A sub-pharmacological test dose does not predict individual docetaxel exposure in prostate cancer patients.

PURPOSE: Docetaxel is a cytotoxic drug used for first-line treatment of various malignancies. It has a narrow therapeutic index and shows wide interpatient variability in clearance and toxicity. Tools for individual dose optimization are needed to maximize efficacy and avoid toxicity. METHODS: We performed a proof-of-concept study (EudraCT 2016-003785-77) to evaluate whether pharmacokinetics after a sub-pharmacological test dose of 1000 µg docetaxel (millidose) could be used to predict therapeutic dose exposure. Thirty prostate cancer patients eligible for treatment with docetaxel as part of routine clinical care were included. An intravenous docetaxel millidose was administered 1-7 days prior to therapeutic docetaxel. After both doses plasma docetaxel concentrations were measured by ultra- high performance liquid chromatography-tandem mass spectrometry. The docetaxel clearance was estimated with non-linear mixed effects modeling. RESULTS: Geometric mean docetaxel clearance was 57.9 L/h (GCV 78.6%) after admission of a millidose and 40.3 L/h (GCV 60.7%) after admission of a therapeutic dose. The millidose and therapeutic dose in a single patient were not significantly correlated (Spearman's rho R = 0.02, P = 0.92). CONCLUSION: Docetaxel pharmacokinetics at milli- and therapeutic dose level showed insufficient correlation for individual dose optimization. However, the clearance of a docetaxel millidose and full dose are within the same order of magnitude. Therefore, docetaxel millidose pharmacokinetics could potentially facilitate prediction of docetaxel pharmacokinetics at a population level in situations where therapeutic dose levels are impractical, such as pharmacokinetic drug-drug interaction studies or pediatric studies.

Maximizing treatment opportunities: assessing protocol waivers' impact on safety and outcome in the Drug Rediscovery Protocol.

PURPOSE: Although eligibility criteria are essential in trial design, overly restrictive criteria contribute to low accrual and limited generalizability. To enhance trial inclusivity, there has been growing interest in broadening eligibility criteria, especially for patients with advanced or treatment-refractory disease. Yet, the impact on patient safety remains uncertain. In the Drug Rediscovery Protocol (DRUP), protocol exceptions are frequently requested and occasionally granted. Here we describe the impact of these waivers on treatment safety and efficacy. PATIENTS AND METHODS: DRUP is a multicenter, non-randomized clinical basket trial treating therapy-refractory cancer patients with molecularly targeted- and immunotherapies outside their registered indications (NCT02925234). Here, all granted waivers were revised, analyzed in terms of safety and efficacy outcome, and compared with outcomes of included patients that did not receive a waiver. RESULTS: Between September 1st 2016 and September 1st 2021, protocol waivers were granted for 82 patients (8%) out of 1019 included patients in DRUP. Most waivers (45%) were granted for general- or drug-related eligibility criteria, other categories were out-of-window testing, treatment and testing exceptions. Serious adverse event rate was similar between patients that received a waiver (pW) and patients that did not (pNW): 39% vs. 41%, respectively (P=0.81). The clinical benefit (either objective response or stable disease ≥ 16 weeks) rate of pW was 40% versus 33% in pNW (P=0.43). CONCLUSION: Safety and clinical benefit were preserved in patients for whom a waiver was granted. These data support a more personalized approach in assessing eligibility criteria, especially in trials with widely used and approved drugs accruing patients without other treatment options.

Cemiplimab in locally advanced or metastatic cutaneous squamous cell carcinoma: prospective real-world data from the DRUG Access Protocol.

