC) who progressed under platinum therapy. The aim of this study was to assess the efficacy and safety of pembrolizumab in a cohort of real-life UC patients. METHODS: This retrospective, observational study included advanced UC patients treated with pembrolizumab in a single institution in France. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS) at 6 months. Secondary endpoints were objective response rate (ORR), duration of response (DOR), disease control rate (DCR) and safety. RESULTS: 78 patients were included in the study. The median OS was 7.3 months (3.8-12.2). The estimated OS rate at 6 months was 61.5% (50.5-72.6). The median PFS was 3.1 months (1.4-7.2). The estimated PFS rate at 6 months was 42.3% (31.1-53.5). The best ORR was 35.9%. The mean DOR was 95.5 days. The DCR was 30.8%. The most common treatment-related adverse events (AEs) of any grade were fatigue (46.2%), diarrhea (11.5%), pruritus (10.3%) and nausea (9.0%). There were no grade 3 AEs that occurred with an incidence of 5% or more. CONCLUSION: Our results confirmed those of randomized clinical trials concerning the treatment with pembrolizumab in patients with advanced UC that progressed after platinum-based chemotherapy.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/pathology , Humans , Retrospective Studies , Urinary Bladder Neoplasms/drug therapyABSTRACT
BACKGROUND: The taxanes docetaxel and cabazitaxel prolong overall survival for men with metastatic castration-resistant prostate cancer (mCRPC), with cabazitaxel approved in the postdocetaxel setting only. Recent data suggest they have similar efficacy but a different safety profile in the first-line mCRPC setting. OBJECTIVE: To assess patient preference between docetaxel and cabazitaxel among men who received one or more doses of each taxane and did not experience progression after the first taxane. DESIGN, SETTING, AND PARTICIPANTS: Chemotherapy-naïve patients with mCRPC were randomized 1:1 to receive docetaxel (75 mg/m2 every 3 wk × 4 cycles) followed by cabazitaxel (25 mg/m2 every 3 wk × 4 cycles) or the reverse sequence. Randomization was stratified by prior abiraterone or enzalutamide use. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was patient preference, assessed via a dedicated questionnaire after the second taxane. Secondary endpoints included reasons for patient preference, prostate-specific antigen response, radiological progression-free survival, and overall survival. This clinical trial is registered at ClinicalTrials.gov as NCT02044354. RESULTS AND LIMITATIONS: Of 195 men randomized, 152 met the prespecified modified intent-to-treat criteria for analysis. Overall, 66 patients (43%) preferred cabazitaxel, 40 (27%) preferred docetaxel, and 46 (30%) had no preference (p = 0.004, adjusted for treatment period effect). More patients preferred treatment period 1 (43%, 95% confidence interval [CI] 36-52%) versus period 2 (27%, 95% CI 20-34%). Patient preference for cabazitaxel was mainly related to less fatigue (72%), better quality of life (64%), and other adverse events (hair loss, pain, nail disorders, edema). Adverse events were consistent with the known safety profile of each drug. CONCLUSIONS: A significantly higher proportion of chemotherapy-naïve men with mCRPC who received both taxanes preferred cabazitaxel over docetaxel. Less fatigue and better quality of life were the two main reasons driving patient choice. PATIENT SUMMARY: Men with metastatic castration-resistant prostate cancer preferred cabazitaxel over docetaxel for chemotherapy, mainly because of less fatigue and better quality of life.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Docetaxel/therapeutic use , Fatigue/chemically induced , Female , Humans , Male , Patient Preference , Prostatic Neoplasms, Castration-Resistant/pathology , Quality of Life , Taxoids/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: Cabazitaxel was shown to improve overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after abiraterone/enzalutamine and docetaxel failure, though benefit by the presence of DNA damage repair (DDR) defects is unknown. With the advent of poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in partially overlapping indications with cabazitaxel, we aimed to determine cabazitaxel activity in men with mCRPC according to their DDR status. METHODS: This is a retrospective multicenter study that enrolled patients with mCRPC treated with cabazitaxel who had undergone DDR tumour tissue profiling. Patients with at least one deleterious germline or somatic alterations were considered DDR positive (DDR+). Each DDR + patient has been matched with a DDR negative (DDR-) from the same institution who underwent the same test. An exploratory cohort of patients found to be DDR + by liquid biopsy was also included. Prostate specific antigen (PSA) decline≥50% (PSA50), PSA progression-free survival (PFS, PSA-PFS), radiographic PFS (rPFS), clinical PFS or radiographic PFS (c/rPFS) and OS were evaluated. RESULTS: Among 190 men (95 DDR+, 95 DDR-) with tissue sequencing, PSA50 was achieved with cabazitaxel in 29/92 (32%) and 33/92 (36%) in patients with DDR+ and DDR- (P = 0.64). The median rPFS was 5.33 months [95%CI 4.34-7.04] versus 5.75 months [95%CI 4.67-7.27] (P = 0.55). The median OS was 15.4 months [95%CI 12.16-26.6] and 11.5 months [95%CI 9.76-14.4] (P = 0.036), respectively. No PSA50 responses on cabazitaxel were observed in BRCA1/2 patients previously treated with PARPi (n = 10). Similar outcomes with cabazitaxel were observed in the liquid biopsy cohort (n = 63 DDR+). CONCLUSIONS: Our study suggests that cabazitaxel is active in patients with mCRPC regardless of their DDR status, although its activity in men pretreated with a PARPi may be lower.
