Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer.

BACKGROUND: Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown. METHODS: In this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg [two 300-mg tablets] twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival. RESULTS: The primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively). CONCLUSIONS: In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, NCT02799602.).

Pazopanib after sunitinib failure in patients with metastatic renal cell carcinoma.

BACKGROUND: Sunitinib is a standard agent for the treatment of metastatic renal cell carcinoma (mRCC). The objective of the study was to evaluate efficacy and safety of pazopanib in the treatment of patients whose mRCC either progressed on sunitinib or who discontinued sunitinib due to adverse effects. MATERIAL AND METHODS: Thirty-one consecutive mRCC patients who received pazopanib after sunitinib failure were included in this retrospective single center study. Pazopanib was continued until disease progression or intolerance. Treatment response was evaluated every 8-12 weeks according to the RECIST criteria. Adverse events were recorded according to the Common Terminology Criteria for Adverse Events. RESULTS: Six patients (19%, 95% CI 12-26%) achieved partial response with pazopanib, 18 (58%) had stable disease, and seven (23%) progressive disease as their best response. Of the 14 patients who received pazopanib as their second-line therapy, six (43%) responded as compared with no responses among 17 patients treated in a later line (p = 0.004). The median progression-free survival time was 7.4 months after starting pazopanib (range, 0.9-15.6 months). Patients who received pazopanib as second-line treatment had median progression-free survival of 11.0 months as compared with 3.8 months among those who received pazopanib in a later line (p = 0.031). Only one (3%) patient discontinued pazopanib due to an adverse event. The most commonly recorded adverse events were anemia, thrombocytopenia, diarrhea, fatigue, and elevation of serum creatinine concentration. Six (19%) patients had one or more grade 3 or 4 adverse events recorded. CONCLUSION: Pazopanib has clinical activity in mRCC as second-line agent after sunitinib failure suggesting lack of complete cross-resistance. Pazopanib was associated with acceptable toxicity, and may be considered as an option after sunitinib failure.

Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer.

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.)

Radium-223 dichloride treatment in metastatic castration-resistant prostate cancer in Finland: A real-world evidence multicenter study.

BACKGROUND: Radium-233 dichloride is an alpha emitter that specifically targets bone metastases in prostate cancer. Results of a previously reported phase III randomized trial showed survival benefit for radium-223 compared to best supportive care in castration-resistant prostate cancer (CRPC) with bone metastases. However, real-world data are also needed with wider inclusion criteria. METHODS: We report results of a retrospective multicenter study including all patients with metastatic CRPC treated with radium-223 in all five university hospitals in Finland since the introduction of the treatment. We identified 160 patients who had received radium-223 in Finland in 2014-2019. RESULTS: The median overall survival (OS) was 13.8 months (range 0.5-57 months), and the median real-world progression-free survival (rwPFS) was 4.9 months (range 0.5-29.8 months). Alkaline phosphatase (ALP) values within the normal range before and during the radium-223 treatment or the reduction of elevated ALP to normal range during treatment were associated with better OS when compared to elevated ALP values before and during treatment (p < 0.0001). High prostate-specific antigen (PSA) level (≥100 µg/L) before radium-223 treatment was associated with poor OS compared to low PSA level (<20 µg/L) (p = 0.0001). Most patients (57%) experienced pain relief. Pain relief indicated better OS (p = 0.002). Radium-223 treatment was well tolerated. Toxicity was mostly low grade. Only 12.5% of the patients had grade III-IV adverse events, most commonly anemia, neutropenia, leucopenia, and thrombocytopenia. CONCLUSION: Radium-223 was well tolerated in routine clinical practice, and most patients achieved pain relief. Pain relief, ALP normalization, lower baseline PSA, and PSA decrease during radium-223 treatment were prognostic for better survival. The efficacy of radium-223 in mCRPC as estimated using OS was comparable to earlier randomized trial in this retrospective real-world study. Our results support using radium-223 for mCRPC patients with symptomatic bone metastases even in the era of new-generation androgen receptor-targeted agents.

First-in-Class Small Molecule to Inhibit CYP11A1 and Steroid Hormone Biosynthesis.