Background: The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC). Methods: Patients with laCSCC or mCSCC received cemiplimab 350 mg fixed dose every three weeks. Primary endpoints were objective clinical benefit rate (CBR), defined as objective response (OR) or stable disease (SD) at 16 weeks, physician-assessed CBR, defined as clinician's documentation of improved disease or SD based on evaluation of all available clinical parameters at 16 weeks, objective response rate (ORR), and safety, defined as grade ≥ 3 treatment related adverse events (TRAEs) occurring up to 30 days after last drug administration. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Findings: Between February 2021 and December 2022, 151 patients started treatment. Objective and physician-assessed CBR were 54.3% (95% CI, 46.0-62.4) and 59.6% (95% CI, 51.3-67.5), respectively. ORR was 35.1% (95% CI, 27.5-43.3). After a median follow-up of 15.2 months, median DoR was not reached. Median PFS and OS were 12.2 (95% CI, 7.0-not reached) and 24.2 months (95% CI, 18.8-not reached), respectively. Sixty-eight TRAEs occurred in 29.8% of patients. Most commonly reported TRAE was a kidney transplant rejection (9.5%). Interpretation: Cemiplimab proved highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice. Funding: The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Janssen, Lilly, Merck, Novartis, Roche, and Sanofi.

Pharmacokinetic boosting of olaparib: A randomised, cross-over study (PROACTIVE-study).

BACKGROUND: Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of olaparib, a CYP3A-substrate, has the potential to reduce PK variability and financial burden. The aim of this study was to investigate equivalence of a boosted, reduced dose of olaparib compared to the non-boosted standard dose. METHODS: This cross-over, multicentre trial compared olaparib 300 mg twice daily (BID) with olaparib 100 mg BID boosted with the strong CYP3A-inhibitor cobicistat 150 mg BID. Patients were randomised to the standard therapy followed by the boosted therapy, or vice versa. After seven days of each therapy, dense PK sampling was performed for noncompartmental PK analysis. Equivalence was defined as a 90% Confidence Interval (CI) of the geometric mean ratio (GMR) of the boosted versus standard therapy area under the plasma concentration-time curve (AUC0-12 h) within no-effect boundaries. These boundaries were set at 0.57-1.25, based on previous pharmacokinetic studies with olaparib capsules and tablets. RESULTS: Of 15 included patients, 12 were eligible for PK analysis. The GMR of the AUC0-12 h was 1.45 (90% CI 1.27-1.65). No grade ≥3 adverse events were reported during the study. CONCLUSIONS: Boosting a 100 mg BID olaparib dose with cobicistat increases olaparib exposure 1.45-fold, compared to the standard dose of 300 mg BID. Equivalence of the boosted olaparib was thus not established. Boosting remains a promising strategy to reduce the olaparib dose as cobicistat increases olaparib exposure Adequate tolerability of the boosted therapy with higher exposure should be established.

TripleAiM1: a nationwide registry of de novo metastatic hormone-sensitive prostate cancer with prospective quality-of-life assessment.

INTRODUCTION: The treatment landscape for de novo metastatic hormone sensitive prostate cancer (mHSPC) is rapidly evolving. With an abundance of available treatment strategies, selecting the optimal strategy for an individual patient is becoming increasingly challenging. TripleAiM1 aims to evaluate the impact of mHSPC treatments on health-related quality of life (HRQoL) and to provide real-world data insights on diagnostics, treatment strategies, patient subgroups and related healthcare expenditure for mHSPC. The aspirational target of TripleAiM1 is that in the near future, a more tailored therapy can be offered based on the individual patient's wishes and needs in accordance with the overarching principle of value-based healthcare. METHODS AND ANALYSIS: We describe the TripleAiM1 study design; a nationwide registry comprising a retrospective and prospective cohort of patients with de novo mHSPC. Starting in May 2020, eligible patients are identified, selected and recruited in 14 participating hospitals in the Netherlands. Our hypothesis is that, in a real-world setting, differences in clinically meaningful HRQoL deterioration will be observed for treatment strategies over time. HRQoL data, assessed with patient-reported outcome measures, costs and clinical data will be collected for 24 months.For the retrospective cohort, all patients diagnosed with de novo mHSPC from January 2017 onwards are eligible for inclusion. Patient and tumour characteristics, imaging modalities and treatment patterns will be analysed descriptively to provide a real-world overview.Time-to-event endpoints will be assessed using the Kaplan-Meier method and regression models will be employed to analyse baseline characteristics associated with an increased likelihood of death, progression and HRQoL deterioration. Longitudinal mixed-effects models will be employed to assess change of patient-reported outcome scores from baseline until the end of follow-up. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Medical Research Ethics Committee, Twente. Study results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NL9719.

