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A randomized trial tested whether the addition of apalutamide, an androgen receptor blocker, to androgen-deprivation therapy might improve radiographic (including MRI-detected) progression–free survival and overall survival. Apalutamide was significantly more effective than placebo for both end points.

ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician’s choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB). Secondary endpoints included overall survival and (serious) adverse events. Upon reaching the time to NLCB, patients could be re-randomized. The primary endpoint was met after 218 randomizations. ARPIs demonstrated ~50% longer time to NLCB compared to taxanes (median, 11.1 versus 6.9 months) and the physician’s choice arm (median, 11.1 versus 7.4 months) in the biomarker-unselected or ‘all’ patient population. ARPIs demonstrated longer overall survival (median, 38.7 versus 21.7 and 21.8 months for taxanes and physician’s choice, respectively). Biomarker signature findings suggest that the largest increase in time to NLCB was observed in AR (single-nucleotide variant/genomic structural rearrangement)-negative and TP53 wild-type patients and TMPRSS2–ERG fusion-positive patients, whereas no difference between ARPIs and taxanes was observed in TP53 -altered patients. In summary, ARPIs outperform taxanes and physician’s choice treatment in patients with metastatic castration-resistant prostate cancer with detectable circulating tumor DNA. ClinicalTrials.gov registration: NCT03903835 . In a biomarker-driven, outcome-adaptive platform trial for patients with metastatic castration-resistant prostate cancer, androgen receptor pathway inhibitors showed longer survival with respect to taxanes and physician’s choice treatment.

In this study, the androgen-receptor inhibitor enzalutamide improved progression-free and overall survival in men with castration-resistant metastatic prostate cancer who had not received chemotherapy. Prostate cancer is the most commonly diagnosed cancer and the sixth leading cause of cancer-related death among men worldwide. 1 Strategies to block androgen-receptor signaling have formed the backbone of prostate-cancer therapy since the first description of the hormonal dependence of this cancer in 1941. 2 Advances in endocrine therapies have improved survival in men with high-risk locoregional prostate cancer. 3 , 4 However, new hormonal agents have been shown to extend survival in men with metastatic castration-resistant disease. 5 – 9 In most patients who are treated for advanced recurrent prostate cancer with androgen-deprivation therapy (comprising a luteinizing hormone–releasing hormone [LHRH] analogue or orchiectomy with . . .

We proposed in 2005 that androgens replace oestrogens as the driver steroids in a subgroup of triple-negative breast cancer (TNBC) with androgen receptor (AR) expression called molecular apocrine (MA) or luminal androgen receptor (LAR). Here, we report the analysis of a clinical trial evaluating the antitumour activity of the anti-androgen darolutamide in MA breast cancer. Our aim was to assess the clinical benefit in patients with AR-positive TNBCs defined by immunohistochemistry and by RNA profiling. In this multicentre, non-comparative, randomised, phase 2 trial, women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–1 and with advanced TNBC that was previously treated with a maximum of one line of chemotherapy were recruited from 45 hospitals in France. After central confirmation of TNBC status and AR positivity (≥10%; SP107 antibody), participants were randomly assigned (2:1) to receive darolutamide 600 mg orally twice daily or capecitabine minimum 1000 mg/m2 twice daily for 2 weeks on and 1 week off, until disease progression, unacceptable toxicity, lost to follow-up, or withdrawal of consent. Randomisation was done centrally using the minimisation procedure and was stratified according to the number of previous lines of chemotherapy. Transcriptomic analysis was used to classify tumours into groups with high and low AR activity (MAhigh and MAlow). The primary clinical endpoint was clinical benefit rate at 16 weeks (confirmed complete response, partial response, or stable disease). The primary translational endpoint was clinical benefit rate in the darolutamide group in MAhigh tumours versus all other tumours. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov (NCT03383679), and is closed to recruitment. Between April 9, 2018, and July 20, 2021, 254 women were screened and 94 were randomly assigned to darolutamide (n=61) or capecitabine (n=33), of whom 90 were evaluable for efficacy analyses. Median follow-up at the data cutoff on July 20, 2022, was 22·5 months (IQR 16·5–30·5). The clinical benefit rate was 29% (17 of 58; 90% CI 19–39) with darolutamide and 59% (19 of 32; 90% CI 45–74) with capecitabine. In patients treated with darolutamide, the clinical benefit rate was 57% (12 of 21; 95% CI 36–78) in MAhigh tumours, and 16% (five of 31; 95% CI 3–29; p=0·0020) in other tumours. The most common grade 3 adverse events were palmar-plantar erythrodysaesthesia syndrome (none of 60 in the darolutamide group vs two [6%] of 33 in the capecitabine group), and headache (three [5%] vs none). No grade 4 or 5 adverse events were observed. Drug-related serious adverse events occurred in three (5%) patients in the darolutamide group and three (9%) in the capecitabine group, which were toxicoderma (n=1) and headache (n=2) in the darolutamide group, and diarrhoea, general physical deterioration, and hepatic cytolysis in the capecitabine group (n=1 each). This study did not reach its prespecified endpoint for darolutamide activity in patients with triple-negative breast cancer selected on the basis of immunohistochemistry for AR. Further studies selecting patients based on RNA profiling might allow better identification of tumours sensitive to anti-androgens. Bayer and Fondation Bergonié.

