A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965

A 47-year-old man with metastatic melanoma presented with refractory hyperlactaemic acidosis following the first dose of the mono-carboxylase transporter 1 inhibitor AZD3965 within a "first time in man" clinical trial. The mechanism of the agent and the temporal relationship suggested that this event was potentially drug related and recruitment was suspended. However, urinary metabolomics showed extensive abnormalities even prior to drug administration, leading to investigations for an underlying metabolic disorder. The lack of clinical symptoms from the elevated lactate and low blood glucose suggested a diagnosis of "hyper-Warburgism", where the high tumour burden was associated with extensive glucose uptake and lactate efflux from malignant cells, and the subsequent impact on blood biochemistry. This was supported by an FDG-PET scan showing extensive glucose uptake in numerous metastases and lack of uptake in the brain. A review of the literature showed 16 case reports of "hyper-Warburgism" in non-haematological malignancies, none of them with melanoma, with most associated with a poor outcome. The patient was treated symptomatically, but died 2 months later. The development of AZD3965 continues with the exclusion of patients with elevated plasma lactate at screening added to the protocol as a safety measure. Trial identification number ClinicalTrials.Gov. NCT01791595

Combining PARP Inhibitors and Androgen Receptor Signalling Inhibitors in Metastatic Prostate Cancer: A Quantitative Synthesis and Meta-analysis

Copyright \ua9 2023. Published by Elsevier B.V. CONTEXT: PARP inhibitors (PARPi) are established treatments for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) deficiency after androgen receptor signalling inhibitor (ARSI) failure. New PARPi + ARSI combinations have been tested in all comers, although their clinical relevance in HRR-proficient tumours remains uncertain. OBJECTIVE: To quantitatively synthesise evidence from randomised trials assessing the efficacy and safety of PARPi + ARSI combinations for first-line treatment of mCRPC. EVIDENCE ACQUISITION: We searched the PubMed, EMBASE, SCOPUS, and Cochrane Library databases up to February 28, 2023. Randomised controlled trials (RCTs) comparing PARPi + ARSI versus placebo + ARSI for first-line treatment of mCRPC were eligible. Two reviewers independently performed screening and data extraction and assessed the risk of bias, while a third reviewer evaluated the eligibility criteria. EVIDENCE SYNTHESIS: Overall, three phase 3 RCTs were included in the systematic review: PROPEL, MAGNITUDE, and TALAPRO-2. A total of 2601 patients with mCRPC were enrolled. Two of these trials (PROPEL and TALAPRO-2) assessed the radiographic progression-free survival benefit of PARPi + ARSI for first-line treatment of mCRPC, independent of HRR status. The pooled hazard ratio was 0.62 (95% confidence interval 0.53-0.72). The pooled hazard ratio for overall survival was 0.84 (95% confidence interval 0.72-0.98), indicating a 16% reduction in the risk of death among patients who received the combination. CONCLUSIONS: Results from this meta-analysis support the use of ARSI + PARPi combinations in biomarker-unselected mCRPC. However, such combinations might be less clinically relevant in HRR-proficient cancers, especially considering the change in treatment landscape for mCRPC. PATIENT SUMMARY: We looked at outcomes from trials testing combinations of two classes of drugs (PARP inhibitors and ARSI) in advanced prostate cancer. We found that these combinations seem to work regardless of gene mutations identified as biomarkers of response to PARP inhibitors when used on their own

The introduction of the Cancer Research UK Stratified Medicine Programme 2 (CRUK SMP2) in North East England; lessons learned and experience gained

Introduction: The CRUK SMP2 programme was set-up to evaluate the feasibility of performing large scale molecular analysis within the NHS on the (often small) diagnostic biopsies obtained in NSCLC. The results are used to allocate patients to an appropriate molecular therapy within the “umbrella” MATRIX trial. Newcastle opened SMP2 on 01/10/2014. Here we report our first year’s experience. Methods: NSCLC patients with PS 0–2 were consented onto the CRUK SMP2. Matched residual diagnostic tissue and blood were sent to All Wales Genetics Laboratory, Cardiff. Samples with >70ng DNA were assessed for 28 oncogenes using Next Genuine Sequencing on the Illumina SMP2 panel. Results: 116 patients were consented from 6/10/14–1/10/15 referred from 12 oncologists. The data on patient/sample flow is shown in Fig 1. Median survival was 161 days from consent. The 1st sample was sent to Cardiff on 28/1/15 as the Illumina panel was undergoing fi- nal validation. 50 samples have been sent; 11 had insufficient DNA; these samples had lower cell number (but with no impact of necrosis/tumour proportion); The most commonly altered gene was K-Ras (13 of 22 adenocarcinomas). Only 2 patients with results from >25 of the 28 genes had no tier 1 or 2 ie potentially treatable molecular abnormalities. The median time from consent to result was 109 days (range 45–250) with delays occurring throughout the pathway. Conclusion: Patients and oncologists are keen to be involved in molecular profiling; but patients need to be consented early to allow results to guide therapy. Prioritisation of samples is key. Not all samples are suitable for analysis due to small cell number or low tumour proportion. Molecular analysis may require extra resource in pathology, if it is to become standard of care. The first 4 patients to start treatment on MATRIX were enrolled from 27/8/15 in Newcastle. Disclosure: All authors have declared no conflicts of interest