Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor ...activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population.
The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1-positive and PD-L1-negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety.
Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. Median duration of response was not reached (range, 1.9 to ≥ 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%.
Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging.
A randomized trial involving patients with metastatic prostate cancer whose disease progressed after receipt of docetaxel and hormonal therapy showed that cabazitaxel was superior to an ...androgen-signaling–targeted agent in extending imaging-based progression-free survival, overall survival, and PSA response.
Androgen deprivation therapy (ADT) has long been the gold standard for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Clinical trials have demonstrated significant survival ...benefits when docetaxel (DOC) or abiraterone acetate (AA) and prednisone (P) are added to ADT, necessitating comparison of these combination treatments.
A systematic review of randomised controlled trials (RCTs) of AA-/ADT-/DOC-containing treatment regimens in newly diagnosed patients with high-risk and/or high-volume mHSPC identified three RCTs (LATITUDE, CHAARTED and GETUG-AFU 15). Network meta-analyses (NMAs) using fixed effects Bayesian methods were performed to compare relative benefits of each treatment on overall survival (OS), radiographic progression-free survival (rPFS) and quality of life (QoL) measured by the Brief Pain Inventory, and the Functional Assessment of Cancer Therapy-Prostate questionnaire. One trial, STAMPEDE, was assessed in exploratory OS analyses.
The hazard ratio (HR) for OS ranged from 0.85 to 0.92, with the Bayesian probability of AA + P + ADT being better than DOC + ADT ranging between 72% and 87%. For rPFS, the HR ranged between 0.71 and 0.76 (Bayesian probability range: 93%–97%). Exploratory analyses including STAMPEDE found similar trends. AA + P + ADT also showed improved QoL compared with DOC + ADT for at least 1 year of therapy, with results being more pronounced at 3 months.
Our findings suggest that AA + P + ADT is at least as effective as DOC + ADT in reducing the risk of death in men with mHSPC and better at preventing disease progression and improving QoL. The NMA provides useful insights to clinicians and other decision-makers on the relative efficacy of treatment options for men with mHSPC.
•Abiraterone, prednisone and androgen deprivation therapy (AA + P + ADT) is at least as effective as docetaxel (DOC)+ADT in reducing the risk of death in patients with metastatic hormone-sensitive prostate cancer (mHSPC).•AA + P + ADT is associated with a lower risk of progression compared with DOC + ADT in mHSPC.•AA + P + ADT is associated with an improved QoL compared with DOC + ADT in mHSPC.•AA + P + ADT is an appropriate option for clinicians treating men with mHSPC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate ...cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC.
Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments.
A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post-random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively).
Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes.
Summary Background Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense ...oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. Methods SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m2 intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov , number NCT01188187 . The trial is completed and final analyses are reported here. Findings Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months 95% CI 20·9–24·8 with docetaxel, prednisone, and custirsen vs 22·0 months 19·5–24·0 with docetaxel and prednisone; hazard ratio HR 0·93, 95% CI 0·79–1·10; p=0·415). The most common adverse events of grade 3 or worse in the docetaxel, prednisone and custirsen group (n=501) compared with the docetaxel and prednisone alone group (n=499) were neutropenia (grade 3, 63 13% vs 28 6%; grade 4, 98 20% vs 77 15%), febrile neutropenia (grade 3, 52 10% vs 31 6%; grade 4, four 1% vs two <1%), and fatigue (grade 3, 53 11% vs 41 8%; grade 4, three 1% vs one <1%). One or more serious adverse events were reported for 214 (43%) of 501 patients treated with docetaxel, prednisone, and custirsen and 181 (36%) of 499 receiving docetaxel and prednisone alone. Adverse events were attributable to 23 (5%) deaths in the docetaxel, prednisone, and custirsen group and 24 (5%) deaths in the docetaxel and prednisone alone group. Interpretation Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone. Funding OncoGenex Technologies.
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Background
Metastatic prostate cancer has a 30% 5-year survival rate despite recent therapeutic advances. There is a need to improve the clinical understanding and treatment of this disease, ...particularly in the real-world setting and among patients who are under-represented in clinical trials.
Objective
We aimed to evaluate the characteristics and clinical outcomes of patients who received their first treatment for metastatic castration-resistant prostate cancer (mCRPC) in routine clinical practice, independent of treatment used, including subgroups with baseline cardiac disease, diabetes mellitus, or visceral metastases.
