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Androgen-deprivation therapy (ADT) has been the mainstay of treatment of metastatic prostate cancer since the first report of its hormonal dependence in the 1940s. Since 2015, the addition of docetaxel and the addition of abiraterone to ADT have conferred substantial overall survival benefit in men with metastatic castration-naïve prostate cancer (mCNPC). The shift of these treatment options for metastatic prostate cancer from the castration-resistant setting to the castration-naïve setting has led to new challenges in the management of this disease. It remains to be determined which patients may benefit most from either early concomitant docetaxel or from abiraterone with ADT, since biomarkers for early therapy response and risk stratification are currently lacking. Therefore, the ability to personalize medicine is hampered. Furthermore, the earlier detection of metastatic prostate cancer by using new imaging modalities makes the application of clinical trial results in daily practice increasingly challenging. Recently, both local radiotherapy to the primary tumor combined with ADT and abiraterone combined with ADT showed a survival benefit in low-volume disease patients. The latest data also demonstrated a survival benefit with the addition of apalutamide or enzalutamide to ADT. The extent of metastatic disease may become one of the most important factors to determine treatment choice. In this review article, we summarize trial data to provide guidance for treatment selection in metastatic castration-naïve prostate cancer.

Background Systemic anti-cancer treatment is hampered by drug resistance (DR). However, little is known about the pharmacokinetic consequences of genetic changes in tumor cells. We hypothesize that somatic point mutations, small indels, copy number variations (sCNV) and/or structural variations in genes encoding drug transporters are drivers of DR mechanisms in tumor cells. We therefore performed an explorative analysis to quantify somatic aberrations that could reflect DR mechanisms and, in parallel, identify their stressors. Methods We interrogated whole-genome sequencing (WGS) data from a Dutch pan-cancer cohort of metastatic cancer patients (N = 3149 at ∼118x and matched peripheral blood at∼38x read depth), of which more than half had failed previous systemic treatment. Somatic aberrations (germline filtered) were analyzed in drug transporters (N = 51), present on the Drug Metabolizing Enzymes and Transporters (DMET™ plus) panel (v.32). Enrichment of somatic DR variants was estimated by assessing nonsynonymous/synonymous mutation ratio deviations (dN/dS) and sCNV were detected with GISTIC2. Results In total, 5137 somatic variants (2645 in treatment-naive and 2484 in pretreated patients) in drug transporter genes were observed in 1651 patients (52.4%) of whom 55.1% were systemically pretreated. Three genes (ABCB4, ABCC5, SLCO1B1) showed dN/dS enrichment (p = 0.0142 - 0.0364). sCNVs (N = 7656; 5849 deep gene-level gains and 1807 deletions) were observed in 1906 patients (60.5%). Interestingly, we identified 20 somatic DR-related variants in 12 patients (58.3% pretreated), not present in the matching germline samples, that were identical to SNP variants on DMET™ plus. Conclusions In the largest metastatic pan-cancer WGS cohort worldwide, we characterized the pharmacogenomic drug transporter landscape in tumor cells. Potentially, the incidence of somatic variants in pharmacogenes accounts for acquired DR in pretreated patients and/or intrinsic DR. We will extend our study with analyses of prior treatments and germline variations, in order to assess the clinical consequences of the variations and improve clinical decision-making. Clinical trial identification NCT01855477. Legal entity responsible for the study The authors. Funding This publication and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT) have made available to the study. Disclosure C. van Herpen: Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Regeneron; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sanofi. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (self): Servier. All other authors have declared no conflicts of interest.