How to create value with constrained budgets in oncological care? A narrative review.

INTRODUCTION: As a result of an increasing focus on patient-centered care within oncology and more pressure on the sustainability of health-care systems, the discussion on what exactly constitutes value re-appears. Policymakers seek to improve patient values; however, funding all values is not sustainable. AREAS COVERED: We collect available evidence from scientific literature and reflect on the concept of value, the possible incorporation of a wide spectrum of values in reimbursement decisions, and alternative strategies to increase value in oncological care. EXPERT OPINION: We state that value holds many different aspects. For reimbursement decisions, we argue that it is simply not feasible to incorporate all patient values because of the need for efficient resource allocation. We argue that we should shift the value debate from the individual perspective of patients to creating value for the cancer population at large. The different strategies we address are as follows: (1) shared decision-making; (2) biomarkers and molecular diagnostics; (3) appropriate evaluation, payment and use of drugs; (4) supportive care; (5) cancer prevention and screening; (6) monitoring late effect; (7) concentration of care and oncological networking; and (8) management of comorbidities. Important preconditions to support these strategies are strategic planning, consistent cancer policies and data availability.

The PRO-RCC study: a long-term PROspective Renal Cell Carcinoma cohort in the Netherlands, providing an infrastructure for 'Trial within Cohorts' study designs.

BACKGROUND: Ongoing research in the field of both localized, locally advanced and metastatic renal cell carcinoma has resulted in the availability of multiple treatment options. Hence, many questions are still unanswered and await further research. A nationwide collaborative registry allows to collect corresponding data. For this purpose, the Dutch PROspective Renal Cell Carcinoma cohort (PRO-RCC) has been founded, for the prospective collection of long-term clinical data, patient reported outcome measures (PROMs) and patient reported experience measures (PREMs). METHODS: PRO-RCC is designed as a multicenter cohort for all Dutch patients with renal cell carcinoma (RCC). Recruitment will start in the Netherlands in 2023. Importantly, participants may also consent to participation in a 'Trial within cohorts' studies (TwiCs). The TwiCs design provides a method to perform (randomized) interventional studies within the registry. The clinical data collection is embedded in the Netherlands Cancer Registry (NCR). Next to the standardly available data on RCC, additional clinical data will be collected. PROMS entail Health-Related Quality of Life (HRQoL), symptom monitoring with optional ecological momentary assessment (EMA) of pain and fatigue, and optional return to work- and/or nutrition questionnaires. PREMS entail satisfaction with care. Both PROMS and PREMS are collected through the PROFILES registry and are accessible for the patient and the treating physician. TRIAL REGISTRATION: Ethical board approval has been obtained (2021_218) and the study has been registered at ClinicalTrials.gov (NCT05326620). DISCUSSION: PRO-RCC is a nationwide long-term cohort for the collection of real-world clinical data, PROMS and PREMS. By facilitating an infrastructure for the collection of prospective data on RCC, PRO-RCC will contribute to observational research in a real-world study population and prove effectiveness in daily clinical practice. The infrastructure of this cohort also enables that interventional studies can be conducted with the TwiCs design, without the disadvantages of classic RCTs such as slow patient accrual and risk of dropping out after randomization.

Cross-Resistance between Platinum-Based Chemotherapy and PARP Inhibitors in Castration-Resistant Prostate Cancer.

Patients with metastatic castration-resistant prostate cancer (mCRPC) harbouring homologous recombination repair-related gene aberrations (HRRm) can derive meaningful benefits from both platinum-based chemotherapy (PlCh) and PARP inhibitors (PARPi). Cross-resistance between these agents is well-recognised in other tumour types but data on prostate cancer is lacking. In this retrospective pre-planned study, we assessed 28 HRRm mCRPC patients who received PlCh and PARPi. Progression-free survival (PFS) on initial therapy was longer than on subsequent therapy (median 5.3 vs. 3.4 months, p = 0.016). The median PFS of PlCh was influenced by the order of agents, with 3.6 months shorter PFS after PARPi than when administered first. The median PFS of PARPi was less influenced, with 0.9 months shorter PFS after PlCh than before. In the PARPi-first subgroup, six out of 16 evaluable patients (37.5%) had a >50% PSA decline to PlCh, and two of eight (25.0%) had a radiographic response to PlCh. In the PlCh-first subgroup, 6/10 (60.0%) had a >50% PSA decline, and 5/9 (55.6%) had a radiographic response to PARPi. These data show >40% of the cohort is sensitive to a subsequent HRR-targeting agent. PlCh appears to induce less cross-resistance than PARPi. Additional data on resistance mechanisms will be crucial in defining an optimal treatment sequence in HRRm mCRPC patients.

