The phase 3 trial CA184-043 evaluated radiotherapy to bone metastases followed by Ipilimumab or placebo in men with metastatic castrate-resistant prostate cancer (mCRPC) who had received docetaxel ...previously. In a prior analysis, the trial’s primary endpoint (overall survival OS) was not improved significantly.
To report the final analysis of OS.
A total of 799 patients were randomized to receive a single dose of radiotherapy to one or more bone metastases followed by either Ipilimumab (n = 399) or placebo (n = 400).
OS was analyzed in the intention-to-treat population. Prespecified and exploratory subset analyses based on Kaplan-Meier/Cox methodology were performed.
During an additional follow-up of approximately 2.4 yr since the primary analysis, 721/799 patients have died. Survival analysis showed crossing of the curves at 7–8 mo, followed by persistent separation of the curves beyond that point, favoring the ipilimumab arm. Given the lack of proportional hazards, a piecewise hazard model showed that the hazard ratio (HR) changed over time: the HR was 1.49 (95% confidence interval 1.12, 1.99) for 0–5 mo, 0.66 (0.51, 0.86) for 5–12 mo, and 0.66 (0.52, 0.84) beyond 12 mo. OS rates were higher in the ipilimumab versus placebo arms at 2 yr (25.2% vs 16.6%), 3 yr (15.3% vs 7.9%), 4 yr (10.1% vs 3.3%), and 5 yr (7.9% vs. 2.7%). Disease progression was the most frequent cause of death in both arms. In seven patients (1.8%) in the ipilimumab arm and one (0.3%) in the placebo arm, the primary cause of death was reported as study drug toxicity. No long-term safety signals were identified.
In this preplanned long-term analysis, OS favored ipilimumab plus radiotherapy versus placebo plus radiotherapy for patients with postdocetaxel mCRPC. OS rates at 3, 4, and 5 yr were approximately two to three times higher in the ipilimumab arm.
After longer follow-up, survival favored the group of men who received ipilimumab, with overall survival rates being two to three times higher at 3 yr and beyond.
In this preplanned long-term analysis, overall survival favored ipilimumab plus radiotherapy versus placebo plus radiotherapy for patients with postdocetaxel metastatic castrate-resistant prostate cancer. Beyond approximately 2 yr of follow-up, long-term survivors were two to three times more prevalent in the ipilimumab arm.
An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to ...progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival.
We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods.
A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval CI, 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87).
This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.).
Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with ...chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.
Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the ...anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane.
In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436.
Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 58% of 289), anaemia (156 54%), and vomiting (111 38%); the most common grade 3 or worse events were haematological (anaemia in 95 33% of 289; thrombocytopenia in 47 16%; and neutropenia in 28 10%). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 6% and anaemia in 13 4%). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment.
Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations.
Janssen Research & Development.
Summary Background No targeted therapies are available for KRAS -mutant non-small-cell lung cancer (NSCLC). Selumetinib is an inhibitor of MEK1/MEK2, downstream of KRAS, with preclinical evidence of ...synergistic activity with docetaxel in KRAS -mutant cancers. We did a prospective, randomised, phase 2 trial to assess selumetinib plus docetaxel in previously treated patients with advanced KRAS -mutant NSCLC. Methods Eligible patients were older than 18 years of age; had histologically or cytologically confirmed stage IIIB–IV KRAS -mutant NSCLC; had failed first-line therapy for advanced NSCLC; had WHO performance status of 0–1; had not received previous therapy with either a MEK inhibitor or docetaxel; and had adequate bone marrow, renal, and liver function. Patients were randomly assigned (in a 1:1 ratio) to either oral selumetinib (75 mg twice daily in a 21 day cycle) or placebo; all patients received intravenous docetaxel (75 mg/m2 on day 1 of a 21 day cycle). Randomisation was done with an interactive voice response system and investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival, analysed for all patients with confirmed KRAS mutations. This study is registered with ClinicalTrials.gov , number NCT00890825. Findings Between April 20, 2009, and June 30, 2010, we randomly assigned 44 patients to receive selumetinib and docetaxel (selumetinib group) and 43 to receive placebo and docetaxel (placebo group). Of these, one patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their tumours were not confirmed to be KRAS -mutation positive. Median overall survival was 9·4 months (6·8–13·6) in the selumetinib group and 5·2 months (95% CI 3·8–non-calculable) in the placebo group (hazard ratio HR for death 0·80, 80% CI 0·56–1·14; one-sided p=0·21). Median progression-free survival was 5·3 months (4·6–6·4) in the selumetinib group and 2·1 months (95% CI 1·4–3·7) in the placebo group (HR for progression 0·58, 80% CI 0·42–0·79; one-sided p=0·014). 16 (37%) patients in the selumetinib group and none in the placebo group had an objective response (p<0·0001). Adverse events of grade 3 or higher occurred in 36 (82%) patients in the selumetinib group and 28 (67%) patients in the placebo group. The most common grade 3–4 adverse events were neutropenia (29 67% of 43 patients in the selumetinib group vs 23 55% of 42 patients in the placebo group), febrile neutropenia (eight 18% of 44 patients in the selumetinib group vs none in the placebo group), dyspnoea (one 2% of 44 patients in the selumetinib group vs five 12% of 42 in the placebo group), and asthenia (four 9% of 44 patients in the selumetinib group vs none in the placebo group). Interpretation Selumetinib plus docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone, in previously treated advanced KRAS -mutant NSCLC. These findings warrant further clinical investigation of selumetinib plus docetaxel in KRAS -mutant NSCLC. Funding AstraZeneca.