Background Metastatic cancer is one of the major causes of death and is associated with poor treatment efficiency. A better understanding of the characteristics of late stage cancer is required to help tailor personalised treatment, reduce overtreatment and improve outcomes. Methods Here we describe the largest pan-cancer study of metastatic solid tumor genomes, including 2,520 whole genome-sequenced tumor-normal pairs, analyzed at a median depth of 106x and 38x respectively, and surveying over 70 million somatic variants. Results Metastatic lesions were found to be very diverse, with mutation characteristics reflecting those of the primary tumor types, although with high rates of whole genome duplication events (56%). Metastatic lesions are relatively homogeneous with the vast majority (96%) of driver mutations being clonal and up to 80% of tumor suppressor genes bi-allelically inactivated through different mutational mechanisms. For 62% of all patients, genetic variants that may be associated with outcome of approved or experimental therapies were detected. These actionable events were distributed over the various mutation types (single and multiple nucleotide variants, insertions and deletions, copy number alterations and structural variants) underlining the importance of comprehensive genomic tumor profiling for cancer precision medicine for advanced cancer treatment. Conclusions Whole genome sequencing on fresh biopsies of metastatic cancer is feasible and identifies not only new insights in genome biology but also new opportunities for patients with both approved and experimental agents. We have created the largest data base of whole genome sequenced metastatic cancer patients which continues to facilitate new precision medicine studies. Legal entity responsible for the study The authors. Funding Hartwig Medical Foundation, Barcode for Life, Dutch Cancer Society. Disclosure E. Cuppen: Honoraria (self), Advisory / Consultancy: InteRNA technologies BV; Honoraria (institution), Advisory / Consultancy: Illumina; Full / Part-time employment, Officer / Board of Directors: Hartwig Medical Foundation. M.P. Lolkema: Advisory / Consultancy: Incyte; Advisory / Consultancy: Amgen; Advisory / Consultancy: Janssen Cilag BV; Advisory / Consultancy: Bayer; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi Aventis Netherlands BV. P. Roepman: Honoraria (institution), Advisory / Consultancy: Illumina. V.C.G. Tjan-Heijnen: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: E. Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca. C. van Herpen: Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: Ipsen ; Advisory / Consultancy: MSD; Advisory / Consultancy: Regeneron; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): BMS ; Research grant / Funding (self): MSD; Research grant / Funding (self): Merck; Research grant / Funding (self): Ipen; Research grant / Funding (self): Novartis ; Research grant / Funding (self): Sanofi . E.F. Smit: Honoraria (institution): AstraZeneca ; Honoraria (institution): BMC; Honoraria (institution): Bayer; Honoraria (institution): Eli Lilly ; Honoraria (institution): MSD; Honoraria (institution): Merck ; Honoraria (institution): Novartis; Honoraria (institution): Pfizer; Honoraria (institution): Takeda; Honoraria (institution): Regeneron; Honoraria (institution): Roche ; Honoraria (institution): Seattle Genetrics; Advisory / Consultancy: Eli Lilly ; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Roche. All other authors have declared no conflicts of interest.

Background Irinotecan is widely used, but also known for its severe toxicities neutropenia and diarrhea. Based on preclinical data, combined caloric and protein restriction (CCPR) might improve treatment tolerability without impairing antitumor effect. Therefore, we studied the influence of CCPR on irinotecan pharmacokinetics and toxicity. Methods In this cross-over trial, patients with liver metastases of solid tumors were included and randomized to treatment with irinotecan preceded by 5 days of CCPR (∼30% caloric and ∼70% protein restriction) during the 1st cycle and a 2nd cycle preceded by a normal diet (ND) or vice versa. During both cycles, 24-hours blood sampling was performed and 24-26 hours after infusion biopsies of both healthy liver (HL) and liver metastasis (LM) were taken. Primary endpoint was the relative difference in geometric means for the active metabolite SN-38 concentration in HL, as analyzed by a linear mixed model. Secondary endpoints included irinotecan and SN-38 concentrations in LM, plasma area under the curve (AUC0-24h), and toxicity. Results Interpatient variability (n = 19) in tissue irinotecan and SN-38 concentrations was high, showing no significant differences in irinotecan (+16.8%, 95% CI: -9.7-51.1%, P = 0.227) and SN-38 (+9.8%, 95% CI: -16.4-44.2%, P = 0.48) concentrations between CCPR and ND in HL, as well as in LM (irinotecan: -38.8%, 90% CI: -59.3:-7.9%, P = 0.05 and SN-38: -13.8%, 90% CI:-40.7-25.4%, P = 0.50). CCPR increased irinotecan plasma AUC0-24h with 7.1% (95% CI: 0.3-14.5%, P = 0.04) compared to ND, while the SN-38 plasma AUC0-24h increased with 50.3% (95% CI: 34.6-67.9%, P Conclusions CCPR resulted in a dramatically increased plasma SN-38 exposure, while toxicity did not change. CCPR did not result in altered irinotecan and SN-38 exposure in HL and LM. CCPR might therefore potentially improve the therapeutic window in patients treated with irinotecan. Clinical trial identification Netherlands Trial Register NL5624 (NTR5731) release date: 2016-03-04. Legal entity responsible for the study A.H.J. Mathijssen. Funding Has not received any funding. Disclosure S.L. Koolen: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Pfizer; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. R.H.J. Mathijssen: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier; Honoraria (institution): Novartis; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Astellas. All other authors have declared no conflicts of interest.