Androgen receptor pathway inhibitors (ARPIs) and docetaxel are established standards of care for chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). We aimed to assess the efficacy and safety of adding nivolumab to docetaxel versus docetaxel alone in ARPI-pretreated, chemotherapy-naive mCRPC. CheckMate 7DX was a double-blind, randomised, phase 3 trial that enrolled adult patients (aged ≥18 years) with histologically confirmed, ARPI-pretreated, and chemotherapy-naive mCRPC at 291 hospitals and cancer centres across 27 countries. Patients had documented progression within 6 months of screening and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to nivolumab (360 mg), or equivalent placebo, and docetaxel (75 mg/m2) intravenously every 3 weeks for up to ten doses, followed by nivolumab (480 mg) or equivalent placebo every 4 weeks. Randomisation, stratified by previous ARPI therapy and visceral disease, was done using interactive response technology in permuted blocks with a block size of six. Patients, investigators, and the trial sponsor were masked to individual patient treatment assignment. The primary endpoints were radiographic progression-free survival by blinded independent central review and overall survival, assessed in all randomly assigned patients. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04100018, and is completed. Between March 11, 2020, and Aug 2, 2022, 1414 patients were screened for eligibility, 1030 of whom were randomly assigned to nivolumab plus docetaxel (n=514) or placebo plus docetaxel (n=516). All participants were male, median age was 70 years (range 34–91), 662 (64%) were White, 240 (23%) were Asian, and 35 (3%) were Black or African American. With a median follow-up of 17·2 months (IQR 13·2–22·0), median radiographic progression-free survival was 9·4 months (95% CI 8·5–10·3) in the nivolumab plus docetaxel group versus 8·7 months (95% CI 8·4–10·0) in the placebo plus docetaxel group (hazard ratio [HR] 0·96 [99% CI 0·77–1·19]; p=0·59) and median overall survival was 18·7 months (95% CI 17·0–21·0) versus 18·9 months (95% CI 17·3–22·0, HR 1·09 [99·41% CI 0·84–1·43]; p=0·36). Grade 3–4 treatment-related adverse events occurred in 223 (44%) of 510 patients in the nivolumab plus docetaxel group and 187 (37%) of 510 in the placebo plus docetaxel group. The most common grade 3–4 events in both treatment groups were neutropenia (37 [7%] in the nivolumab plus docetaxel group and 50 [10%] in the placebo plus docetaxel group) and decreased neutrophil count (41 [8%] and 39 [8%]). Any-grade treatment-related serious adverse events occurred in 107 (21%) patients in the nivolumab plus docetaxel group and 77 (15%) in the placebo plus docetaxel group. 12 deaths were attributed to nivolumab plus docetaxel (three due to sepsis; one each due to Guillain–Barré syndrome, diverticulitis, myocarditis, liver injury, peritonitis, pneumonitis, pneumonia, and diarrhoea; and one due to unknown causes) and one was attributed to placebo plus docetaxel (due to pneumocystis). Nivolumab plus docetaxel did not improve progression-free survival or overall survival versus placebo plus docetaxel in patients with ARPI-pretreated, chemotherapy-naive mCRPC. These findings do not support the use of combinations of anti-PD-1 immune checkpoint inhibitors and docetaxel in the treatment of unselected populations of patients with ARPI-pretreated, chemotherapy-naive mCRPC. Bristol Myers Squibb.

Darolutamide, a new antiandrogen agent, was tested in men with recurrence of prostate cancer and a PSA doubling time of less than 10 months. Darolutamide was associated with metastasis-free survival of 40.4 months, as compared with 18.4 months for placebo. Toxic effects were similar in the two groups.

Standard therapy for metastatic, hormone-sensitive prostate cancer is androgen-deprivation therapy, usually with docetaxel. A large, multinational, phase 3 trial assessed the addition of the androgen-receptor blocker darolutamide to standard therapy. At 4 years, survival was higher with darolutamide than with placebo (62.7% vs. 50.4%), with no major differences in the frequency of adverse events.