Patients and methods
Prospective, noninterventional analysis of patient record data in the multicenter Prostate Cancer Registry (PCR) of men with mCRPC. The data were collected in 16 countries with the aim of recruiting more than 3000 patients between 2013 and 2016. The study end date was 9 July 2018. Data evaluated included baseline characteristics, treatment exposure, and efficacy outcomes overall survival (OS) and time to progression (TTP) of patients treated with abiraterone acetate plus prednisone or prednisolone (collectively, “abiraterone”), enzalutamide, or docetaxel. Descriptive outcomes are reported from the overall patient population and subgroups of patients with baseline cardiovascular disease, diabetes mellitus, or visceral metastases. The treatment effects for time to progression were compared for the overall patient population.
Results
The study enrollment period lasted 2.5 years, and each patient was followed for a maximum of 3 years. A total of 1874 patients in the PCR had not received previous mCRPC treatment at baseline, although they had received androgen-deprivation therapy. Prevalent co-morbidities included cardiovascular disease in 65.4% and diabetes mellitus in 17.4% of patients. Baseline characteristics suggested that patients with more advanced disease received docetaxel treatment. In the overall patient population, the median time to progression with abiraterone, enzalutamide, and docetaxel as first-line mCRPC therapy was 9.6, 10.3, and 7.6 months, respectively, and median OS was 27.1, 27.1, and 27.9 months, respectively. Outcomes in the subgroups of patients with cardiovascular disease or diabetes mellitus were similar to those of the whole population in the analysis. As expected, patients with visceral metastases had shorter TTP and OS than patients in the overall population.
Conclusions
This analysis shows, for the first time, the effectiveness in parallel of first-line abiraterone, enzalutamide, and docetaxel in mCRPC, including in patients with co-morbidities such as cardiovascular disease or diabetes mellitus or in patients with visceral metastases. These real-world findings from the PCR provide meaningful information to help manage mCRPC, particularly in patients under-represented in clinical studies.
Trial Registration
ClinicalTrials.gov identifier NCT02236637; registered September 2014.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Residual androgen production causes tumor progression in metastatic, castration-resistant prostate cancer (mCRPC) patients. Abiraterone acetate (AA), a prodrug of abiraterone, is an oral CYP-17 ...inhibitor that blocks androgen production. It was hypothesized that adherence-enhancing measures (AEM) might be beneficial for mCRPC patients receiving abiraterone acetate plus prednisone (AA + P). This multicenter, prospective, 2-arm trial allocated mCRPC patients who were progressive after docetaxel-based chemotherapy or asymptomatic/mildly symptomatic after failure of an androgen deprivation therapy to Arm A (with AEM) or Arm B (without AEM) by center-based cluster-randomization. The primary objective was to assess the influence of AEM on discontinuation rates and medication adherence in mCRPC patients treated with AA + P. A total of 360 patients were allocated to Arm A, and 315 patients to Arm B. At month 3, the rate of treatment discontinuation, not due to disease progression or the start of new cancer therapy, was low in both arms (A: 9.0% vs. B: 7.3%, OR = 1.230). Few patients had a medium/low Morisky Medication Adherence Scale (MMAS-4) score (A: 6.4% vs. B: 9.1%, OR = 0.685). The results obtained did not suggest any clear adherence difference between Arm A and Arm B. In patients with mCRPC taking AA + P medication, adherence seemed to be generally high.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose In prostate cancer cases the early diagnosis of tumors carrying a high risk of progression is of the utmost importance. There is an urgent clinical need to avoid unnecessary biopsies and ...subsequent overtreatment. We validated annexin A3 as a diagnostic marker for prostatic disease in typical clinical populations and relevant segments, such as patients with a negative digital rectal examination and low prostate specific antigen. Materials and Methods We performed a blinded clinical study ( ClinicalTrials.gov Identifier NCT00400894 ) from September 2005 to January 2007 in 591 patients who were continuously recruited from 4 European urological clinics. Urine was obtained directly after digital rectal examination and the annexin A3 concentration in urine was quantified by Western blot. Statistical analysis included combinations of annexin A3 with total, percent free, complexed and percent complexed prostate specific antigen. Results Combined readouts of prostate specific antigen and urinary annexin A3 were superior to all others with an area under the ROC curve of 0.82 for a total prostate specific antigen range of 2 to 6 ng/ml, 0.83 for a total prostate specific antigen range of 4 to 10 ng/ml and 0.81 in all patients. The best performing prostate specific antigen derivative was percent free prostate specific antigen with an area under the ROC curve of 0.68 for a total prostate specific antigen range of 2 to 6 ng/ml, 0.72 for a total prostate specific antigen range of 4 to 10 ng/ml and 0.73 in all patients. Annexin A3 has an inverse relationship to cancer and, therefore, its specificity was much better than that of prostate specific antigen. Conclusions Annexin A3 quantification in urine provides a novel noninvasive biomarker with high specificity. Annexin A3 is complementary to prostate specific antigen or to any other cancer marker. It has a huge potential to avoid unnecessary biopsies with a particular strength in the clinically relevant large group of patients who have a negative digital rectal examination and prostate specific antigen in the lower range of values (2 to 10 ng/ml).