Background For individual treatment planning in patients with metastatic castration resistant prostate cancer (mCRPC), molecular analyses are increasingly used. As most patients have bone only disease, bone biopsies are often the only source for tumour tissue. However, the success rate of computed tomography (CT)-guided bone biopsies for molecular analyses in mCRPC patients is only 36.5-44%. Positron emission tomography (PET) using 68Ga-PSMA is a promising tool to increase the success rate of bone biopsies for molecular analyses in mCRPC patients. Methods In this multicenter study, the success rate of 68Ga-PSMA guided bone biopsies for molecular diagnostics was retrospectively evaluated in a subset of mCRPC patients who underwent a bone biopsy for whole-genome DNA sequencing within the CPCT-02 study (NCT01855477). To evaluate whether biopsies were obtained from a 68Ga-PSMA positive lesion, rigid body image registration of 68Ga-PSMA PET/CT and interventional CT was performed. This technique provided volume of interest (VOI) based quantification of 68Ga-PSMA uptake at the exact biopsy site. In addition, the potential impact of molecular analyses on clinical decision making was evaluated. Results Sixty-nine 68Ga-PSMA-guided biopsies were eligible for primary analysis. Based on tumor percentage ≥ 30%, 70% of 68Ga-PSMA-guided biopsies was eligible for molecular analyses. At biopsy sites with positive, inconclusive or negative 68Ga-PSMA uptake, tumour percentage was ≥ 30% in 73%, 55% and 36% of the biopsies, respectively (p = 0.0850). At sites of biopsies with a tumour percentage ≥ 30%, standardized uptake value (SUV)max and SUVmean of 68Ga-PSMA were significantly higher (p = 0.0260 and p = 0.0129 respectively), whereas Hounsfield units (HU)mean and HUmax on CT were significantly lower (p = 0.0189 and p = 0.0494 respectively). Molecular analyses identified potentially targetable aberrations including PTEN loss, AR amplifications, and BRCA variants. Conclusions 68Ga-PSMA PET/CT is a useful technique to improve the success rate of CT-guided bone biopsies for molecular analyses in mCRPC patients. Successful bone biopsies for molecular analyses can improve individual treatment planning by detecting targetable mutations. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure R. de Wit: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Janssen; Advisory / Consultancy: Clovis. N. Mehra: Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi Genzyme; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Bayer. A.A.M. Van der Veldt: Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: Pierre Fabre; Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: Sanofi; Honoraria (institution), Advisory / Consultancy: Ipsen. M.P. Lolkema: Research grant / Funding (institution): JNJ; Research grant / Funding (institution): Astellas. All other authors have declared no conflicts of interest.

Background Ineffective chemotherapy may partly be caused by subtherapeutic intratumoral drug levels. Nanomedicines are developed to improve the therapeutic index, by increasing intratumoral drug exposure and preserving healthy tissue. CPC634 is a new nanoparticle entrapping docetaxel. Here, we hypothesized that CPC634 increases intratumoral docetaxel level and overall duration of exposure. Methods In this randomized cross-over study we assessed both plasma and intratumoral pharmacokinetics (PK) of docetaxel after intravenous administration of 75 mg/m2 conventional docetaxel (Cd) and CPC634. We aimed to identify a 25% increase of intratumoral docetaxel exposure after CPC634 infusion compared to Cd. Adult patients were randomized to receive Cd in cycle 1 and CPC634 in cycle 2 or vice versa. Tumor biopsies were taken 24, 48, 72, 96, 168 or 336 hours after infusion during both cycles. Total docetaxel concentration (TDC) was determined for both drugs and released docetaxel for CPC634 in tumor tissue and plasma. PK data were analyzed using mixed modeling. Results In total, 21 evaluable patients were included. In plasma, the area under the curve (AUCinf) of released docetaxel was higher (+27%, 95% CI: 11-44%, P = 0.001) while peak plasma concentration (Cmax) (-91%, 95% CI: -92:-89%, P Conclusions The plasma PK profile of CPC634 is favorable compared to Cd since a lower Cmax, lower clearance and prolonged higher systemic exposure is seen. Higher intratumoral TDC levels were reached with CPC634, while released docetaxel levels were comparable to Cd. The almost 4-fold increased tumor accumulation for prolonged period of time of TDC supports the expectation that CPC634 will exhibit beneficial efficacy/safety balance. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in platinum resistant ovarian cancer patients (NCT03742713) are currently ongoing. Clinical trial identification Netherlands Trial Registry NL6299 (NTR6474). Legal entity responsible for the study Prof. Dr. A.H.J. Mathijssen as principle investigator. Funding Cristal Therapeutics. Disclosure C.J.F. Rijcken: Officer / Board of Directors: Cristal Therapeutics; Leadership role: Cristal Therapeutics; Shareholder / Stockholder / Stock options: Cristal Therapeutics; Full / Part-time employment: Cristal Therapeutics. R. Hanssen: Full / Part-time employment: Cristal Therapeutics. R.H.J. Mathijssen: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier; Honoraria (institution): Novartis; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Astellas. S.L. Koolen: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. All other authors have declared no conflicts of interest.