A Systematic Review and Multilevel Regression Analysis Reveals the Comorbidity Prevalence in Cancer.

Comorbidities can have major implications for cancer care, as they might impact the timing of cancer diagnosis, compromise optimal care, affect treatment outcomes, and increase healthcare costs. Thus, it is important to comprehensively evaluate cancer comorbidities and examine trends over time. Here, we performed a systematic literature review on the prevalence and types of comorbidities for the five most common forms of cancer. Observational studies from Organisation for Economic Co-operation and Development countries published between 1990 and 2020 in English or Dutch that used routinely collected data from a representative population were included. The search yielded 3,070 articles, of which, 161 were eligible for data analyses. Multilevel analyses were performed to evaluate determinants of variation in comorbidity prevalence and trends over time. The weighted average comorbidity prevalence was 33.4%, and comorbidities were the most common in lung cancer (46.7%) and colorectal cancer (40.0%), followed by prostate cancer (28.5%), melanoma cancer (28.3%), and breast cancer (22.4%). The most common types of comorbidities were hypertension (29.7%), pulmonary diseases (15.9%), and diabetes (13.5%). After adjusting for gender, type of comorbidity index, age, data source (patient records vs. claims), and country, a significant increase in comorbidities of 0.54% per year was observed. Overall, a large and increasing proportion of the oncologic population is dealing with comorbidities, which could be used to inform and adapt treatment options to improve health outcomes and reduce healthcare costs. SIGNIFICANCE: Comorbidities are frequent and increasing in patients with cancer, emphasizing the importance of exploring optimal ways for uniform comorbidity registration and incorporating comorbidity management into cancer care.

Cancer treatments touch a wide range of values that count for patients and other stakeholders: What are the implications for decision-making?

BACKGROUND: Cancer rates and expenditures are increasing, resulting in debates on the exact value of this care. Perspectives on what exactly constitutes worthwhile values differ. This study aims to explore all values-elements regarding new oncological treatments for patients with cancer and all stakeholders involved and to assess their implications in different decision-making procedures. METHOD: Thirty-one individual in-depth interviews were conducted with different stakeholders to identify values within oncology. A focus group with seven experts was performed to explore its possible implications in decision-making procedures. RESULTS: The overarching themes of values identified were impact on daily life and future, costs for patients and loved ones, quality of life, impact on loved ones, societal impact and quality of treatments. The expert panel revealed that the extended exploration of values that matter to patients is deemed useful in patient-level decision-making, information provision, patient empowerment and support during and after treatment. For national reimbursement decisions, implications for the broad range of values seems less clear. CONCLUSION: Clinical values are not the only ones that matter to oncological patients and the stakeholders in the field. We found a much broader range of values. Proper recognition of values that count might add to patient-level decision-making, but implications for reimbursement decisions are less clear. The results could be useful to guide clinicians and policymakers when it comes to decision-making in oncology. Making more explicit which values counts for whom guarantees a more systematic approach to decision-making on all levels.

Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study.