In the interim analyses of the LATITUDE study, the addition of abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) led to a significant improvement in overall survival and ...radiographic progression-free survival compared with placebos plus ADT in men with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (mCSPC). Here, we present long-term survival outcomes and safety of abiraterone acetate plus prednisone and ADT from the final analysis of the LATITUDE study.
This is a multicentre, randomised, double-blind, phase 3 trial done at 235 sites in 34 countries. Eligible patients (men aged ≥18 years) had newly diagnosed, histologically or cytologically confirmed prostate cancer with metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and at least two of the three high-risk prognostic factors (Gleason score of ≥8, presence of three or more lesions on bone scan, or presence of measurable visceral metastasis except lymph node metastasis). Patients were randomly assigned (1:1) to receive abiraterone acetate (1000 mg) once daily orally plus prednisone (5 mg) once daily orally and ADT (abiraterone acetate plus prednisone group) or matching placebos plus ADT (placebo group); each treatment cycle was 28 days. Randomisation was done by a centralised interactive web response system in a country-by-country scheme using permuted block randomisation, stratified by presence of visceral disease and ECOG performance status. The coprimary endpoint of overall survival was assessed in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT01715285 and is complete.
Between Feb 12, 2013, and Dec 11, 2014, 1209 patients were screened, of whom ten were ineligible because of study site violations. 1199 patients were randomly assigned to either the abiraterone acetate plus prednisone group (n=597) or placebo group (n=602). After the results of the first interim analysis (cutoff date Oct 31, 2016), the study was unmasked to patients and investigators, and patients in the placebo group were allowed to cross over to receive abiraterone acetate and prednisone plus ADT treatment as per a protocol amendment (Feb 15, 2017) in an open-label extension phase of the study (up to 18 months from the protocol amendment). This final analysis (data cutoff Aug 15, 2018) was done after a median follow-up of 51·8 months (IQR 47·2–57·0) and 618 deaths (275 46% of 597 in the abiraterone acetate plus prednisone group and 343 57% of 602 in the placebo group). Overall survival was significantly longer in the abiraterone acetate plus prednisone group (median 53·3 months 95% CI 48·2–not reached) than in the placebo group (36·5 months 33·5–40·0), with a hazard ratio of 0·66 (95% CI 0·56–0·78; p<0·0001). The most common grade 3–4 adverse events were hypertension (125 21% in the abiraterone acetate plus prednisone group vs 60 10% in the placebo group vs three 4% in the 72 patients who crossed over from placebo to abiraterone acetate plus prednisone) and hypokalaemia (70 12% vs ten 2% vs two 3%). Serious adverse events of any grade occurred in 192 (32%) of 597 patients in the abiraterone acetate plus prednisone group, 151 (25%) of 602 in the placebo group, and four (6%) of 72 in the crossover group. The most common treatment-related serious adverse event was hypokalaemia (four 1% patients in the abiraterone acetate plus prednisone group and none in the other groups). Treatment-related deaths occurred in three (<1%) patients each in the abiraterone acetate plus prednisone group (gastric ulcer perforation, sudden death, and cerebrovascular accident) and the placebo group (sudden death, cerebrovascular accident, and pneumonia), with none in the crossover group.
The combination of abiraterone acetate plus prednisone with ADT was associated with significantly longer overall survival than placebos plus ADT in men with newly diagnosed high-risk mCSPC and had a manageable safety profile. These findings support the use of abiraterone acetate plus prednisone as a standard of care in patients with high-risk mCSPC.
Janssen Research & Development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The addition of abiraterone, a drug that blocks endogenous androgen synthesis, to standard androgen-deprivation therapy in patients with newly diagnosed, metastatic prostate cancer significantly ...increased overall survival, with a low rate of adverse effects.
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