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.
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.
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).
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.).
Background
There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration‐resistant prostate cancer (CRPC).
Methods
We conducted a ...phase II trial of enzalutamide in first‐line chemo‐naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2‐ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR‐V7) in CTCs and plasma Androgen Receptor copy number gain (AR‐gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical–molecular prognostic model using penalized cox‐proportional hazard model. This model was validated in an independent cohort.
Results
Ninety‐eight patients were included. TMPRSS2‐ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR‐V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)‐PFS (4.2 vs. 14.7 m; p < 0.0001), rad‐PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C‐Index 0.70) and the addition of plasma AR (C‐Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C‐index 0.78) that was validated in an independent cohort.
Conclusions
TMPRSS2‐ERG detection did not correlate with differential activity of enzalutamide in first‐line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers.
Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear.
In this ...phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated.
A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval CI, 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels.
Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).
The paper aims to evaluate the efficacy and safety of 223Ra in patients who progressed after first-line androgen deprivation therapy.
EXCAAPE (NCT03002220) was a multicentre, single-arm, open-label, ...non-controlled phase IIa trial in 52 patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases who have progressed on abiraterone acetate or enzalutamide, up to six doses of 223Ra (55 kBq/kg of body weight per month). The primary end-point was radiographic progression-free survival (rPFS). Secondary end-points included rPFS based on androgen receptor splice variant 7 (AR-V7) expression in circulating tumour cells (CTCs), overall survival, and safety.
Median rPFS was 5.5 months (95% CI 5.3–5.5). Median rPFS of patients with AR-V7(−) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2–not reached) and was significantly greater for AR-V7(−) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01). 223Ra was well tolerated; anaemia and thrombocytopenia were the most common grade 3/4 adverse events (5.8% and 11.5%, respectively).
223Ra seems to be a reasonable treatment for patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases progressing on novel hormonal therapy and had an acceptable safety profile.
•223Ra had a promising antitumour activity in patients with metastatic castration-resistant prostate cancer with asymptomatic bone metastases.•223Ra showed an acceptable safety profile similar to that reported in other studies.•Overall survival of androgen receptor splice variant 7 (−) patients was significantly higher than androgen receptor splice variant 7 (+) patients.
Recent data suggested that plasma Ghrelin O-Acyl Transferase enzyme (GOAT) levels could represent a new diagnostic biomarker for prostate cancer (PCa). In this study, we aimed to explore the ...diagnostic and prognostic/aggressiveness capacity of GOAT in urine, as well as to interrogate its putative pathophysiological role in PCa. We analysed urine/plasma levels of GOAT in a cohort of 993 patients. In vitro (i.e., cell-proliferation) and in vivo (tumor-growth in a xenograft-model) approaches were performed in response to the modulation of GOAT expression/activity in PCa cells. Our results demonstrate that plasma and urine GOAT levels were significantly elevated in PCa patients compared to controls. Remarkably, GOAT significantly outperformed PSA in the diagnosis of PCa and significant PCa in patients with PSA levels ranging from 3 to 10 ng/mL (the so-called PSA grey-zone). Additionally, urine GOAT levels were associated to clinical (e.g., Gleason-score, PSA levels) and molecular (e.g.,
/
/
expression) aggressiveness parameters. Indeed,
overexpression increased, while its silencing/blockade decreased cell-proliferation in PCa cells. Moreover, xenograft tumors derived from GOAT-overexpressing PCa (DU145) cells were significantly higher than those derived from the mock-overexpressing cells. Altogether, our results demonstrate that GOAT could be used as a diagnostic and aggressiveness marker in urine and a therapeutic target in PCa.
Axitinib monotherapy obtained approval in pre-treated mRCC patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain ...increased benefit from this drug and its combinations still need to be identified.
Retrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival PFS ≥9 months vs. disease progression/refractory patients RP). A multivariate logistic-regression model was used to analyse clinical factors. Efficacy and safety were also analysed.
In total, 157 patients who received axitinib in second or subsequent line were evaluated (91 LR and 66 RP). Older age at start of axitinib and haemoglobin levels > LLN were independent predictive factors for LR in multivariate analyses. In LR patients, median (m) PFS was 18.1 months, median overall survival was 36.0 months and objective response rate (ORR) was 45.5%. In 59 LR patients receiving axitinib in second-line, mPFS was 18.7 months, mOS was 44.8 months and ORR was 43.9%. mOS was significantly longer in second line compared to subsequent lines (44.8 vs. 26.5 months; P = .009). In LR vs. RP, mPFS with sunitinib in first-line was correlated with mPFS with axitinib in second-line (27.2 vs. 10.9 months P < .001). The safety profile was manageable and consistent with known data.
This study confirms the long-term benefits of axitinib in a selected population, helping clinicians to select the best sequential approach and patients who could obtain a greater benefit from axitinib.
Patients with metastatic renal cell carcinoma (mRCC) who may benefit most from axitinib still need to be identified. AXILONG study confirms long-term benefits in a selected population in which age at axitinib initiation and haemoglobin baseline levels were significantly associated although further validation may be required. First-line sunitinib outcomes were also correlated with prolonged response. These results might be helpful in real-life management of mRCC patients.