Background: Mesenchymal Consensus Molecular Subtype 4 (CMS4) colon cancer is associated with poor prognosis and therapy resistance. In this proof-of-concept study, we assessed whether a rationally chosen drug could mitigate the distinguishing molecular features of primary CMS4 colon cancer. Methods: In the ImPACCT trial, informed consent was obtained for molecular subtyping at initial diagnosis of colon cancer using a validated RT-qPCR CMS4-test on three biopsies per tumor (Phase-1, n=69 patients), and for neoadjuvant CMS4-targeting therapy with imatinib (Phase-2, n=5). Pre- and post-treatment tumor biopsies were analyzed by RNA-sequencing and immunohistochemistry. Imatinib-induced gene expression changes were associated with molecular subtypes and survival in an independent cohort of 3232 primary colon cancer. Results: The CMS4-test classified 52/172 biopsies as CMS4 (30%). Five patients consented to imatinib treatment prior to surgery, yielding 15 pre- and 15 post-treatment samples for molecular analysis. Imatinib treatment caused significant suppression of mesenchymal genes and upregulation of genes encoding epithelial junctions. The gene expression changes induced by imatinib were associated with improved survival and a shift from CMS4 to CMS2. Conclusion: Imatinib may have value as a CMS-switching drug in primary colon cancer and induces a gene expression program that is associated with improved survival.

Cancer treatment and decision making in individuals with intellectual disabilities: a scoping literature review.

Adults with intellectual disabilities face disparities in receipt of cancer-related care, which could contribute to an increase in the rate of cancer-related deaths in this population. Yet, relatively little is known about the optimal cancer treatment or treatment decision making in adults with intellectual disabilities. This scoping review assessed PubMed and Embase for available literature on the description of cancer treatment and treatment decision making in patients with intellectual disabilities, published in English between Jan 1, 2000, and April 30, 2020. We appraised 90 included articles and extracted quotes addressing aspects related to cancer treatment and treatment decision making in patients with intellectual disabilities. Themes and subcategories were subsequently derived. Our findings revealed that the available literature describes that people with intellectual disabilities tend to have less intensive cancer treatment than generally administered, but with little evidence supporting this approach. This finding indicates that this medically vulnerable patient population needs tailored attention in both cancer care and research. We propose changes to practice and conclude by addressing the urgent need to pay specific attention to this patient population.

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19: an update from the Dutch Oncology COVID-19 Consortium.

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic.

Impact of molecular tumour board discussion on targeted therapy allocation in advanced prostate cancer.

BACKGROUND: Molecular tumour boards (MTB) optimally match oncological therapies to patients with genetic aberrations. Prostate cancer (PCa) is underrepresented in these MTB discussions. This study describes the impact of routine genetic profiling and MTB referral on the outcome of PCa patients in a tertiary referral centre. METHODS: All PCa patients that received next-generation sequencing results and/or were discussed at an MTB between Jan 1, 2017 and Jan 1, 2020 were included. Genetically matched therapies (GMT) in clinical trials or compassionate use were linked to actionable alterations. Response to these agents was retrospectively evaluated. RESULTS: Out of the 277 genetically profiled PCa patients, 215 (78%) were discussed in at least one MTB meeting. A GMT was recommended to 102 patients (47%), of which 63 patients (62%) initiated the GMT. The most recommended therapies were PARP inhibitors (n = 74), programmed death-(ligand) 1 inhibitors (n = 21) and tyrosine kinase inhibitors (n = 19). Once started, 41.3% had a PFS of ≥6 months, 43.5% a PSA decline ≥50% and 38.5% an objective radiographic response. CONCLUSION: Recommendation for a GMT is achieved in almost half of the patients with advanced prostate cancer, with GMT initiation leading to durable responses in over 40% of patients. These data justify routine referral of selected PCa patients to MTB's.

[Oncological treatment of patients with intellectual disability: too limited?] / Oncologische behandeling van patiënten met een verstandelijke beperking.

Genetic factors and lifestyle contribute to specific risks for developing cancer in people with intellectual disabilities. However, early detection and oncological care are less accessible to people with intellectual disabilities than to the general population, contributing to relatively more cancer-related deaths in this population. In order to optimally adapt oncological care to the characteristics and needs of people with intellectual disabilities, regular treatment may need to be adjusted sometimes. Yet, little is known about treatment adjustments in this setting. Scientific articles describing adaptations in oncological care for people with intellectual disabilities often provide no reasons as to why these changes were made. Adequately adapted oncological care for people with intellectual disabilities therefore mainly depends on affinity and experience of individual clinicians. Awareness for abnormal symptoms, genetic factors, and collaboration with other care providers, like the intellectual disability physician is advised.

Manufacturers' views on outcome-based agreements.

