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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 .

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BACKGROUND: Immune checkpoint inhibitors (ICIs) have been established as a routine treatment in patients with metastatic urothelial cancer (mUC). However, there has been no standard of care after progression on ICIs. We investigated real-world treatment patterns and efficacy of chemotherapy (CHT) after pembrolizumab, in the era before introduction of maintenance avelumab and antibody-drug conjugates (ADC). PATIENTS AND METHODS: An observational, retrospective study was conducted at twelve Nordic centers. Patients with mUC were treated according to investigator´s choice of CHT after pembrolizumab. Primary endpoint was overall response (ORR) and disease control rate (DCR); secondary endpoints were progression-free (PFS) and overall survival (OS). RESULTS: In total, 102 patients were included whereof 23 patients received CHT after pembrolizumab as second line treatment (subcohort A) and 79 patients in third line (subcohort B). Platinum-gemcitabine combinations were the most common regimens in subcohort A, and vinflunine in subcohort B. The ORR and DCR were 36% and 47%, respectively. Presence of liver metastases was independently associated with lower ORR and DCR. The PFS and OS were 3.3 months and 7.7 months, respectively. Eastern Cooperative Oncology Group Performance Status (ECOG PS) and number of previous cycles of pembrolizumab were found to be independent prognostic factors associated with OS. CONCLUSION: In a real-world setting, CHT showed clinically meaningful response rates and survival in mUC patients after progression with pembrolizumab. Clinical benefit may primarily be achieved in patients with favorable ECOG PS, in patients treated with > 6 cycles pembrolizumab as well as in patients without presence of liver metastases.

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BACKGROUND: Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression-free survival (PFS) remains modest, potentially explained by tumor molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis. METHODS: The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC. DISCUSSION: Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study. CONCLUSIONS: The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03903835. Date of registration: April 4, 2019. Status: Recruiting.

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