A computerized method to automatically detect malignant masses on digital mammograms based on bilateral subtraction to identify asymmetries between left and right breast images was developed. After ...the digitization, in order to align left and right mammograms the breast border and nipple were automatically detected. Images were corrected to avoid differences in brightness due to the recording procedure. Left and right mammograms were subtracted and a threshold was applied to obtain a binary image with the information of suspicious areas. The suspicious regions or asymmetries were delimited by a region growing algorithm. Size and eccentricity tests were used to eliminate false-positive responses and texture features were extracted from suspicious regions to reject normal tissue regions. The scheme, tested in 70 pairs of digital mammograms, achieved a true-positive rate of 71% with an average number of 0.67 false positives per image. Computerized detection was evaluated by using free-response operating characteristic analysis (FROC). An area under the AFROC
(A
1
)
of 0.667 was obtained. Our results show that the scheme may be helpful to the radiologists by serving as a second reader in mammographic screening. The low number of false positives indicates that our scheme would not confuse the radiologist by suggesting normal regions as suspicious.
There are limited data on toxicity and surgical safety associated with neoadjuvant programmed death ligand 1 (PD-L1) inhibitors prior to radical cystectomy (RC) in patients with muscle-invasive ...bladder cancer (MIBC).
To present a comprehensive safety analysis of the largest neoadjuvant series, with focus on timing and severity of toxicity and surgical complications occurring after neoadjuvant atezolizumab in patients with MIBC enrolled in the ABACUS trial.
ABACUS (NCT02662309) is an open-label, multicenter, phase II trial for patients with histologically confirmed (T2-T4aN0M0) MIBC, awaiting RC. Patients either were ineligible or refused cisplatin-based neoadjuvant chemotherapy.
Two cycles of neoadjuvant atezolizumab (1200 mg, every 3 wk) followed by RC.
Description of atezolizumab toxicity profile in the neoadjuvant setting, impact on surgery, and delayed immune-mediated adverse events (AEs) were assessed.
Ninety-five patients received treatment. Of them, 44% (42/95) had atezolizumab-related AEs during the neoadjuvant period (fatigue 20%, decreased appetite 6%, and transaminases increased 6%). Treatment-related grade 3–5 AEs occurred in 11% (10/95) of patients during the study. Of the patients, 21% (20/95) received only one cycle of atezolizumab due to AEs; 92% (87/95) underwent RC. No surgery was delayed due to atezolizumab-related toxicities. Surgical complications occurred in 62% (54/87) of patients. Of these patients, 43% (37/87) and 20% (17/87) had minor (grade 1–2) and major (grade 3–5) complications, respectively. Thirteen of 87 (15%) patients had post-RC atezolizumab-related AEs, including adrenal insufficiency and transaminases increased. Three deaths occurred during the period of study-related interventions (one non–treatment-related aspiration pneumonia, one immune-related myocardial infarction, and one cardiogenic shock after RC). Not all surgical safety parameters were available.
Two cycles of neoadjuvant atezolizumab are well tolerated and do not seem to impact surgical complication rates. Owing to the long half-life, AEs may occur in the postoperative period, including endocrine abnormalities requiring attention and intervention.
Here, we report a comprehensive dataset of patients receiving neoadjuvant immune checkpoint inhibitors before radical cystectomy. Treatment with neoadjuvant atezolizumab is safe and does not seem to complicate surgery significantly.
Neoadjuvant treatment with atezolizumab followed by radical cystectomy is associated with fewer adverse events and low surgical complication rates. Long-term side effects can occur due the long half-life of atezolizumab.
A computerized scheme to detect clustered microcalcifications in digital mammograms has been developed. Detection of individual microcalcifications in regions of interest (ROIs) was also performed. ...The mammograms were previously classified into fatty and dense, according to their breast tissue. The most appropriate wavelet basis and reconstruction levels were selected. To select the wavelet basis, 40 profiles of microcalcifications were decomposed and reconstructed using different types of wavelet functions and different combinations of wavelet coefficients. The symlets with a basis of length 8 were chosen for fatty tissue. For dense tissue, the Daubechies’ wavelets with a four-element basis were employed. Two methods to detect individual microcalcifications were evaluated: (a) two-dimensional wavelet transform, and (b) one-dimensional wavelet transform. The second technique yielded the best results, and was used to detect clustered microcalcifications in the complete mammogram. When detecting individual microcalcifications by using two-dimensional wavelet transform we have obtained, for fatty ROIs, a sensitivity of 71.11% at a false positive rate of 7.13 per image. For dense ROIs the sensitivity was 60.76% and the false positive rate, 7.33. The areas
(A
1
)
under the AFROC curves were
0.33±0.04
and
0.28±0.02,
respectively. The one-dimensional wavelet transform method yielded 80.44% of sensitivity and 6.43 false positives per image
(A
1
=0.39±0.03)
for fatty ROIs, and 62.17% and 5.82 false positives per image
(A
1
=0.37±0.02)
for dense ROIs. For the detection of clusters of microcalcifications in the entire mammogram, the sensitivity was 80.00% with 0.94 false positives per image
(A
1
=0.77±0.09)
for fatty mammograms, and 72.85% of sensitivity at a false positive detection rate of 2.21 per image
(A
1
=0.64±0.07)
for dense mammograms. Globally, a sensitivity of 76.43% at a false positive detection rate of 1.57 per image was obtained.
PDF
