Non-small cell lung cancer (NSCLC) that overexpresses human epidermal growth factor receptor 2 (HER2) is associated with poor prognosis, and no HER2-targeting therapies for HER2-overexpressing NSCLC are currently approved in the first-line setting. Pembrolizumab plus pemetrexed and platinum-based chemotherapy is a recommended first-line treatment option for nonsquamous NSCLC with no actionable genomic alterations. However, improved outcomes with pembrolizumab-based therapies correlate with higher programmed death-ligand 1 (PD-L1) levels, underscoring the need for more targeted treatment options for patients with lower PD-L1 tumor proportion scores (TPS; <50%). DESTINY-Lung06 is a multicenter, open-label, randomized, phase III trial evaluating the efficacy and safety of trastuzumab deruxtecan (T-DXd) in combination with pembrolizumab in the first-line setting in patients with HER2-overexpressing (≥25% moderate/strong membrane staining), PD-L1 TPS <50% NSCLC. Planned enrollment will be approximately 686 patients randomly assigned to either T-DXd 5.4 mg/kg with pembrolizumab 200 mg intravenously every 3 weeks (Q3W) or pembrolizumab 200 mg plus pemetrexed 500 mg/m[2] with platinum-based chemotherapy (cisplatin 75 mg/m[2] or carboplatin under the concentration-time curve 5 mg min/mL) intravenously Q3W. Progression-free survival by blinded independent central review and overall survival are the primary and key secondary endpoints of the study, respectively.Clinical trial registration: www.ClinicalTrials.gov identifier is NCT06899126; EudraCT identifier is 2024-515658-26-00.

Pancreatic ductal adenocarcinomas (PDACs) are found to account for more than 5% of all cancer-related deaths worldwide. The 5-year survival rates are still low (<5% for in the metastatic setting). In patients with metastatic disease, combination chemotherapy regimens are currently standard of care. PDACs are K-RAS addicted (incidence >90%), however, RAS oncogenes have been regarded to be "undruggable." Several highly specific inhibitors have been developed with atebimetinib (MEK inhibitor), daraxonrasib (tri-complex pan-K-RAS inhibitor), zoldonrasib (tri-complex K-RAS G12D inhibitor), INCB161734 (non-covalent ON/OFF inhibitor specific for K-RAS G12D), HRS-4642 (liposomal G12D inhibitor), and setidegrasib (G12D degrader) currently undergoing phase III evaluation in first-line PDACs. Five trials (RASolute-305 [zoldonrasib], DAWN-303 [INCB161734], MAPKeeper-301 [atebimetinib]), HRS-4642, and setidegrasib are comparing chemotherapy plus inhibitor with chemotherapy alone. In contrast, RASolute-303 (daraxonrasib) is a three-arms randomized trial with an additional arm being daraxonrasib monotherapy. Since the benefits provided by chemotherapy regimens are limited, it is conceivable that the novel targeted approaches may have the potential to overcome these limitations. Of note, outcomes for some of these compounds numerically exceeded the historical benchmarks with standard chemotherapy suggesting that a chemotherapy backbone might no longer be needed in the future.

In unfavorable intermediate-risk prostate cancer, radiotherapy plus androgen deprivation therapy (ADT) is standard, but GnRH agonists can cause testosterone flare and delayed hormonal recovery, negatively affecting erectile function (EF) and quality of life (QoL). Relugolix, an oral GnRH antagonist, enables rapid testosterone suppression and faster recovery after discontinuation. The REDI-CaP trial investigates whether combining Relugolix with high-precision stereotactic body radiotherapy (SBRT) aims to improve EF recovery while evaluating whether cancer control is maintained.REDI-CaP is a prospective, single-arm, single-center Phase II study enrolling 55 patients (accounting for an anticipated 10% attrition rate, to yield 50 evaluable patients for the primary analysis). Participants receive Relugolix 120 mg daily for 6 months (AIFA-approved off-label use). SBRT is delivered with the CyberKnife system (36.25 Gy in 5 fractions) during the fourth month of ADT. The primary endpoint is EF recovery 6 months after ADT cessation, defined as an IIEF-5 score >17 or an increase of ≥5 points from baseline. Secondary endpoints include biochemical progression-free survival, acute and late toxicity, and patient-reported outcomes.Approved by the Institutional Ethics Committee; conducted according to ICH-GCP and the Declaration of Helsinki.The REDI-CaP trial is designed to investigate whether integrating pharmacology with advanced radiotherapy can help preserve patients' quality of life while assessing cancer control outcomes.Clinical Trial Registration: www.clinicaltrials.gov identifier is NCT07302451 and EU CT 2025-521170-33-00.

Stereotactic body radiotherapy (SBRT) is effective for localized prostate cancer, yet many recurrences originate from the intraprostatic tumor mass (ITM). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) and multiparametric magnetic resonance imaging (mpMRI) enable precise ITM localization and support focal dose escalation. This trial assesses whether PSMA-PET/mpMRI-guided boosting during SBRT improves biochemical control without excess toxicity. This is a single-center, prospective, randomized (1:1), controlled, open-label clinical trial conducted at Huashan Hospital, Fudan University. A total of 128 men with newly diagnosed localized prostate adenocarcinoma will be enrolled and randomized to receive either (1) standard SBRT (39 Gy in 6 fractions) or (2) PSMA-PET/mpMRI-guided focal dose-escalated SBRT (up to 48 Gy in 6 fractions). All participants will receive androgen deprivation therapy (ADT) according to National Comprehensive Cancer Network (NCCN) risk group and clinical practice. The primary endpoint is biochemical progression-free survival (PSA-PFS), defined by the Phoenix criteria. Secondary endpoints include local progression-free survival (LPFS), distant metastasis-free survival (DMFS), overall survival (OS), prostate cancer-specific survival (PCSS), toxicity (CTCAE v5.0), and patient-reported quality of life (EPIC-26 and SF-12). Survival outcomes will be analyzed using Kaplan-Meier estimates and compared via log-rank testing.Clinical trial registration:www.chictr.org.cnidentifier ChiCTR2500114310.

Patients with advanced TNBC with PD-L1 CPS < 10 are typically treated with chemotherapy and experience poor outcomes. Sacituzumab tirumotecan (sac-TMT; MK-2870/SKB264) is a trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate with a unique, bifunctional linker that maximizes payload delivery to tumor cells. Combining sac-TMT with immunotherapy may improve outcomes given their complementary respective direct cytotoxic and immune-mediated antitumor effects regardless of tumor PD-L1 expression. The TroFuse-011 study evaluates sac-TMT with/without pembrolizumab versus treatment of physician's choice (TPC; paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin) in previously untreated, centrally confirmed, locally recurrent unresectable or metastatic TNBC with PD-L1 CPS <10. Eligible adults with measurable disease per RECIST version 1.1, ECOG PS 0/1, and tumor tissue sample for central PD-L1 and TROP2 testing will be randomized to receive sac-TMT (arm A), sac-TMT plus pembrolizumab (arm B), or TPC (arm C). Primary endpoints include progression-free survival (PFS; arm A vs C and arm B vs C) and overall survival (OS; arm A vs C). Secondary endpoints include PFS (arm B vs A), OS (arm B vs C and arm B vs A), objective response rate (arm A vs C and arm B vs C), duration of response, patient-reported outcomes, and safety. Enrollment is ongoing.Clinical trial registration: www.clinicaltrials.gov identifier is NCT06841354.