Subject(s)
Antineoplastic Agents/therapeutic use , DNA Repair/genetics , Prostatic Neoplasms, Castration-Resistant/drug therapy , Taxoids/therapeutic use , Humans , Male , Progression-Free Survival , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Retrospective StudiesABSTRACT
INTRODUCTION: Less than one-third of bladder cancers are non-pure urothelial carcinoma [with variant histological (VH) or non-urothelial carcinoma (non-UC)] for which no treatment guidelines are available. We aim to evaluate the efficacy of systemic treatments in VH or non-UC bladder cancers. MATERIALS: Multicenter retrospective analysis of patients treated for advanced or metastatic VH or non-UC bladder cancers. Primary endpoint was overall response rate (ORR) according to treatment line, regimen and histology subtype. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Between 2005 and 2020, 46 patients from seven centers were included. The median age was 66 years (58.75; 74.75), 65.2% were male and 67.2% presented VH. At first line, the ORR for the entire population was 54.4% and median OS was 21.6 months (95% confidence interval [CI]: 14.2-38.6). The ORR of the 37 patients treated with chemotherapy at first line was 62.2% with median PFS and OS of 7.3 (95% CI: 4.5-8.6) and 21.6 months (95% CI: 14.2-35.7), respectively. Dose dense MVAC and platinum doublet chemotherapy had the highest ORR (71.4% and 65.2%). The 9 patients treated with immunotherapy at first line had an ORR of 22.2%, a median PFS of 3.3 months (95% CI:2.3-NR) and the median OS was not reached (95% CI:13.8-NR). Response to treatment varied depending on the histological sub-types and on the treatment type. CONCLUSION: Chemotherapy and immunotherapy have shown to be effective in VH or non-UC cancers, a rare histological subtype for which we currently have very little data in the literature.
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Despite recent advances, treatment options for men with metastatic castration-resistant prostate cancer (mCRPC) progressing after next-generation hormonal agents (NHAs) are limited and provide only modest survival benefit. Thus, an unmet need remains for mCRPC patients after treatment with targeted endocrine therapy or NHA therapy. Pembrolizumab, a humanized monoclonal antibody for PD-1, has been found to have activity as monotherapy in patients with mCRPC and as combination therapy in a Phase Ib/II study with docetaxel and prednisone/prednisolone for patients previously treated with enzalutamide or abiraterone acetate. The aim of the randomized, double-blind, Phase III KEYNOTE-921 study is to evaluate the efficacy and safety of pembrolizumab plus docetaxel in patients with mCRPC who were previously treated with an NHA. Clinical trial registration: NCT03834506 (ClinicalTrials.gov).