Background Blocking both receptor and ligand of the vascular endothelial growth factor (receptor) VEGF(R) pathway might be feasible and increase antitumor activity. This phase I study investigated telatinib, an oral tyrosine kinase inhibitor targeting VEGFR-2, combined with bevacizumab, in adults with solid tumors. Patients and methods Twenty-six patients were treated in successive cohorts with telatinib (twice-daily continuously, 450–900 mg) or bevacizumab (bi-weekly, starting dose 5 mg/kg). Safety, pharmacokinetics, endothelial (progenitor) cell (E(P)C)/growth factor kinetics and efficacy were assessed. Results Most frequent adverse events were pain, nausea, voice changes and fatigue. Five dose-limiting toxicities (DLTs) occurred: hypertension (cohort I and II), bowel perforation, lipase increase and atrial flutter (cohort III). Cumulative toxicity resulted in a bevacizumab dose reduction to 1 mg/kg (cohort III). Due to three DLTs (n = 14), this cohort represented the best-tolerated dose level. Bevacizumab effectively neutralized plasma VEGF even at 1 mg/kg. Twelve patients had stable disease (clinical benefit 46%). EPC and SDF-1α levels increased during monotherapy telatinib. Conclusions Telatinib (450 mg b.i.d.) combined with bevacizumab (1 mg/kg bi-weekly) shows antitumor activity, but accumulating constitutional toxicity impedes long-term treatment of patients. Therefore, this combination will not be pursued in a phase II setting.

Aim: Retrospective analyses of clinical studies of pazopanib showed an increased median PFS in patients with plasma trough levels (TLs) ≥ 20.6 mg/L compared to patients with lower TLs (49.4 wks vs. 20.3 wks). This is in line with preclinical data showing optimal efficacy at concentrations above 17.5 mg/L. Due to inter-individual variability in plasma exposure, target TLs are not reached in ∼30% of patients with the current dosing schedule of 800 mg daily. Therefore, a Phase I study was performed to determine the safety and feasibility of pharmacokinetically (PK)-guided dosing of pazopanib. Methods: 30 patients with solid tumors with a potential benefit from pazopanib treatment were included. Weekly TLs were measured by LC-MS/MS. At week 3, 5 and 7 the dose could be increased when the measured TL was Results: At data cut-off (April 2014) the planned total of 30 patients was included of which 26 patients had completed the PK evaluation period of 8 weeks or had stopped treatment due to toxicity (n = 4). 14 out of 26 patients had at least one TL below the target during this period. Of these, 8 patients had successful dose increases of 25% to 125% (1,000 to 1,800 mg), without non-tolerable toxicity. The mean TL (CV%, range) increased from 12.3(41.9, 7.80 – 22.5) to 22.4 (44.0, 8.77 – 43.1) mg/L. In the remaining 6 patients dose escalation was not possible due to toxicity. 12 out of 26 patients had all TLs above target. Of these 12 patients, 8 patients needed a dose reduction due to grade 3 and 4 toxicity and, therefore, the mean TL in this group decreased from 49.1 (39.9, 30.2 – 79.5) to 26.3 (27.5, 17.8 – 36.0) mg/L. Conclusions: Individualized pharmacokinetically guided dosing of pazopanib is feasible and safe and leads to a higher proportion of patient reaching the desired target exposure. Additional (randomized) clinical trials on outcome parameters such as response rate and progression free survival are needed. Disclosure: All authors have declared no conflicts of interest.