Pan-cancer whole-genome analyses of metastatic solid tumours.

Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.

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.

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.

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.

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.

Screening and Stepped Care Targeting Psychological Distress in Patients With Metastatic Colorectal Cancer: The TES Cluster Randomized Trial.

BACKGROUND: This study evaluated the effectiveness of a screening and stepped care program (the TES program) in reducing psychological distress compared with care as usual (CAU) in patients with metastatic colorectal cancer starting with first-line systemic palliative treatment. PATIENTS AND METHODS: In this cluster randomized trial, 16 hospitals were assigned to the TES program or CAU. Patients in the TES arm were screened for psychological distress with the Hospital Anxiety and Depression Scale and the Distress Thermometer/Problem List (at baseline and 10 and 18 weeks). Stepped care was offered to patients with distress or expressed needs, and it consisted of watchful waiting, guided self-help, face-to-face problem-solving therapy, or referral to specialized mental healthcare. The primary outcome was change in psychological distress over time, and secondary outcomes were quality of life, satisfaction with care, and recognition and referral of distressed patients by clinicians. Linear mixed models and effect sizes were used to evaluate differences. RESULTS: A total of 349 patients were randomized; 184 received the TES program and 165 received CAU. In the TES arm, 60.3% of the patients screened positive for psychological distress, 26.1% of which entered the stepped care program (14.7% used only watchful waiting and 11.4% used at least one of the other treatment steps). The observed low use of the TES program led us to pursue a futility analysis, which showed a small conditional power and therefore resulted in halted recruitment for this study. No difference was seen in change in psychological distress over time between the 2 groups (effect size, -0.16; 95% CI, -0.35 to 0.03; P>.05). The TES group reported higher satisfaction with the received treatment and better cognitive quality of life (all P<.05). CONCLUSIONS: As a result of the low use of stepped care, a combined screening and treatment program targeting psychological distress in patients with metastatic colorectal cancer did not improve psychological distress. Our results suggest that enhanced evaluation of psychosocial concerns may improve aspects of patient well-being.

Four-year effects of exercise on fatigue and physical activity in patients with cancer.

BACKGROUND: In the earlier randomized controlled Physical Activity during Cancer Treatment (PACT) study, we found beneficial effects of an 18-week supervised exercise program on fatigue in patients with newly diagnosed breast or colon cancer undergoing adjuvant treatment. The present study assessed long-term effects of the exercise program on levels of fatigue and physical activity 4 years after participation in the PACT study. METHODS: The original study was a two-armed, multicenter randomized controlled trial comparing an 18-week supervised exercise program to usual care among 204 breast cancer patients and 33 colon cancer patients undergoing adjuvant treatment. Of the 237 PACT participants, 197 participants were eligible and approached to participate in the 4-year post-baseline measurements, and 128 patients responded. We assessed fatigue and physical activity levels at 4 years post-baseline and compared this to levels at baseline, post-intervention (18 weeks post-baseline), and at 36 weeks post-baseline. RESULTS: Intention-to-treat mixed linear effects model analyses showed that cancer patients in the intervention group reported significantly higher moderate-to-vigorous total physical activity levels (141.46 min/week (95% confidence interval (CI) 1.31, 281.61, effect size (ES) = 0.22) after 4 years compared to the usual care group. Furthermore, cancer patients in the intervention group tended to experience less physical fatigue at 4 years post-baseline compared to the usual care group (- 1.13, 95% CI -2.45, 0.20, ES = 0.22), although the result was not statistically significant. CONCLUSION: Patients with breast or colon cancer who participated in the 18-week exercise intervention showed significant higher levels of moderate-to-vigorous total physical activity levels and a tendency towards lower physical fatigue levels 4 years post-baseline. Our result indicate that exercising during chemotherapy is a promising strategy for minimizing treatment-related side effects, both short and long term. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571 , Dutch Trial Register NTR2138 . Trial registered on 9 December 2009.

A randomised, phase II study of repeated rhenium-188-HEDP combined with docetaxel and prednisone versus docetaxel and prednisone alone in castration-resistant prostate cancer (CRPC) metastatic to bone; the Taxium II trial.