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Docetaxel/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Clinical Trials, Phase III as Topic , Docetaxel/adverse effects , Double-Blind Method , Humans , Male , Middle Aged , Multicenter Studies as Topic , Prednisolone/administration & dosage , Prednisolone/adverse effects , Prednisone/administration & dosage , Prednisone/adverse effects , Progression-Free Survival , Prostate/diagnostic imaging , Prostate/pathology , Prostatic Neoplasms, Castration-Resistant/diagnosis , Prostatic Neoplasms, Castration-Resistant/mortality , Prostatic Neoplasms, Castration-Resistant/pathology , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: The combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulatory properties of antiangiogenic agents may help designing multidrug schedules based on specific immune synergisms. METHODS: We used orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines to elucidate the immunomodulatory effect of the antiangiogenic agent pazopanib in mRCC patients. Nine patients were studied longitudinally over a period of 6 months. We also analyzed transcriptional data from The Cancer Genome Atlas (TCGA) RCC cohort (N = 571) to assess the prognostic implications of our findings. The effect of pazopanib was assessed in vitro on NK cells and T cells. Additionally, myeloid-derived suppressor (MDSC)-like cells were generated from CD14+ monocytes transfected with mimics of miRNAs associated with MDSC function in the presence or absence of pazopanib. RESULTS: Pazopanib administration caused a rapid and dramatic reshaping in terms of frequency and transcriptional activity of multiple blood immune cell subsets, with a downsizing of MDSC and regulatory T cells in favor of a strong enhancement in PD-1 expressing cytotoxic T and Natural Killer effectors. These changes were paired with an increase of the expression of transcripts reflecting activation of immune-effector functions. This immunomodulation was marked but transient, peaking at the third month of treatment. Moreover, the intratumoral expression level of a MDSC signature (MDSC INT) was strongly associated with poor prognosis in RCC patients. In vitro experiments indicate that the observed immunomodulation might be due to an inhibitory effect on MDSC-mediated suppression, rather than a direct effect on NK and T cells. CONCLUSIONS: The marked but transient nature of this immunomodulation, peaking at the third month of treatment, provides the rationale for the use of antiangiogenics as a preconditioning strategy to improve the efficacy of ICB.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/immunology , Immunomodulation , Indazoles/therapeutic use , Kidney Neoplasms/immunology , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Tumor Microenvironment , Aged , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Male , Myeloid-Derived Suppressor Cells/immunology , Prognosis , Survival Rate , Transcriptome , Tumor Cells, CulturedABSTRACT
BACKGROUND: Cabozantinib strongly inhibits osteoclast differentiation and bone resorption in vitro. We aimed to evaluate its effect on bone turnover markers (BTMs) in metastatic renal cell carcinoma. METHODS: This is a monocentric prospective study on patients with mRCC treated with cabozantinib between October 2016 and July 2018. We collected blood samples at baseline and after 3 and 6 months of treatment. We compared sets of data obtained from plasma samples in the whole population with unpaired 2-tailed Student t tests and data for a subset of patients for which all timepoints were available with paired 2-tailed Student t tests. We used the Kaplan-Meier method for survival analyses and the log-rank test to compare the curves. RESULTS: Our analysis included 39 patients. At month 3, the mean C-terminal cross-linked telopeptides of type I collagen (CTx) and the mean N-terminal propeptide of type 1 collagen (PINP) levels were significantly decreased in the whole population (p = 0.013 and p < 0.0001, respectively), as well as at paired analysis (p = 0.015 and p = 0.045, respectively). No differences were observed between baseline and 6 months (p = 0.053 and p = 0.087, respectively). After 3 months, the mean parathyroid hormone (PTH) levels significantly increased in the whole population (p = 0.004), as well as at paired analysis; the mean PTH levels increased significantly at 3 and 6 months, respectively (p = 0.019 and p = 0.041, respectively). Changes in BTM levels were not associated with outcome. CONCLUSIONS: Cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx and showed a transient secondary increase of PTH.
Subject(s)
Anilides/pharmacology , Antineoplastic Agents/pharmacology , Biomarkers , Bone and Bones/drug effects , Bone and Bones/metabolism , Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/metabolism , Pyridines/pharmacology , Anilides/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Neoplasms/metabolism , Bone Neoplasms/secondary , Bone Remodeling/drug effects , Bone and Bones/pathology , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Disease Management , Female , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Male , Prospective Studies , Pyridines/therapeutic useABSTRACT
BACKGROUND: A great number of DNA-damage repair (DDR) pathways have been recognized to be frequently dysregulated in advanced stages of prostate cancer. DNA-repair defects in prostate cancer represents a clinically relevant disease subset. Tumors whose ability to repair double-strand DNA breaks by homologous recombination is compromised, are highly sensitive to blockade of the repair of DNA single-strand breaks via the inhibition of the enzyme poly(ADP) ribose polymerase (PARP). METHODS: A systematic review of the literature has been conducted in January 2020 using PubMed Medline database in line with the recommendations from the PRISMA guidelines. The following string terms were used for searching clinical trial articles: castration resistant OR castrate resistance OR castration refractory AND prostate cancer AND PARP OR poly(ADP-ribose) polymerase inhibitor OR DNA-repair OR homologous recombination repair. On-going clinical trials with olaparib, niraparib, talazoparib, veliparib, and rucaparib in mCRPC were searched on the clinicalTrials.gov website. RESULTS: From this research 176 articles were identified. After title screening and abstract reading, five papers and four abstract were considered for the systematic review. Thirty-two clinical trials were also identified: from these 16 trials which did not include mCRPC patients or only prostate cancer patients, trials not yet recruiting and trials including radio-metabolic treatments were excluded. Sixteen trials were included and discussed in the paper. CONCLUSIONS: Olaparib has been the first agent showing a benefit in terms of rPFS and ORR alone or in combination with abiraterone plus prednisone in patients with DDR deficiency prostate cancer. Also rucaparib showed a benefit in terms of PSA response rate and ORR in patients with BRCA2 and BRCA1 mutation in a phase-II study. Other phase-III clinical trials are evaluating niraparib and talazoparib, alone or in combination with AR signaling inhibitors.