INTRODUCTION: Outcome-based agreements (OBAs) are occasionally deployed to relieve the burden of high drug prices on healthcare budgets. However, it is not clear when manufacturers are willing to collaborate in establishing such agreements. Therefore, we explored the feasibility of OBAs from the manufacturer's point of view. METHODS: Dutch market-access experts from eight major pharmaceutical companies, globally active in the field of oncology, were interviewed. Opinions were compiled, and interviewees and their colleagues were then given the chance to review the manuscript for additional comments. RESULTS: Most interviewees believe that OBAs can be useful in providing access to off-label use of authorised medicines, especially when no alternative treatment is available for seriously ill patients. For the licenced indications, manufacturers seem to be more inclined to collaborate when there is a potential incentive to improve market-access (e.g., if the product is not used because of concerns regarding its effectiveness). However, manufacturers are less likely to collaborate when there are greater financial risks for the company. Further concerns were definition of outcome or performance, the impact of compliance on the effectiveness of a drug, administrative burden, uncertainty regarding revenue recognition and the challenges of reimbursing combination therapies. DISCUSSION: Market-access interviewees were generally positive about OBAs, however they were more reluctant towards OBAs for registered indications with low response-rate. The definition of performance or outcome and its clinical relevance and validity, the feasibility of OBAs and their administrative burden are relevant aspects that need to be addressed in advance. Ideally, countries should collaborate to share the outline of OBAs and create shared databases to accumulate evidence.

Mechanisms of Immune Checkpoint Inhibitor-Mediated Colitis.

Immune checkpoint inhibitors (ICIs) have provided tremendous clinical benefit in several cancer types. However, systemic activation of the immune system also leads to several immune-related adverse events. Of these, ICI-mediated colitis (IMC) occurs frequently and is the one with the highest absolute fatality. To improve current treatment strategies, it is important to understand the cellular mechanisms that induce this form of colitis. In this review, we discuss important pathways that are altered in IMC in mouse models and in human colon biopsy samples. This reveals a complex interplay between several types of immune cells and the gut microbiome. In addition to a mechanistic understanding, patients at risk should be identifiable before ICI therapy. Here we propose to focus on T-cell subsets that interact with bacteria after inducing epithelial damage. Especially, intestinal resident immune cells are of interest. This may lead to a better understanding of IMC and provides opportunities for prevention and management.

Impact of DNA damage repair defects and aggressive variant features on response to carboplatin-based chemotherapy in metastatic castration-resistant prostate cancer.

Platinum-based chemotherapy is not standard of care for unselected or genetically selected metastatic castration-resistant prostate cancer (mCRPC) patients. A retrospective assessment of 71 patients was performed on platinum use in the Netherlands. Genetically unselected patients yielded low response rates. For a predefined subanalysis of all patients with comprehensive next-generation sequencing, 30 patients were grouped based on the presence of pathogenic aberrations in genes associated with DNA damage repair (DDR) or aggressive variant prostate cancer (AVPC). Fourteen patients (47%) were DDR deficient (DDRd), of which seven with inactivated BRCA2 (BRCA2mut). Six patients classified as AVPC. DDRd patients showed beneficial biochemical response to carboplatin, largely driven by all BRCA2mut patients having >50% prostate-specific antigen (PSA) decline and objective radiographic response. In the wild-type BRCA2 subgroup, 35% had a >50% PSA decline (P = .006) and 16% radiographic response (P < .001). Median overall survival was 21 months for BRCA2mut patients vs 7 months (P = .041) for those with functional BRCA2. AVPC patients demonstrated comparable responses to non-AVPC, including a similar overall survival, despite the poor prognosis for this subgroup. In the scope of the registration of poly-(ADP)-ribose polymerase inhibitors (PARPi) for mCRPC, we provide initial insights on cross-resistance between PARPi and platinum compounds. By combining the literature and our study, we identified 18 patients who received both agents. In this cohort, only BRCA2mut patients treated with platinum first (n = 4), responded to both agents. We confirm that BRCA2 inactivation is associated with meaningful responses to carboplatin, suggesting a role for both PARPi and platinum-based chemotherapy in preselected mCRPC patients.