Summary Background Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after ...radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. Methods We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT00861614. Findings From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5–12·7) with ipilimumab and 10·0 months (8·3–11·0) with placebo (hazard ratio HR 0·85, 0·72–1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0–5 months was 1·46 (95% CI 1·10–1·95), for 5–12 months was 0·65 (0·50–0·85), and beyond 12 months was 0·60 (0·43–0·86). The most common grade 3–4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3–4 adverse events included diarrhoea (64 16% of 393 patients in the ipilimumab group vs seven 2% of 396 in the placebo group), fatigue (40 11% vs 35 9%), anaemia (40 10% vs 43 11%), and colitis (18 5% vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. Interpretation Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. Funding Bristol-Myers Squibb.
To compare single-agent pemetrexed (P) versus the combination of carboplatin and pemetrexed (CP) in first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) with an Eastern ...Cooperative Oncology Group (ECOG) performance status (PS) of 2.
In a multicenter phase III randomized trial, patients with advanced NSCLC, ECOG PS of 2, any histology at first and later amended to nonsquamous only, no prior chemotherapy, and adequate organ function were randomly assigned to P alone (500 mg/m(2)) or CP (area under the curve of 5 and 500 mg/m(2), respectively) administered every 3 weeks for a total of four cycles. The primary end point was overall survival (OS).
A total of 205 eligible patients were enrolled from eight centers in Brazil and one in the United States from April 2008 to July 2011. The response rates were 10.3% for P and 23.8% for CP (P = .032). In the intent-to-treat population, the median PFS was 2.8 months for P and 5.8 months for CP (hazard ratio HR, 0.46; 95% CI, 0.35 to 0.63; P < .001), and the median OS was 5.3 months for P and 9.3 months for CP (HR, 0.62; 95% CI, 0.46 to 0.83; P = .001). One-year survival rates were 21.9% and 40.1%, respectively. Similar results were seen when patients with squamous disease were excluded from the analysis. Anemia (grade 3, 3.9%; grade 4, 11.7%) and neutropenia (grade 3, 1%; grade 4, 6.8%) were more frequent with CP. There were four treatment-related deaths in the CP arm.
Combination chemotherapy with CP significantly improves survival in patients with advanced NSCLC and ECOG PS of 2.
Summary Background Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, ...we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas. Methods We did this multinational, randomised, double-blind, placebo-controlled phase 3 study at 44 centres in ten countries. Patients aged 18 years and older with metastatic soft-tissue sarcomas, an Eastern Cooperative Oncology Group performance status of 0–2, and who had previously received treatment with anthracycline and ifosfamide were randomly assigned (1:1) to intravenous infusion of ombrabulin 25 mg/m2 plus cisplatin 75 mg/m2 or intravenous infusion of placebo plus cisplatin 75 mg/m2 every 3 weeks. Patients were allocated to treatment using a permuted blocks randomisation scheme (block size of four) via an interactive voice-response system, and stratified by histological subtype. Patients, medical staff, study investigators, and individuals who handled and analysed the data were masked to treatment assignment. Our primary endpoint was median progression-free survival in the intention-to-treat population. Safety analyses were done on all randomised patients who received at least one dose of study drug. This trial is now closed, and is registered with ClinicalTrials.gov , number NCT00699517. Findings Between June 13, 2008, and April 26, 2012, we randomly assigned 355 patients to ombrabulin plus cisplatin (n=176) or placebo plus cisplatin (n=179). Median duration of follow-up was 27·9 (IQR 20·9–33·2) in the placebo group and 30·5 months (20·7–37·6) in the ombrabulin group. Progression-free survival was slightly, but significantly, improved in the ombrabulin group compared with the placebo group (median 1·54 months 95% CI 1·45–2·69 vs 1·41 1·38–1·58 months; hazard ratio 0·76 95% CI 0·59–0·98; p=0·0302). Grade 3 or 4 adverse events occurred more frequently in individuals in the ombrabulin group than in those in the placebo group and included neutropenia (34 19% in the ombrabulin group vs 14 8% in the placebo group) and thrombocytopenia (15 8% vs six 3% for placebo). Adverse events leading to death occurred in 18 patients in the ombrabulin group and 10 patients in the placebo group. Interpretation The combination of ombrabulin and cisplatin significantly improved progression-free survival; however, it did not show a sufficient clinical benefit in patients with advanced soft-tissue sarcomas to support its use as a therapeutic option. Predictive biomarkers are needed for the rational clinical development of tumour vascular-disrupting drugs for soft-tissue sarcomas. Funding Sanofi.