Subject(s)
Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Prostatic Neoplasms/drug therapy , BRCA1 Protein/genetics , BRCA1 Protein/metabolism , BRCA2 Protein/genetics , BRCA2 Protein/metabolism , Clinical Trials as Topic , Humans , Male , Mutation , Neoplasm Metastasis , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Randomized Controlled Trials as Topic , Survival Rate , Treatment OutcomeABSTRACT
The frontline treatment options for patients with metastatic renal cell carcinoma (mRCC) are evolving rapidly since the approval of combination immunotherapies by the U.S. Food and Drug Administration (USFDA) and the European Medicines Agency (EMA). In particular, in combination with vascular endothelial growth factor receptor (VEGFR) tyrosine-kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs) have significantly improved the outcome of patients with mRCC compared to TKI monotherapy. Here, we review the preclinical data supporting the combination of ICIs with VEGFR TKIs. The VEGF-signaling inhibition could ideally sustain immunotherapy through a positive modulation of the tumor microenvironment (TME). Antiangiogenetics, in fact, with their inhibitory activity on myelopoiesis that indirectly reduces myeloid-derived suppressor cells (MDSCs) and regulatory T cells' (Tregs) frequency and function, could have a role in determining an effective anti-tumor immune response. These findings are relevant for the challenges posed to clinicians concerning the clinical impact on treatment strategies for mRCC.
ABSTRACT
Circulating tumor cells (CTCs) are promising biomarkers for prognosis, therapeutic response prediction, and treatment monitoring in cancer patients. Despite its epithelial origin, renal cell carcinoma (RCC) shows low expression of epithelial markers hindering CTC-enrichment approaches exploiting epithelial cell surface proteins. In 21 blood samples serially collected from 10 patients with metastatic RCC entering the TARIBO trial, we overcame this limitation using the marker-independent Parsortix™ approach for CTC-enrichment coupled with positive and negative selection with the DEPArray™ with single cell recovery and analysis for copy number alterations (CNA) by next generation sequencing NGS. Two CTC subpopulations were identified: epithelial CTC (eCTC) and non-conventional CTC (ncCTC) lacking epithelial and leukocyte markers. With a threshold ≥1CTC/10 mL of blood, the positivity rates were 28% for eCTC, 62% for ncCTCs, and 71% considering both CTC types. In two patients with detectable eCTCs at baseline, progression free survival was less than 5 months. In an index case, hierarchical structure by translational oncology (TRONCO) identified three clones among 14 CTCs collected at progression and at baseline, each containing cells with a 9p21.3loss, a well-known metastasis driving subclonal alteration. CTCs detection in RCC can be increased by marker-independent approaches, and CTC molecular characterization can allow detection of subclonal events possibly related to tumor progression.
