Up to 30% of patients with metastatic castration-resistant prostate cancer have deleterious mutations in genes involved in homologous recombination repair of DNA damage. The use of the PARP inhibitor ...olaparib in such patients was associated with longer progression-free survival and a longer time to pain progression than control therapy.
Among patients with metastatic breast cancer and a germline
BRCA
mutation, daily treatment with the PARP inhibitor olaparib was associated with longer progression-free survival than standard ...single-agent chemotherapy.
Summary Background Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of ...skeletal-related events in men with bone metastases from castration-resistant prostate cancer. Methods In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00321620 , and has been completed. Findings 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9–18·5) for patients on denosumab and 11·2 months (IQR 5·6–17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8–24·9) with denosumab compared with 17·1 months (15·0–19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71–0·95; p=0·0002 for non-inferiority; p=0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 13%) than in the zoledronic acid group (55 6%; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 2% vs 12 1%; p=0·09). Interpretation Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. Funding Amgen.
Denosumab, an anti-RANK ligand monoclonal antibody, significantly increases bone metastasis-free survival (BMFS; hazard ratio HR, 0.85; P = .028) and delays time to first bone metastasis in men with ...nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months.
A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died.
In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets.
Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.
Abstract The clinical sequelae from bone metastases, termed skeletal-related events, are among the most frequent and debilitating complications in patients with advanced cancer. Bone metastases are ...characterized by pathologically increased osteoclast activity, and accumulating evidence indicates that tumor cells interact within the bone to stimulate the RANK-RANK ligand (RANKL) pathway. RANKL is an essential mediator of osteoclast formation, function, and survival. Because of the central role of RANKL in cancer-induced bone destruction, the inhibition of RANKL has the potential to result in the reduction of pathologic bone resorption. Denosumab is a fully human monoclonal antibody specific for RANKL that inhibits the formation, activation, and survival of osteoclasts. This in turn decreases bone resorption and reduces cancer-induced bone destruction. As a result of its unique and specific mechanism of action, denosumab is being investigated for use in patients with advanced malignancies involving bone to prevent the occurrence of skeletal-related events.
Summary Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We ...assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. Methods In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen PSA ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov , number NCT00286091. Findings 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 95% CI 25·4–33·3 vs 25·2 22·2–29·5 months; hazard ratio HR 0·85, 95% CI 0·73–0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 95% CI 29·5–38·0 vs 29·5 22·4–33·1 months; HR 0·84, 95% CI 0·71–0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 95% CI 40·1–not estimable months vs placebo, 44·8 40·1–not estimable months; HR 1·01, 95% CI 0·85–1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo. Interpretation This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. Funding Amgen Inc.
To characterize changes in lean body mass (LBM) in men with prostate cancer receiving androgen-deprivation therapy (ADT).
We prospectively evaluated LBM in a prespecified substudy of a randomized ...controlled trial of denosumab to prevent fractures in men receiving ADT for nonmetastatic prostate cancer. LBM was measured by total-body dual-energy x-ray absorptiometry at study baseline and at 12, 24, and 36 months. The analyses included 252 patients (132, denosumab; 120, placebo) with a baseline and at least one on-study LBM assessment. Patients were stratified by age (< 70 v ≥ 70 years) and by ADT duration (≤ 6 v > 6 months).
Median ADT duration was 20.4 months at study baseline. Mean LBM decreased significantly from baseline, by 1.0% at month 12 (95% CI, 0.4% to 1.5%; P < .001; n = 248), by 2.1% at month 24 (95% CI, 1.5% to 2.7%; P < .001; n = 205), and by 2.4% at month 36 (95% CI, 1.6% to 3.2%; P < .001; n = 168). Men age ≥ 70 years (n = 127) had significantly greater changes in LBM at all measured time points than younger men. At 36 months, LBM decreased by 2.8% in men age ≥ 70 years and by 0.9% in younger men (P = .035). Men with ≤ 6 months of ADT at study entry (n = 36) had a greater rate of decrease in LBM compared with men who had received more than 6 months of ADT at study entry (3.7% v 2.0%; P = .0645).
In men receiving ADT, LBM decreased significantly after 12, 24, and 36 months.