BACKGROUND: Rhenium-188-HEDP is a beta-emitting radiopharmaceutical used for palliation of metastatic bone pain. We investigated whether the addition of rhenium-188-HEDP to docetaxel/prednisone improved efficacy of chemotherapy in patients with CRPC. METHODS: Patients with progressive CRPC and osteoblastic bone metastases were randomised for first-line docetaxel 75 mg/m2 3-weekly plus prednisone with or without 2 injections of rhenium-188-HEDP after the third (40 MBq/kg) and after the sixth (20 MBq/kg) cycle of docetaxel. Primary endpoint was progression-free survival (PFS), defined as either PSA, radiographic or clinical progression. Patients were stratified by extent of bone metastases and hospital. RESULTS: Forty-two patients were randomised for standard treatment and 46 patients for combination therapy. Median number of cycles of docetaxel was 9 in the control group and 8 in the experimental group. Median follow-up was 18.4 months. Two patients from the experimental group did not start treatment after randomisation. In the intention to treat analysis no differences in PFS, survival and PSA became apparent between the two groups. In an exploratory per-protocol analysis median overall survival was significantly longer in the experimental group (33.8 months (95%CI 31.75-35.85)) than in the control group (21.0 months (95%CI 13.61-28.39); p 0.012). Also median PFS in patients with a baseline phosphatase >220U/L was significantly better with combination treatment (9.0 months (95%CI 3.92-14.08) versus 6.2 months (95%CI 3.08-9.32); log rank p 0.005). As expected, thrombocytopenia (grade I/II) was reported more frequently in the experimental group (25% versus 0%). CONCLUSION: Combined treatment with rhenium-188-HEDP and docetaxel did not prolong PFS in patients with CRPC. The observed survival benefit in the per-protocol analysis warrants further studies in the combined treatment of chemotherapy and radiopharmaceuticals.

Effects of an 18-week exercise programme started early during breast cancer treatment: a randomised controlled trial.

BACKGROUND: Exercise started shortly after breast cancer diagnosis might prevent or diminish fatigue complaints. The Physical Activity during Cancer Treatment (PACT) study was designed to primarily examine the effects of an 18-week exercise intervention, offered in the daily clinical practice setting and starting within 6 weeks after diagnosis, on preventing an increase in fatigue. METHODS: This multi-centre controlled trial randomly assigned 204 breast cancer patients to usual care (n = 102) or supervised aerobic and resistance exercise (n = 102). By design, all patients received chemotherapy between baseline and 18 weeks. Fatigue (i.e., primary outcome at 18 weeks), quality of life, anxiety, depression, and physical fitness were measured at 18 and 36 weeks. RESULTS: Intention-to-treat mixed linear model analyses showed that physical fatigue increased significantly less during cancer treatment in the intervention group compared to control (mean between-group differences at 18 weeks: -1.3; 95 % CI -2.5 to -0.1; effect size -0.30). Results for general fatigue were comparable but did not reach statistical significance (-1.0, 95%CI -2.1; 0.1; effect size -0.23). At 18 weeks, submaximal cardiorespiratory fitness and several muscle strength tests (leg extension and flexion) were significantly higher in the intervention group compared to control, whereas peak oxygen uptake did not differ between groups. At 36 weeks these differences were no longer statistically significant. Quality of life outcomes favoured the exercise group but were not significantly different between groups. CONCLUSIONS: A supervised 18-week exercise programme offered early in routine care during adjuvant breast cancer treatment showed positive effects on physical fatigue, submaximal cardiorespiratory fitness, and muscle strength. Exercise early during treatment of breast cancer can be recommended. At 36 weeks, these effects were no longer statistically significant. This might have been caused by the control participants' high physical activity levels during follow-up. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571, Dutch Trial Register NTR2138. Trial registered on December 9th, 2009.

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.

Impact of TP53 loss-of-function alterations on the response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer patients.

Rationale: PSMA-targeting radioligand therapy (PSMA-RLT) has shown promise in metastatic castration-resistant prostate cancer (mCRPC), particularly in PSMA-avid tumours. However, predicting response remains challenging. Preclinical data suggests aberrant p53-signalling as a predictor of poor response. Methods: The patient population of this pre-planned retrospective cohort study consists of 96 patients with mCRPC who underwent treatment with PSMA-RLT and were molecularly profiled by whole-genome sequencing and or targeted next-generation sequencing. Response to PSMA-RLT was assessed per molecular subtype, including TP53-mutational status. Results: Patients with TP53 loss-of-function alterations had a shorter median progression-free survival (3.7 versus 6.2 months, P<0.001), a lower median PSA change (-55% vs. -75%, P=0.012) and shorter overall survival from initiation of PMSA-RLT (7.6 vs. 13.9 months, P=0.003) compared to TP53-wildtype patients. Pathogenic alterations in AR, MYC, BRCA1, or BRCA2 as well as in genes linked to the PI3K or MAPK pathways or genes involved in homologous recombination repair, were not associated with response. Only lactate dehydrogenase was, alongside TP53-status, significantly associated with response. Transcriptome analysis of 21 patients, identified six p53 signalling genes whose low expression was associated to a shorter progression-free survival (P<0.05). Conclusion: TP53 loss-of-function may serve as a prognostic factor for PSMA-RLT outcomes in patients with mCRPC.

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. EXPERIMENTAL DESIGN: DRUP is a multicenter, nonrandomized clinical basket trial treating patients with therapy-refractory cancer 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 comparedwithoutcomes of includedpatientswho didnot receive awaiver. RESULTS: Between September 1, 2016, and September 1, 2021, protocol waivers were granted for 82 patients (8%) of 1,019 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 who received a waiver (pW) and patients who 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). CONCLUSIONS: 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. See related commentary by Waqar and Govindan, p. 3655.

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.

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.

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.

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.

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.

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.