Subject(s)
Biomarkers, Tumor , Carcinoma, Renal Cell , Chromosome Deletion , Chromosomes, Human, Pair 9/genetics , Kidney Neoplasms , Neoplastic Cells, Circulating , Single-Cell Analysis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Female , High-Throughput Nucleotide Sequencing , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplastic Cells, Circulating/metabolism , Neoplastic Cells, Circulating/pathologyABSTRACT
OBJECTIVES: stereotactic body radiation therapy (SBRT) use has increased overtime for the management of metastatic renal cell carcinoma (mRCC) patients, with a likely good control of irradiated lesions. We planned a retrospective multicenter Italian study, with the aim of investigating the outcome of treatment with SBRT for non-brain secondary lesions in mRCC patients. METHODS: all consecutive metastatic non-brain lesions from mRCC that underwent SBRT at nine Italian institutions from January 2015 to June 2017 were considered. The primary endpoint of the study was the lesion-PFS, calculated from SBRT initiation to the local progression of the irradiated lesion. RESULTS: 57 extracranial metastatic lesions from 48 patients with primary mRCC were treated with SBRT. At the median follow-up of 26.4 months, the median lesion-PFS was not reached (43 censored); 72.4% of lesions were progression-free at 40 months, with significantly better lesion-PFS for small metastatic lesions (<14â¯mm). SBRT was safe and the 1-year local disease control was 87.7%. After SBRT, 18 patients (37.5%) permanently interrupted systemic therapy. CONCLUSIONS: consistently with the previous literature, our findings support the use of SBRT in selected mRCC patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Renal Cell/therapy , Kidney Neoplasms/therapy , Radiosurgery , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/secondary , Chemoradiotherapy/methods , Chemoradiotherapy/statistics & numerical data , Female , Follow-Up Studies , Humans , Italy/epidemiology , Kidney/diagnostic imaging , Kidney/pathology , Kidney Neoplasms/diagnosis , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Male , Middle Aged , Progression-Free Survival , Retrospective Studies , Tomography, X-Ray Computed , Tumor Burden/drug effects , Tumor Burden/radiation effectsABSTRACT
BACKGROUND: In selected metastatic renal cell carcinoma (mRCC) patients, radical metastasectomy followed by observation is a potential strategy. It is still to be defined whether systemic therapy should be administered following metastasectomy. OBJECTIVE: To assess the potential benefit of postoperative treatment with sorafenib compared with observation alone after radical metastasectomy in mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: The RESORT trial was a multicenter, randomized, open-label, phase 2 study conducted between November 2012 and November 2017 in Italy. Patients with clear-cell mRCC pretreated with nephrectomy and undergoing radical metastasectomy (three or fewer lesions) were eligible for the study. Patients were randomized (1:1) within 12 wk from metastasectomy to sorafenib (standard dose 400â¯mg twice daily) or observation for a maximum of 52 wk. Stratification factors were interval from nephrectomy, site, and number of lesions. Overall, 76 patients were screened and 69 were randomized: 33 were assigned to sorafenib and 36 to observation. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival and the safety profile. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RFS curves were estimated with the Kaplan-Meier method, and the log-rank test was used to statistically compare the curves. RESULTS AND LIMITATIONS: At a median follow-up of 38 mo, median RFS was 37 mo (95% confidence interval [CI] 20-not available [NA]) in the observation arm versus 21 mo (95% CI 11-NA) in the sorafenib arm (log-rank test pâ¯=â¯0.404), with 12-, 24-, and 36-mo RFS probability of 74% versus 63%, 59% versus 49%, and 50% versus 41%, respectively, in the observation versus the sorafenib arm. Any-grade adverse event (AE) rates were 84% in the sorafenib arm and 31% in the observation arm; grade ≥3â¯AE rates were 22% and 3% in the sorafenib and the observation arm, respectively, with a rate of treatment discontinuation for AEs of 19% in the sorafenib arm. CONCLUSIONS: This prospective study showed that systemic treatment with sorafenib did not increase RFS as compared with observation in mRCC patients following radical metastasectomy. PATIENT SUMMARY: This article reports the clinical outcome of patients with metastatic renal cell carcinoma treated with sorafenib or managed with an observation-alone strategy after the radical surgery of metastases. We found that sorafenib did not improve the patient outcome in terms of relapse-free survival in this selected population.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/surgery , Metastasectomy/methods , Sorafenib/therapeutic use , Adult , Aged , Antineoplastic Agents/pharmacology , Female , Humans , Male , Middle Aged , Sorafenib/pharmacologyABSTRACT
Enzalutamide and abiraterone have been shown to improve progression-free survival (PFS) and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients. Moreover, some patients may not benefit from the inhibition of androgen receptor (AR) activity or, alternatively, may develop secondary resistance. Detection in patients' circulating tumor cells (CTCs) of ARV7, a splicing variant of AR lacking the ligand-binding domain, showed a link with treatment failure. Independent confirmation of the predictive role of CTC status combined with ARV7 detection is, therefore, a priority for extending personalized biomarker-driven treatments to all patients. In this prospective observational study, CTC status and the expression of AR and ARV7 were measured in 37 mCRPC patients, before starting treatment with enzalutamide or abiraterone, by employing commercially available kits. CTC status was positive in 21/37 patients: 46% and 24% of CTC-positive patients were defined as AR- and ARV7-positive, respectively. Kaplan-Meier estimates showed that positivity for each variable was significantly associated with poorer radiological PFS, PSA-PFS, and OS. All considered treatment outcomes worsened when going from CTC-negative to CTC-positive/ARV7-negative to CTC-positive/ARV7-positive patients, both in the global case series and in patients stratified into three groups based on basal PSA levels. Presently, technical approaches appear to be mature for introducing CTC/ARV7 tests in clinical practice.