Binding of steroid hormones to their cognate receptors regulates the growth of most prostate and breast cancers. We hypothesized that CYP11A inhibition might halt the synthesis of all steroid hormones, because CYP11A is the only enzyme that catalyses the first step of steroid hormone biosynthesis. We speculated that a CYP11A inhibitor could be administered safely provided that the steroids essential for life are replaced. Virtual screening and systematic structure-activity relationship optimization were used to develop ODM-208, the first-in-class, selective, nonsteroidal, oral CYP11A1 inhibitor. Safety of ODM-208 was assessed in rats and Beagle dogs, and efficacy in a VCaP castration-resistant prostate cancer (CRPC) xenograft mouse model, in mice and dogs, and in six patients with metastatic CRPC. Blood steroid hormone concentrations were measured using liquid chromatography-mass spectrometry. ODM-208 binds to CYP11A1 and inhibited its enzymatic activity. ODM-208 administration led to rapid, complete, durable, and reversible inhibition of the steroid hormone biosynthesis in an adrenocortical carcinoma cell model in vitro, in adult noncastrated male mice and dogs, and in patients with CRPC. All measured serum steroid hormone concentrations reached undetectable levels within a few weeks from the start of ODM-208 administration. ODM-208 was well tolerated with steroid hormone replacement. The toxicity findings were considered related to CYP11A1 inhibition and were reversed after stopping of the compound administration. Steroid hormone biosynthesis can be effectively inhibited with a small-molecule inhibitor of CYP11A1. The findings suggest that administration of ODM-208 is feasible with concomitant corticosteroid replacement therapy.

Hypertension as predictor of sunitinib treatment outcome in metastatic renal cell carcinoma.

UNLABELLED: Hypertension and hypothyreoidism are frequent side effects of VEGFR-inhibitors. We investigated whether hypertension or hypothyreoidism diagnosed during sunitinib treatment is associated with treatment efficacy. MATERIAL AND METHODS: Sixty-four consecutive patients with metastatic renal cell cancer (RCC) were treated with sunitinib in a single center. Hypertension was defined as persistent blood pressure >150/100 mmHg or blood pressure requiring intensification of pre-existing anti-hypertensive medication. Hypothyreoidism was defined as elevation of TSH levels and clinical symptoms requiring hormone replacement therapy (≥Gr. II hypothyreoidim). RESULTS: Twenty-four (38%) patients developed hypertension and 12 (19%) hypothyreoidism. The dose of sunitinib administered was not significantly associated with hypertension or hypothyreoidism. There was no correlation between hypertension and hypothyreoidism. Hypertension was associated with frequent tumor response to sunitinib, a long time to disease progression and long overall survival (p= 0.001, 0.0003 and 0.001, respectively). In a multivariate analysis, hypertension was an independent predictor of progression-free survival (hazard ratio, 0.21; 95% CI 0.076 to 0.59, p=0.0030). There were no statistically significant differences in the frequency of ≥ grade 3 adverse events between patients with or without hypertension. CONCLUSION: Sunitinib-associated hypertension may be a strong predictive marker for treatment efficacy in metastatic RCC.

Biweekly Cabazitaxel Is a Safe Treatment Option for Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients After Docetaxel - A Final Analysis of the Prosty II Trial.

BACKGROUND/AIM: Our phase III trial showed that biweekly docetaxel (D) is better tolerated than triweekly D in metastatic castration-resistant prostate cancer (mCRPC). The safety of biweekly cabazitaxel (CBZ) post-docetaxel was studied in mCRPC. PATIENTS AND METHODS: Altogether, 60 patients received CBZ 16 mg/m2 i.v. on day 1 and day 14 of a 4-week cycle. The mean serum PSA levels were 305 ng/ml, and the mean age 67 years. The primary endpoint was safety according to CTCAEv4.0. RESULTS: A total of 255 4-week cycles of CBZ were administered. The most common grade 3/4 adverse events were neutropenia (16.7%), pain (13.3%), fatigue (10.0%), anemia (5.0%) and non-neutropenic infection (10.0%). PSA responses occurred in 10 patients (16.7%). Clinical benefit rate was 38.3% and median survival 10 months. CONCLUSION: Biweekly CBZ is a well-tolerated treatment resulting in meaningful benefits for heavily pretreated mCRPC patients.

Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer.

