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Conventional imaging using CT and bone scan has insufficient sensitivity when staging men with high-risk localised prostate cancer. We aimed to investigate whether novel imaging using prostate-specific membrane antigen (PSMA) PET-CT might improve accuracy and affect management. In this multicentre, two-arm, randomised study, we recruited men with biopsy-proven prostate cancer and high-risk features at ten hospitals in Australia. Patients were randomly assigned to conventional imaging with CT and bone scanning or gallium-68 PSMA-11 PET-CT. First-line imaging was done within 21 days following randomisation. Patients crossed over unless three or more distant metastases were identified. The primary outcome was accuracy of first-line imaging for identifying either pelvic nodal or distant-metastatic disease defined by the receiver-operating curve using a predefined reference-standard including histopathology, imaging, and biochemistry at 6-month follow-up. This trial is registered with the Australian New Zealand Clinical Trials Registry, ANZCTR12617000005358. From March 22, 2017 to Nov 02, 2018, 339 men were assessed for eligibility and 302 men were randomly assigned. 152 (50%) men were randomly assigned to conventional imaging and 150 (50%) to PSMA PET-CT. Of 295 (98%) men with follow-up, 87 (30%) had pelvic nodal or distant metastatic disease. PSMA PET-CT had a 27% (95% CI 23–31) greater accuracy than that of conventional imaging (92% [88–95] vs 65% [60–69]; p<0·0001). We found a lower sensitivity (38% [24–52] vs 85% [74–96]) and specificity (91% [85–97] vs 98% [95–100]) for conventional imaging compared with PSMA PET-CT. Subgroup analyses also showed the superiority of PSMA PET-CT (area under the curve of the receiver operating characteristic curve 91% vs 59% [32% absolute difference; 28–35] for patients with pelvic nodal metastases, and 95% vs 74% [22% absolute difference; 18–26] for patients with distant metastases). First-line conventional imaging conferred management change less frequently (23 [15%] men [10–22] vs 41 [28%] men [21–36]; p=0·008) and had more equivocal findings (23% [17–31] vs 7% [4–13]) than PSMA PET-CT did. Radiation exposure was 10·9 mSv (95% CI 9·8–12·0) higher for conventional imaging than for PSMA PET-CT (19·2 mSv vs 8·4 mSv; p<0·001). We found high reporter agreement for PSMA PET-CT (κ=0·87 for nodal and κ=0·88 for distant metastases). In patients who underwent second-line image, management change occurred in seven (5%) of 136 patients following conventional imaging, and in 39 (27%) of 146 following PSMA PET-CT. PSMA PET-CT is a suitable replacement for conventional imaging, providing superior accuracy, to the combined findings of CT and bone scanning. Movember and Prostate Cancer Foundation of Australia. [Display omitted]

Treatment Modalities and Managing Administration Significance & Background: The evolving treatment paradigm in oncology has created an unmet need for administration options to improve patients' treatment experience and reduce healthcare inefficiencies. SC delivery may address these challenges and is typically preferred by patients over IV delivery (O'Shaughnessy et al. Eur J Cancer 2021; Lonardi et al. ESMO 2022). CheckMate 67T (NCT04810078) is an ongoing multicenter, randomized, open-label, phase 3 study comparing NIVO SC and IV in previously treated patients with advanced/metastatic ccRCC. Primary efficacy and safety results (8 months' minimum follow-up) were previously presented (ASCO GU 2024; ASCO 2024). Purpose: Provide updated efficacy and safety results from CheckMate 67T after extended 15-months' minimum follow-up. Interventions: Patients were randomized 1:1 to receive either NIVO SC 1200mg + recombinant human hyaluronidase PH20 Q4W or NIVO IV 3mg/kg Q2W until disease progression, unacceptable toxicity, consent withdrawal, completion of 2 years' treatment, or death. Results: In total, 495 patients were randomized into NIVO SC (n=248) or NIVO IV (n=247) arms. Baseline characteristics were balanced between arms. Consistent with the primary analysis, after 15 months of follow-up, efficacy was similar for NIVO SC vs IV, including objective response rate (26.6% [95% CI, 21.2-32.6] vs 20.6% [15.8-26.2]) and median progression-free survival (6.3 [5.1-7.5] vs 5.7 [5.2-7.4] months). Overall survival rate (95% CI) at 12 months was 72.4% (66.2-77.6) and 72.9% (66.7-78.2) with NIVO SC and NIVO IV, respectively. The safety profile of NIVO SC remained consistent vs NIVO IV, with no new safety signals identified and comparable rates of adverse events (AEs) between the arms: AEs, 93% (230/247) vs 94% (231/245); treatment-related (TR) AEs, 62% (152/247) vs 66% (161/245). TR local injection site reactions (LISRs) occurred in patients in both SC (7%, 18/247) and IV (2%, 5/245) arms. In the SC arm, most patients with LISR (17/18) experienced grade 1 reactions, whereas in the IV arm, most patients with LISR (4/5) had grade 2 reactions. In both arms, a similar proportion of patients with TR LISRs required medication: NIVO SC, 2% (5/247); NIVO IV, 2% (5/245). Discussion: Efficacy and safety profiles of NIVO SC in this analysis were comparable with NIVO IV, consistent with the primary analysis. These updated results continue to support NIVO SC as a new option with reduced administration time (<5 min) to improve patient experience and healthcare efficiency.

