Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations

Dealing with resistance to mTOR inhibitors in cancer : new ways to improve therapeutic strategies in breast and bladder cancers

The Phosphoinositide 3-Kinase (PI3K)/ Protein Kinase B (Akt)/ mammalian Target of Rapamycin (mTOR) pathway is one of the most dysregulated signalling cascades in human cancer. As this pathway is critically involved in cell proliferation, survival and angiogenesis, mTOR appears as a promising target for cancer therapy. Although rapamycin and derivatives (rapalogs) have demonstrated antiproliferative properties in a wide spectrum of pre-clinical models, they achieve only modest efficacy in clinical trials. This work, by exploring the antitumoral efficacy of rapalogs in two common human cancers, highlighted novel insights in the mTOR pathway understanding. The first part investigated the antitumoral activity of mTOR inhibitors in bladder cancer and, by integrating clinical and experimental approaches, deconstructed the resistance mechanisms developed by PTEN-deficient tumors against these agents. In a phase II trial, we evaluated everolimus in monotherapy in patients with advanced bladder cancer. Despite the frequent mTOR pathway alterations reported in bladder cancer, everolimus achieved limited clinical efficacy. In an exploratory way, we performed a retrospective immunohistochemical analysis of the PI3K/ Akt/ mTOR pathway in the pre-treated tumor samples, focusing on the expression of PTEN, a tumor suppressor protein that negatively regulates PI3K. Interestingly, loss of PTEN was observed only in patients insensitive to everolimus, contrasting with pre-clinical studies that showed that PTEN-deficient tumors could be more sensitive to mTOR inhibitors due to an unrepressed PI3K/ Akt activation and a subsequent constitutive stimulation of mTOR. Using several bladder cancer cell lines with different PTEN status, we observed that the absence of PTEN was indeed associated with resistance to rapamycin. We then demonstrated that PTEN-deficient tumors were not able to abrogate the Akt activation induced by mTOR inhibition, resulting in a sustained stimulation of multiple Akt-dependent survival pathways that counteract the anti-proliferative effects of rapamycin. Furthermore, we showed that the addition of a PI3K inhibitor to rapamycin could reverse this resistance induced by PTEN loss. In regards of these data, we are currently conducting a phase II trial evaluating the efficacy of BEZ-235, an inhibitor of both mTOR and PI3K catalytic activity in patients with advanced bladder cancer. The second part of this work explored the influence of hypoxia, commonly found in breast cancer, on the antitumoral efficacy of rapamycin. We observed in vitro that in a subset of breast cancer cells, hypoxia could decrease the efficacy of rapamycin through a strong stimulation of autophagy and that inhibition of autophagy by chloroquine (CQ) could reverse this resistance developed in hypoxia. Interestingly, this benefit induced by this association was not observed in our in vivo model when treating tumors at early stage of development. This was explained by the fact that rapamycin, by improving the oxygenation within the tumor, could render tumor cells less dependent of autophagy and thus less sensitive to CQ. Supporting this hypothesis, a robust antitumoral effect was observed when initiating this combined treatment in late-stage hypoxic and autophagy-dependent tumors. In conclusion, this work improves the current understanding of the mTOR pathway and reveals two additional potential mechanisms of resistance to rapalogs and attracting ways to improve efficacy of mTOR inhibitors.(MED - Sciences médicales) -- UCL, 201

The Evolution of Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma

Urothelial carcinoma is an aggressive cancer and development of metastases remains a challenge for clinicians. Immune checkpoint inhibitors (ICIs) are significantly improving the outcomes of patients with metastatic urothelial cancer (mUC). These agents were first used in monotherapy after failure of platinum-based chemotherapy, but different strategies explored the optimal use of ICIs in a first-line metastatic setting. The “maintenance” strategy consists of the introduction of ICIs in patients who experienced benefit from first-line chemotherapy in a metastatic setting. This allows an earlier use of ICIs, without waiting for disease progression. We review the optimal management of mUC in the era of ICIs, based on the key clinical messages arising from the pivotal trials

Thérapies ciblées dans le carcinome rénal: Description de la voie signalétique mTOR (mammalian target of rapamycin) et de l'importance de son inhibition dans le traitement du carcinome rénal

La voie signalétique mTOR (mammalian Target of Rapamycin) joue un rôle important dans la tumorigenèse du cancer du rein. Elle stimule non seulement la croissance et la prolifération cellulaire mais également l’angiogenèse, si prépondérante dans les cancers rénaux. Cette voie mTOR se révèle donc être une cible thérapeutique de choix dans le traitement de ce cancer . Deux nouvelles molécules, le Temsirolimus et l’Everolimus ont notamment fait leurs preuves que ce soit en première ligne ou en deuxième ligne, après échec des inhibiteurs tyrosine kinase (sunitinib ou sorafenib) ou anticorps contre le Vascular Endothelial Growth Factor (bevacizumab)

Molecular biology and targeted therapies for urothelial carcinoma

Metastatic urothelial cancer (UC) is associated with poor prognosis. In the first-line setting, platinum-based chemotherapy is the standard of care but resistance rapidly occurs. With no validated treatment proven to increase survival after platinum failure, there is an urgent unmet medical need to develop new and efficacious cytotoxic agents. A better understanding of the molecular signaling pathways regulating UC has led to the development of new and innovative therapeutic strategies. Despite this, many recent drugs show only modest activity as single agents, and combining them with standard chemotherapy does not seem to enhance efficacy. Ongoing research is producing, however, a generation of new drugs that are showing promising results in clinical trials. This paper aims to review the most important mechanisms in bladder cancer tumorigenesis and describe the new therapeutic options currently undergoing evaluation in clinical trials