BACKGROUND: We compared docetaxel with vinorelbine for the adjuvant treatment of early breast cancer. Women with tumors that overexpressed HER2/neu were also assigned to receive concomitant treatment with trastuzumab or no such treatment. METHODS: We randomly assigned 1010 women with axillary-node-positive or high-risk node-negative cancer to receive three cycles of docetaxel or vinorelbine, followed by (in both groups) three cycles of fluorouracil, epirubicin, and cyclophosphamide. The 232 women whose tumors had an amplified HER2/neu gene were further assigned to receive or not to receive nine weekly trastuzumab infusions. The primary end point was recurrence-free survival. RESULTS: Recurrence-free survival at three years was better with docetaxel than with vinorelbine (91 percent vs. 86 percent; hazard ratio for recurrence or death, 0.58; 95 percent confidence interval, 0.40 to 0.85; P=0.005), but overall survival did not differ between the groups (P=0.15). Within the subgroup of patients who had HER2/neu-positive cancer, those who received trastuzumab had better three-year recurrence-free survival than those who did not receive the antibody (89 percent vs. 78 percent; hazard ratio for recurrence or death, 0.42; 95 percent confidence interval, 0.21 to 0.83; P=0.01). Docetaxel was associated with more adverse effects than was vinorelbine. Trastuzumab was not associated with decreased left ventricular ejection fraction or cardiac failure. CONCLUSIONS: Adjuvant treatment with docetaxel, as compared with vinorelbine, improves recurrence-free survival in women with early breast cancer. A short course of trastuzumab administered concomitantly with docetaxel or vinorelbine is effective in women with breast cancer who have an amplified HER2/neu gene. (International Standard Randomised Controlled Trial number, ISRCTN76560285.).

Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial.

PURPOSE: Docetaxel has not been compared with vinorelbine as adjuvant treatment of early breast cancer. Efficacy and long-term safety of a short course of adjuvant trastuzumab administered concomitantly with chemotherapy for human epidermal growth factor receptor 2 (HER2) -positive cancer are unknown. PATIENTS AND METHODS: One thousand ten women with axillary node-positive or high-risk node-negative breast cancer were randomly assigned to receive three cycles of docetaxel or vinorelbine, followed in both groups by three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Women with HER2-positive cancer (n = 232) were further assigned to either receive or not receive trastuzumab for 9 weeks with docetaxel or vinorelbine. The median follow-up time was 62 months after random assignment. RESULTS: Women assigned to docetaxel had better distant disease-free survival (DDFS) than those assigned to vinorelbine (hazard ratio [HR] = 0.66; 95% CI, 0.49 to 0.91; P = .010). In the subgroup of HER2-positive disease, patients treated with trastuzumab tended to have better DDFS than those treated with chemotherapy only (HR = 0.65; 95% CI, 0.38 to 1.12; P = .12; with adjustment for presence of axillary nodal metastases, HR = 0.57; P = .047). In exploratory analyses, docetaxel, trastuzumab, and FEC improved DDFS compared with docetaxel plus FEC (HR = 0.32; P = .029) and vinorelbine, trastuzumab, and FEC (HR = 0.31; P = .020). The median left ventricular ejection fraction of trastuzumab-treated patients remained unaltered during the 5-year follow-up; only one woman treated with trastuzumab was diagnosed with a heart failure. CONCLUSION: Adjuvant treatment with docetaxel improves DDFS compared with vinorelbine. A brief course of trastuzumab administered concomitantly with docetaxel is safe and effective and warrants further evaluation.

Metabolic characterization of childhood brain tumors: comparison of 18F-fluorodeoxyglucose and 11C-methionine positron emission tomography.

BACKGROUND: Positron emission tomography (PET) scans of primary brain tumors were performed in pediatric patients to examine whether metabolic characteristics could be used as an index of clinical aggressiveness. METHODS: Twenty-seven pediatric patients with untreated primary central nervous system neoplasms were studied with PET scans using 2-[(18)F] fluoro-2-deoxy-D-glucose (FDG) and/or L-[methyl-(11)C] methionine (MET). Metabolic characteristics as assessed with FDG and MET standardized uptake values (SUV) and SUV-to-normal brain ratios were compared with histopathology and selected histochemical features such as proliferation activity (Ki-67(MIB-1)) and apoptotic, vascular, and cell density indices. The median followup time was 43 months. RESULTS: The accumulation of both FDG and MET was significantly higher in high-grade than in low-grade tumors, but a considerable overlap was found. The accumulation of both tracers was associated positively with age. High-grade tumors showed higher proliferative activity and vascularity than the low-grade tumors. In univariate analysis, FDG-PET, MET-PET, and apoptotic index were independent predictors of event-free survival. CONCLUSION: We found that both FDG and MET uptake in pediatric brain tumors are associated with malignancy grade. However, no clear limits of SUVs and SUV-to-normal brain ratios can be set between low-grade and high-grade tumors, which makes the assessment of malignancy grade using metabolic imaging with PET scan difficult in individual cases. Although FDG-PET and MET-PET do not compensate for histopathologic evaluation, they may give valuable additional information especially if invasive procedures to obtain histopathologic samples are not feasible.