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The benefit of regional nodal irradiation in the treatment of breast cancer is well established for patients with pathologically positive axillary nodes, but whether it is also beneficial for patients whose nodes become pathologically tumor free (ypN0) after neoadjuvant chemotherapy remains unclear. We evaluated whether regional nodal irradiation improves outcomes in patients with biopsy-proven, node-positive breast cancer who reach ypN0 status after neoadjuvant chemotherapy. Patients with breast cancer with a clinical stage of T1 to T3 (tumor size, ≤2 cm to >5 cm), N1, and M0 (indicating spread to one to three axillary lymph nodes but no distant metastasis) who had ypN0 status after neoadjuvant chemotherapy were randomly assigned to receive regional nodal irradiation or no regional nodal irradiation. The primary end point was the interval of freedom from invasive breast cancer recurrence or death from breast cancer (invasive breast cancer recurrence-free interval). Secondary end points included the locoregional recurrence-free interval, the distant recurrence-free interval, disease-free survival, and overall survival. Safety was also assessed. A total of 1641 patients were enrolled in the trial; 1556 were included in the primary-event analysis: 772 in the irradiation group and 784 in the no-irradiation group. After a median follow-up of 59.5 months, 109 primary end-point events (50 in the irradiation group and 59 in the no-irradiation group) had occurred. Regional nodal irradiation did not significantly increase the invasive breast cancer recurrence-free interval (hazard ratio, 0.88; 95% confidence interval, 0.60 to 1.28; P = 0.51). Point estimates of survival free from the primary end-point events were 92.7% in the irradiation group and 91.8% in the no-irradiation group. Regional nodal irradiation did not increase the locoregional recurrence-free interval, the distant recurrence-free interval, disease-free survival, or overall survival. No deaths related to the protocol-specified therapy were reported, and no unexpected adverse events were observed. Grade 4 adverse events occurred in 0.5% of patients in the irradiation group and 0.1% of those in the no-irradiation group. The addition of adjuvant regional nodal irradiation did not decrease the risk of invasive breast cancer recurrence or death from breast cancer in patients who had negative axillary nodes after neoadjuvant chemotherapy. (Funded by the National Institutes of Health; NSABP B-51-Radiation Therapy Oncology Group 1304 ClinicalTrials.gov number, NCT01872975.).

The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low 1 – 5 , highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation 6 – 13 . In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST 14 ) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1–PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK–STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types. A pick-the-winner clinical trial design in patients with metastatic triple-negative breast cancer shows that immune induction with doxorubicin or cisplatin may improve clinical responses to PD-1 blockade and induce a more favorable tumor microenvironment.

Cancer progression is driven in part by genomic alterations 1 . The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations 2 , leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies 3 , 4 . Although DNA sequencing has been implemented in practice, it remains unclear how to use its results. A total of 1,462 patients with HER2-non-overexpressing metastatic breast cancer were enroled to receive genomic profiling in the SAFIR02-BREAST trial. Two hundred and thirty-eight of these patients were randomized in two trials (nos. NCT02299999 and NCT03386162) comparing the efficacy of maintenance treatment 5 with a targeted therapy matched to genomic alteration. Targeted therapies matched to genomics improves progression-free survival when genomic alterations are classified as level I/II according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) 6 (adjusted hazards ratio (HR): 0.41, 90% confidence interval (CI): 0.27–0.61, P  < 0.001), but not when alterations are unselected using ESCAT (adjusted HR: 0.77, 95% CI: 0.56–1.06, P  = 0.109). No improvement in progression-free survival was observed in the targeted therapies arm (unadjusted HR: 1.15, 95% CI: 0.76–1.75) for patients presenting with ESCAT alteration beyond level I/II. Patients with germline BRCA1/2 mutations ( n  = 49) derived high benefit from olaparib (g BRCA1 : HR = 0.36, 90% CI: 0.14–0.89; g BRCA2 : HR = 0.37, 90% CI: 0.17–0.78). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with metastatic breast cancer. Targeted therapies matched to genomics improved progression-free survival when genomic alterations were classified as level I/II (according to ESCAT), and genomics should thus be driven by target actionability in patients with metastatic breast cancer.