In men with metastatic, hormone-sensitive prostate cancer who were receiving testosterone suppression, the addition of enzalutamide led to significantly longer progression-free and overall survival than the addition of standard nonsteroidal antiandrogen therapy. The better outcome was less clear among patients who had received docetaxel.

In VISION, the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 [177Lu]Lu-PSMA-617 (vipivotide tetraxetan) improved radiographic progression-free survival and overall survival when added to protocol-permitted standard of care in patients with metastatic castration-resistant prostate cancer. Here, we report additional health-related quality of life (HRQOL), pain, and symptomatic skeletal event results. This multicentre, open-label, randomised, phase 3 trial was conducted at 84 cancer centres in nine countries in North America and Europe. Eligible patients were aged 18 years or older; had progressive PSMA-positive metastatic castration-resistant prostate cancer; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2; and had previously received of at least one androgen receptor pathway inhibitor and one or two taxane-containing regimens. Patients were randomly assigned (2:1) to receive either [177Lu]Lu-PSMA-617 plus protocol-permitted standard of care ([177Lu]Lu-PSMA-617 group) or standard of care alone (control group) using permuted blocks. Randomisation was stratified by baseline lactate dehydrogenase concentration, liver metastases, ECOG performance status, and androgen receptor pathway inhibitor inclusion in standard of care. Patients in the [177Lu]Lu-PSMA-617 group received intravenous infusions of 7·4 gigabecquerel (GBq; 200 millicurie [mCi]) [177Lu]Lu-PSMA-617 every 6 weeks for four cycles plus two optional additional cycles. Standard of care included approved hormonal treatments, bisphosphonates, and radiotherapy. The alternate primary endpoints were radiographic progression-free survival and overall survival, which have been reported. Here we report the key secondary endpoint of time to first symptomatic skeletal event, and other secondary endpoints of HRQOL assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-5L, and pain assessed with the Brief Pain Inventory-Short Form (BPI-SF). Patient-reported outcomes and symptomatic skeletal events were analysed in all patients who were randomly assigned after implementation of measures designed to reduce the dropout rate in the control group (on or after March 5, 2019), and safety was analysed according to treatment received in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, NCT03511664, and is active but not recruiting. Between June 4, 2018, and Oct 23, 2019, 831 patients were enrolled, of whom 581 were randomly assigned to the [177Lu]Lu-PSMA-617 group (n=385) or control group (n=196) on or after March 5, 2019, and were included in analyses of HRQOL, pain, and time to first symptomatic skeletal event. The median age of patients was 71 years (IQR 65–75) in the [177Lu]Lu-PSMA-617 group and 72·0 years (66–76) in the control group. Median time to first symptomatic skeletal event or death was 11·5 months (95% CI 10·3–13·2) in the [177Lu]Lu-PSMA-617 group and 6·8 months (5·2–8·5) in the control group (hazard ratio [HR] 0·50, 95% CI 0·40–0·62). Time to worsening was delayed in the [177Lu]Lu-PSMA-617 group versus the control group for FACT-P score (HR 0·54, 0·45–0·66) and subdomains, BPI-SF pain intensity score (0·52, 0·42–0·63), and EQ-5D-5L utility score (0·65, 0·54–0·78). Grade 3 or 4 haematological adverse events included decreased haemoglobin (80 [15%] of 529 assessable patients who received [177Lu]Lu-PSMA-617 plus standard of care vs 13 [6%] of 205 who received standard of care only), lymphocyte concentrations (269 [51%] vs 39 [19%]), and platelet counts (49 [9%] vs five [2%]). Treatment-related adverse events leading to death occurred in five (1%) patients who received [177Lu]Lu-PSMA-617 plus standard of care (pancytopenia [n=2], bone marrow failure [n=1], subdural haematoma [n=1], and intracranial haemorrhage [n=1]) and no patients who received standard of care only. [177Lu]Lu-PSMA-617 plus standard of care delayed time to worsening in HRQOL and time to skeletal events compared with standard of care alone. These findings support the use of [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer who received previous androgen receptor pathway inhibitor and taxane treatment. Advanced Accelerator Applications (Novartis).

The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline <50%), and 25 patients were classified as responders (PSA decline ≥50%). Failure to achieve a PSA50 was associated with shorter progression-free survival, time on treatment, and overall survival, demonstrating PSA50’s utility. Targeted DNA-sequencing was performed on 26 of 36 biopsies, and RNA-sequencing was performed on 25 of 36 biopsies that contained sufficient material. Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis (GSEA) to identify pathways whose activity state correlated with de novo resistance. TP53 gene alterations were more common in nonresponders, although this did not reach statistical significance (P = 0.055). AR gene alterations and AR expression were similar between groups. Importantly, however, transcriptional measurements demonstrated that specific gene sets— including those linked to low AR transcriptional activity and a stemness program—were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance.