Arras Cedex, France

Darolutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Metastatic prostate cancer remains incurable despite several major improvements in the treatment. In the case of pretreated metastatic castration-resistant disease (mCRPC) the options remain scarce and there is still an unmet need in this patient population. For the majority of patients with metastatic hormone-sensitive prostate cancer (mHSPC) the combination of androgen deprivation (ADT) and ARPI (or even a triplet treatment with ADT, docetaxel and darolutamide or abiraterone) has become standard of care. However, when patients become metastatic castration resistant (mCRPC) over time a change of systemic treatment is necessary and thus this paradigm switch in treatment of mHSPC has had a major impact on treatment of mCRPC patients. Many patients developing metastatic castration-resistant disease these days have not only received ADT but also an ARPI and, in some cases, also docetaxel. Therefore, the treatment options in the first line setting of mCRPC are restricted and the outcome is poorer compared to the past. Improvement of first line mCRPC is an important unmet clinical need. The SAKK has demonstrated in two earlier studies that maintenance treatment with an ARPI (orteronel in SAKK 08/11 or darolutamide in SAKK 08/16) can improve radiographic progression-free survival in pretreated mCRPC patients after ARPI and/or taxane based. This maintenance concept could be introduced more generally in the first line setting of mCRPC. In the SAKK 08/16 trial, darolutamide maintenance was shown to prolong progression-free survival (PFS) compared to placebo, in patients with mCRPC who had received prior ARPI, and whose disease did not progress during taxane therapy. This benefit was more pronounced in patients with prior response to ARPI. Taken together it is hypothesized that the continued AR-pathway blockade with darolutamide in patients progressing from mHSPC to mCRPC on ARPI treatment can improve outcome when it is added to a standard first line mCRPC therapy and then continued as maintenance. SAKK proposes to add the ARPI darolutamide to standard first line mCRPC treatment consisting of either taxane chemotherapy (docetaxel or cabazitaxel), olaparib, radium 223 or LuPSMA. The choice of standard of care treatment is up to the investigator, respecting the country specific approvals. Darolutamide will be given concomitantly with the chosen first line treatment and will be continued as maintenance afterwards until radiographic progression.

XL092 in Patients With Metastatic Castration-Resistant Prostate Cancer

Trial of Pembrolizumab in Metastatic Castration Resistant Prostate Cancer

Open-label, single arm, phase II trial initially pursuing a two-stage Simon Minimax design. The null hypothesis Po will be 0.20; the alternative hypothesis Pa will be 0.40 (type 1 error will be 0.05 and type 2 error will be 0.10). Patients with metastatic CRPC tumours characterised by high mutational load, high microsatellite instability as established, for example, by the Promega MSI 1.2 analysis system, or a DNA repair defect including loss of MMR, identified on archival or fresh tissue biopsy specimens (through a TMG approved sequencing study e.g. the MAESTRO study) who have either exhausted established active anticancer drugs, or preferred not to have established agents, will be offered entry into the PERSEUS1 study. Part A: Part A is an open-label, single arm, two-stage Simon Minimax design phase II trial. Stage 1: Patients will continue their LHRH analogue therapy. This cohort will include 24 patients as the first stage of a two-stage Phase II. If more than 5 responses in these first 24 patients are reported then the study will proceed to stage 2. Anti-tumour activity will be assessed (measured by response rates) by PSA, imaging assessments (CT & bone scans or when indicated whole body MRI) and CTC count measures. Whole Body MRI (WB-MRI) will be performed instead of CT in patients with contraindications to CT contrast), or instead of bone scan in patients with widespread bone disease at baseline thought to be non-evaluable by PCWG criteria due to inability to reliably identify two new lesions. Stage 2: This will enrol a further 21 patients to a total of 45 patients. Ineffectiveness will be concluded if ≤5 and ≤13 responses are seen in the stage 1 and stage 2 respectively and the null hypothesis will be rejected (i.e. further research would be warranted) if >13 responses are reported from the first 45 patients. With this Simon Minimax design the probability of early termination of this trial when the true response probability (P0) is <0.20 is 0.66. Part B: Biomarker enrichment stage: If the null hypothesis is rejected (and with Sponsor approval and confirmation of sufficient funding) the study will continue with stratified recruitment into biomarker defined cohorts in order to increase the precision with which the response rate can be estimated within mCRPC molecular subgroups of interest. It is anticipated that approximately 55 patients will be included in Part B, which will make a total of 100 mCRPC patients in part A and B together, including ≥9 patients for each of: A) MMR defective mCRPC; B) High mutational load mCRPC without MMR defects; C) mCRPC with deleterious homologous recombination (HR) DNA repair aberrations (BRCA2, ATM, BRCA1, PALB2, others); D) mCRPC with deleterious nucleotide excision repair (NER) aberrations; E) mCRPC with deleterious base excision repair (BER) aberrations; F) mCRPC with deleterious aberrations in non-homologous end-joining (NHEJ). Eligibility for more than one cohort is anticipated to be uncommon; where this occurs "allocation" to a cohort will be determined in discussion with the CI based on initial sequencing results and with priority given to driver (rather than sub-clonal) mutations. Patients recruited in Part A will be retrospectively "allocated" to a cohort on the basis of their initial sequencing data (reported prior to trial entry) prior to any response assessments, for the purposes of analysis. Within each biomarker subgroup (A-F) this will allow us to reject the probability of a >30% response rate if we see no responses in 9-patients, with a 5% false negative risk (Gehan design). If ≥1 responses are seen in 9 patients in a subtype, recruitment will continue to that subtype with a further 20-25 patients such that the final estimate of the response rate has a standard error of 10%. Response rates with confidence intervals will be reported for each subtype. In the absence of any safety concerns from the IDMC, recruitment will continue seamlessly from Part A stage 1 to Part A stage 2 and from Part A stage 2 to the Part B biomarker enrichment cohorts. It is possible that at the time of the Part A stage 1 and 2 overall analysis (based on 45 patients), the graduation of some of the more common subgroups to the enrichment phase will be known (e.g. if more than 1 response from 9 patients recruited to a biomarker subgroup that cohort would continue to at least 20 patients). Conversely, if no successes have been seen in 9 patients of a particular subtype, recruitment to that subtype would not proceed to the enrichment stage. The biomarker defined cohorts may accrue at different rates related to genomic prevalence. At each stop/go decision point (end of enrichment stage 1 in a particular cohort) overall progress of all the ongoing enrichment cohorts will be reviewed by the IDMC/TSC. They will be asked to advise on the value of continued accrual to the cohorts particularly in light of slow recruitment.

177Lu-LNC1011 in Patients with Metastatic Castration-resistant Prostate Cancer

[177Lu]Lu-LNC1011 is a novel long-circulating PSMA therapeutic probe. This study represents the first human investigation, aiming to explore its maximum tolerated dose (MTD), safety, dosimetry, and initial treatment efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC).This study employed an open-label, non-randomized design, representing the first human trial of its kind. It utilized a standard 3+3 dose-escalation approach, focusing on patients with metastatic castration-resistant prostate cancer, initiating treatment at a dose of 1.85 GBq over a 6-week period. Subsequent cohorts received a dose escalation of 0.925 GBq from the previous cohort.

Gedatolisib in Combination With Darolutamide in Metastatic Castration-Resistant Prostate Cancer

This is a Phase 1/2, open-label, randomized, dose finding and dose expansion study to evaluate the safety, preliminary efficacy, and pharmacokinetics of gedatolisib, a pan-PI3K/mTOR inhibitor, in combination with darolutamide, a next-generation androgen receptor inhibitor, in patients with metastatic castration-resistant prostate cancer following progression on a next-generation androgen receptor inhibitor. The aim of the Phase 1 portion of the study is to evaluate dose limiting toxicities and to determine the recommended Phase 2 dose. The aim of the Phase 2 portion of the study is to further assess the safety and preliminary efficacy of the drug combination.

Study of Cabozantinib and Nivolumab in Metastatic Castration Resistant Prostate Cancer

Eligible subjects will undergo a baseline biopsy prior to treatment initiation. They will then initiate treatment with cabozantinib (40 mg orally daily) and nivolumab (480 mg intravenously every four weeks). An on-treatment biopsy will be performed during Cycle 2. Subjects will continue treatment until radiographic progression, toxicity or withdrawal. Prostate-specific antigen (PSA) levels will be evaluated once every cycle. Radiographic assessments will occur every two cycles for one year and then every three cycles thereafter. Cycle length is 28 days.

Study of Apalutamide With Carotuximab in Metastatic, Castration-Resistant Prostate Cancer

177Lu-PSMA-EB-01 in Patients With Metastatic Castration-resistant Prostate Cancer

Prostate cancer is the most frequent malignant tumor in men worldwide. Prostate-specific membrane antigen (PSMA), is a surface molecule specifically expressed by prostate tumors which was shown to be a valid target for radiotherapy. 177Lu-PSMA-617, a urea-based compound, provide an effective target for the treatment of metastatic castration-resistant prostate cancer. However, a major problem in the therapeutic use of 177Lu-PSMA-617 has been its short half-life and fast rate of clearance. The investigators designed and synthesized a new radiopharmaceutical, named 177Lu-PSMA-EB-01. EB（Evans Blue）can bind to albumin to slow down its plasma clearance rate, thereby increasing tumor accumulation and reducing the total dosage of Lu-177. Hence, EB-PSMA-01 may be an option for consideration due to limited supply of Lu-177, by which more patients may be benefited by this version of 177Lu-EB-PSMA-01. This study was designed to investigate the safety, dosimetry and preliminary effects of 177Lu-EB-PSMA-01 in patients with metastatic castration resistant prostate cancer.

Study of TVB-2640 in Men With Metastatic Castration-Resistant Prostate Cancer

This phase I, open-label, dose-escalation study is designed to evaluate the dose limiting toxicities (DLTs) and maximum-tolerated dose (MTD) of TVB-2640 plus Enzalutamide and establish the TVB-2640 dose recommended for further investigation in phase 2 (i.e., recommended phase 2 dose [RP2D]). Patients with a confirmed histological or cytological diagnosis of prostate cancer (PC), evidence of metastatic PC on imaging (bone scan and/or CT/MRI scan), serum testosterone <50 ng/dl, who had progressed on androgen-depletion therapy (ADT), with documented progressive metastatic castration-resistant prostate cancer (mCRPC) based on Prostate Cancer Working Group 3 (PCWG3) criteria and no previously treatment with cytotoxic chemotherapy are eligible. This study represents the first clinical evaluation of TVB-2640 in combination with Enzalutamide. All patients will receive Enzalutamide monotherapy at the approved dose of 160 mg once daily for 28 days to reach the steady state as determined by measuring Enzalutamide and des-methyl-Enzalutamide levels. Participants who complete the Enzalutamide run-in period will begin oral TVB-2640 at the dose of 100 mg. The dose escalation scheme will be the Bayesian optimal interval (BOIN) design with additional dose levels of 100 mg, 150mg, 200 mg, 250 mg, and 300mg daily. The maximum sample size for the phase I will be 30 patients and the target DLT rate is 25% or less and a maximum of 9 patients at any dose level.

Pembrolizumab, Carboplatin and Cabazitaxel in Aggressive Metastatic Castration Resistant Prostate Cancer (PEAPOD_FOS)

Aggressive variant prostate cancer is a clinically defined subset of metastatic castration resistant prostate cancers characterized by the absence of response to AR targeted agents and neuroendocrine features. The treatments that are currently available are not effective and represent an unmet clinical need. This subgroup has been molecularly characterized and associate loss of key tumor suppressors, including TP53, PTEN and RB, and neuroendocrine features. Carboplatin and cabazitaxel have demonstrated promising activity in this scenario although virtually all patients succumb to the disease. Pembrolizumab has demonstrated activity in neuroendocrine tumors. In this trial will be evaluated the activity and safety of pembrolizumab in combination with the most active chemotherapy regiment available to date in aggressive variant prostate cancer, carboplatin plus cabazitaxel