Background:
This analysis evaluated patient-reported outcomes (PROs) to assess health-related quality of life (HRQoL) in the phase III MONALEESA-7 trial, which previously demonstrated improvements in ...progression-free survival (PFS) and overall survival (OS) with ribociclib (cyclin-dependent kinase 4/6 inhibitor) + endocrine therapy (ET) compared with placebo + ET in pre- and perimenopausal patients with hormone-receptor-positive, HER2-negative (HR+/HER2−) advanced breast cancer (ABC).
Methods:
The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire C30 (QLQ-C30) and the EQ-5D-5L were used to evaluate HRQoL.
Results:
EORTC QLQ-C30 assessments were evaluable for 335 patients in the ribociclib arm and 337 patients in the placebo arm. Adherence rates at baseline and ⩾1 postbaseline time point were 90% and 83%, respectively. Patients treated with ribociclib + ET had a longer time to deterioration (TTD) ⩾ 10% in global HRQoL {hazard ratio (HR), 0.67 95% confidence interval (CI), 0.52–0.86}. TTD ⩾ 10% in global HRQoL was delayed in ribociclib-treated patients without versus with disease progression HR, 0.31 (95% CI, 0.21–0.48). TTD ⩾ 10% in pain was longer with ribociclib + ET than with placebo + ET HR, 0.65 (95% CI, 0.45–0.92). Patients who received a nonsteroidal aromatase inhibitor experienced similar benefits with ribociclib versus placebo in global HRQoL and pain.
Conclusion:
HRQoL was maintained longer in patients who received ribociclib + ET versus placebo + ET. These data, combined with previously reported improvements in PFS and OS, support a strong clinical benefit-to-risk ratio with ribociclib-based treatment in pre- and perimenopausal patients with HR+/HER2− ABC.
Androgen deprivation therapy (ADT) combined with apalutamide, abiraterone acetate plus prednisone, enzalutamide, or docetaxel are the standard treatments for advanced castration-sensitive prostate ...cancer (CSPC). We investigated ADT-free alternatives for advanced CSPC.
LACOG 0415 is a phase 2, open-label, non-comparative, randomized trial. Patients with advanced CSPC were randomized (1:1:1) to receive goserelin plus abiraterone acetate and prednisone (ADT plus AAP arm), apalutamide (APA arm), or apalutamide plus abiraterone acetate and prednisone (APA plus AAP arm). The primary endpoint was the proportion of patients with PSA of ≤0.2 ng/mL at week 25 in the modified intention-to-treat population. Safety analyses were performed in all patients with at least one dose of the study drug.
Of 128 randomized patients, 120 patients were evaluable for PSA response at week 25; 17.2% had a high-risk biochemical recurrence, 8.6% had locally advanced disease, and 74.2% had distant metastases. At week 25, PSA of ≤0.2 ng/mL was observed in 75.6% (95%CI 59.7%–87.6%), 60.0% (95%CI 43.3%–75.1%), and 79.5% (95%CI 63.5%–90.7%) of patients in ADT plus AAP, APA, and APA plus AAP arms, respectively. PSA decline of ≥80% was observed in 100%, 90.0%, and 97.4%, respectively. Grade 3–4 AEs were observed in 31.0%, 21.4% and 36.4%, respectively. Testosterone levels increased significantly in the APA arm and decreased significantly in ADT plus AAP and APA plus AAP arms.
ADT-free alternatives provide a high PSA response in advanced CSPC, although the APA arm did not reach the expected rate of PSA of ≤0.2 ng/mL at week 25. These results warrant further investigation of ADT-free treatments as alternatives in advanced CSPC.
ClinicalTrials.govNCT02867020.
•ADT-free alternatives provide high PSA response in advanced CSPC.•Although the APA arm did not reach the expected rate of PSA of ≤0.2 ng/mL at week 25.•The three arms had a distinct toxicity profile and similar HRQoL.
PDF
