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Lu-PSMA-617 is a radioligand with high affinity for prostate-specific membrane antigen (PSMA), enabling targeted β-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castration-resistant prostate cancer. We now report their longer-term outcomes, including a 20-patient extension cohort and outcomes of subsequent systemic treatments after completion of trial therapy. Methods: Fifty patients with PSMA-avid metastatic castration-resistant prostate cancer who had progressed after standard therapies received up to 4 cycles of 177 Lu-PSMA every 6 wk. Endpoints included prostate-specific antigen (PSA) response (Prostate Cancer Working Group 2), toxicity (Common Terminology Criteria for Adverse Events, version 4.03), imaging response, patient-reported health-related quality of life, progression-free survival, and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including 177 Lu-PSMA. Results: Seventy-five men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 mo) and extensive prior treatment, including prior docetaxel (84%), cabazitaxel (48%), and abiraterone or enzalutamide (92%). The mean administered radioactivity was 7.5 GBq/cycle. A PSA decline of at least 50% was achieved in 32 of 50 patients (64%; 95% confidence interval [CI], 50%-77%), including 22 patients (44%; 95% CI, 30%-59%) with at least an 80% decrease. Of 27 patients with measurable soft-tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to 177 Lu-PSMA were self-limiting G1-G2 dry mouth (66%), transient G1-G2 nausea (48%), G3-G4 thrombocytopenia (10%), and G3 anemia (10%). Brief Pain Inventory severity and interference scores decreased at all time points, including at the 3-mo follow-up, with a decrease of −1.2 (95% CI, −0.5 to −1.9; P 5 0.001) and −1.0 (95% CI, −0.2 to −0.18; P 5 0.013), respectively. At a median follow-up of 31.4 mo, median overall survival was 13.3 mo (95% CI, 10.5-18.7 mo), with a significantly longer survival of 18.4 mo (95% CI, 13.8-23.8 mo) in patients achieving a PSA decline of at least 50%. At progression after prior response, further 177 Lu-PSMA was administered to 15 (30%) patients (median of 2 cycles commencing 359 d from enrollment), with a PSA decline of at least 50% in 11 patients (73%). Four of 21 patients (19%) receiving other systemic therapies on progression experienced a PSA decline of at least 50%. There were no unexpected adverse events with 177 Lu-PSMA retreatment. Conclusion: This expanded 50-patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity, and improved quality of life with 177 Lu-PSMA radioligand therapy. On progression, rechallenge 177 Lu-PSMA demonstrated higher response rates than other systemic t...

Targeting the ataxia telangiectasia and Rad3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects and replication stress, including inactivation of ataxia telangiectasia mutated (ATM) signaling. We report the dose-escalation portion of the phase I first-inhuman trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5-80 mg twice daily (BID) in 21 patients with advanced solid tumors. The maximum tolerated dose was 40 mg BID 3 days on/4 days off. Commonest adverse events were manageable and reversible hematological toxicities. Partial responses were achieved in 4 patients and stable disease in 8 patients. Median duration of response was 315.5 days. Responders had ATM protein loss and/or deleterious ATM mutations and received doses 40 mg BID. Overall, BAY 1895344 is well tolerated with antitumor activity against cancers with certain DDR defects, including ATM loss. An expansion phase continues in patients with DDR deficiency. SIGNIFICANCE Oral BAY 1895344 was tolerable with antitumor activity in heavily pre-treated patients with various advanced solid tumors, particularly those with ATM deleterious mutations and/or loss of ATM protein; pharmacodynamic results supported a mechanism of action of increased DNA damage. Further study is warranted in this patient population.

Microbes hijack prostate cancer therapy Androgens such as testosterone and dihydrotestosterone are essential for male reproduction and sexual function. Androgens can also influence the growth of prostate tumor cells, and androgen deprivation therapy (ADT) either by surgical means (castration) or pharmacological approaches (hormone suppression), is the cornerstone of current prostate cancer treatments. Pernigoni et al . found that when the body was deprived of androgens during ADT, the gut microbiome could produce androgens from androgen precursors (see the Perspective by McCulloch and Trinchieri). Gut commensal microbiota in ADT-treated patients or castrated mice produced androgens that were absorbed into the systemic circulation. These microbe-derived androgens appeared to favor the growth of prostate cancer and helped to facilitate development into a castration- or endocrine therapy–resistant state. —PNK

Prostate cancer (PCa) is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation is a risk factor for prostate carcinogenesis, with diet, chemical injury, and an altered microbiome being causally implicated. Inflammation can expand intra-prostatic myeloid cells that promote immunosuppression, DNA double-strand breaks, and activate androgen receptor (AR) target genes. AR signalling and free radicals mediate further DNA damage, thereby driving the chronic activation of DNA repair genes (DRG) and tumour suppressor genes, rendering them more susceptible to endogenous and exogenous mutagens. These processes are accelerated in the context of germline DRG defects. We provide an update on recent advances in our understanding of the mechanisms through which inflammation and immune-dysregulation facilitate prostate carcinogenesis. We explore novel therapeutic and prevention strategies harnessing these discoveries.

CDK12 aberrations have been reported as a biomarker of response to immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). Herein, we characterize CDK12mutated mCRPC, presenting clinical, genomic, and tumor-infiltrating lymphocyte data.

term benefit. Clinical vigilance, prompt multimodal diagnosis and multidisciplinary management are paramount for the treatment of immune-mediated myocarditis.

Context: Prostate-specific membrane antigen (PSMA) is a promising, novel theranostic target in advanced prostate cancer (PCa). Multiple PSMA-targeted therapies are currently in clinical development, with some agents showing impressive antitumour activity, although optimal patient selection and therapeutic resistance remain ongoing challenges. Objective: To review the biology of PSMA and recent advances in PSMA-targeted therapies in PCa, and to discuss potential strategies for patient selection and further therapeutic development. Evidence acquisition: A comprehensive literature search was performed using PubMed and review of American Society of Clinical Oncology and European Society of Medical Oncology annual meeting abstracts up to April 2021. Evidence synthesis: PSMA is a largely extracellular protein that is frequently, but heterogeneously, expressed by PCa cells. PSMA expression is associated with disease progression, worse clinical outcomes and the presence of tumour defects in DNA damage repair (DDR). PSMA is also expressed by other cancer cell types and is implicated in glutamate and folate metabolism. It may confer a tumour survival advantage in conditions of cellular stress. PSMA regulation is complex, and recent studies have shed light on interactions with androgen receptor, PI3K/Akt, and DDR signalling. A phase 2 clinical trial has shown that 177 Lu-PSMA-617 causes tumour shrinkage and delays disease progression in a significant subset of patients with metastatic castration-resistant PCa in comparison to second-line chemotherapy. Numerous novel PSMA-targeting immunotherapies, small molecules, and antibody therapies are currently in clinical development, including in earlier stages of PCa, with emerging evidence of antitumour activity. To date, the regulation and function of PSMA in PCa cells remain poorly understood. Conclusions: There has been rapid recent progress in PSMA-targeted therapies for the management of advanced PCa. Dissection of PSMA biology will help to identify biomarkers for and resistance mechanisms to these therapies and facilitate further therapeutic development to improve PCa patient outcomes. Patient summary: There have been major advances in the development of therapies targeting a molecule, PSMA, in PCa. Radioactive molecules targeting PSMA can cause tumour shrinkage and delay progression in some patients with lethal disease. Future