To investigate the efficacy and safety of zoledronic acid for the treatment of bone metastases from breast cancer.
Women with bone metastases (N = 228) were randomly assigned to receive 4 mg ...zoledronic acid (n = 114) or placebo (n = 114) via 15-minute infusions every 4 weeks for 1 year. The primary efficacy end point was the skeletal-related event (SRE) rate ratio between treatment groups. An SRE was defined as pathologic fracture, spinal cord compression, and radiation or surgery to bone. Secondary end points included percentage of patients with at least one SRE, time-to-first SRE, and Andersen-Gill multiple-event analysis.
The SRE rate ratio at 1 year (excluding HCM and adjusted for prior fracture) was 0.61 (permutation test; P = .027), indicating that zoledronic acid reduced the rate of SRE by 39% compared with placebo. The percentage of patients with at least one SRE (excluding HCM) was significantly reduced by 20% by zoledronic acid (29.8% v 49.6% for placebo; P = .003). Zoledronic acid significantly delayed time-to-first SRE (median not reached v 364 days; Cox regression; P = .007) and reduced the risk of SREs by 41% in multiple event analysis (risk ratio = 0.59; P = .019) compared with placebo. Zoledronic acid was well tolerated with a safety profile similar to placebo. No patient treated with zoledronic acid had grade 3 or 4 serum creatinine increase.
Zoledronic acid significantly reduced skeletal complications compared with placebo across multiple end points in Japanese women with bone metastases from breast cancer.
The OlympiAD Phase III study (NCT02000622) established the clinical benefits of olaparib tablet monotherapy (300 mg twice daily) over chemotherapy treatment of physician's choice (TPC) in patients ...with a germline BRCA1/2 mutation (gBRCAm) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who had received ≤2 chemotherapy lines in the metastatic setting. Here, we report pre-specified analyses of data from Asian (China, Japan, Korea and Taiwan) patients in the study. All patients were randomized 2:1 to olaparib tablets (300 mg twice daily) or single-agent chemotherapy TPC (21-day cycles of either capecitabine, eribulin or vinorelbine). The primary endpoint was progression-free survival assessed by blinded independent central review. The prevalence of gBRCAm in the OlympiAD Asian subgroup screened for study recruitment was 13.5%. Patient demographics and disease characteristics of the Asian subgroup (87/302 patients) were generally well balanced between treatment arms. Asian patients in the olaparib arm achieved longer median progression-free survival, assessed by blinded independent central review, versus the chemotherapy TPC arm (5.7 vs 4.2 months; HR = 0.53 95% CI: 0.29-0.97), which was consistent with findings in the global OlympiAD study population. Findings on secondary efficacy and safety/tolerability outcome measures in Asian patients were also similar to those observed in the global OlympiAD study population. The OlympiAD study was not powered to detect race-related differences between treatment groups; however, the consistency of our findings with the global OlympiAD study population suggests that previously reported findings are generalizable to Asian patients.
To describe the natural history of nonmetastatic prostate cancer and rising prostate-specific antigen (PSA) despite androgen deprivation therapy.
The 201 patients in this report were the placebo ...control group from an aborted randomized controlled trial to evaluate the effects of zoledronic acid on time to first bone metastasis in men with prostate cancer, no bone metastases, and rising PSA despite androgen deprivation therapy. Relationships between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were baseline PSA, Gleason sum, history of bilateral orchiectomies, regional lymph node metastases at diagnosis, prior prostatectomy, time from androgen deprivation therapy to random assignment, time from diagnosis to random assignment, and PSA velocity.
At 2 years, 33% of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastases and overall survival were not reached. Baseline PSA level greater than 10 ng/mL (relative risk, 3.18; 95% CI, 1.74 to 5.80; P < .001) and PSA velocity (4.34 for each 0.01 increase in PSA velocity; 95% CI, 2.30 to 8.21; P < .001) independently predicted shorter time to first bone metastasis. Baseline PSA and PSA velocity also independently predicted overall survival and metastasis-free survival. Other covariates did not consistently predict clinical outcomes.
Men with nonmetastatic prostate cancer and rising PSA despite androgen deprivation therapy have a relatively indolent natural history. Baseline PSA and PSA velocity independently predict time to first bone metastasis and survival.
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