Discussion
histotype-based, cancers, toxicity, tumours, cancer, TTP, high-grade glioma, cancer deaths, tumour, gallbladder cancers, cancer histotypes, cholangiocarcinoma
CANCERS, PERIVASCULAR EPITHELIOID CELL TUMOUR, ADVERSE EVENTS, GALLBLADDER ADENOCARCINOMA, DISEASE, TUMOURS, METASTATIC CHOLANGIOCARCINOMA, CANCER, RELAPSED OVARIAN CANCER, TUMOUR, NEUROENDOCRINE CARCINOMA, GALLBLADDER CANCERS, TTP, CHOLANGIOCARCINOMA
In this signal-seeking trial, 14 of 48 patients (29%) achieved either an OTR or a favourable TTP ratio. This encouraging result fulfils the original co-primary endpoint of objective response and TTP2/1 >1.3.O + D demonstrates a signal of clinical activity with a PFS6 rate of 35% (group 1) and 38% (group 2) across a range of tumour histotypes harbouring a HRR gene alteration. This is further supported by the durability of the objective tumour responses and an improvement in disease trajectory for individual patients, captured by the TTP2/1 ratios. Three patients (19%) achieved an OTR in group 1, along with three additional TTP2/1 evaluable patients (23%) who experienced a TTP2/1 ratio >1.3. In group 2, three patients (9%) achieved an OTR, and five additional patients (18%) demonstrated an improved TTP2/1 ratio. A median OS of 11.3 (group 1) and 15.1 (group 2) months is also favourable in a cohort comprised of rare cancers with poor prognoses. Combination treatment revealed no new toxicity concerns, with adverse events consistent with earlier trials [To our knowledge, this study is the first to demonstrate durable objective tumour responses to PARP plus PD-L1 inhibition in a gallbladder adenocarcinoma, cholangiocarcinoma, neuroendocrine carcinoma, a uterine perivascular epithelioid cell tumour (PeCOMA) and high-grade glioma, all selected on the basis of somatic or germline HRR gene alterations. Most of the cancers where we observed an OTR have limited therapeutic options beyond the first-line setting. Median OS for patients with locally advanced or metastatic cholangiocarcinoma and  gallbladder cancers treated with cisplatin-gemcitabine, or gemcitabine alone is only 11.7 and 8.1 months, respectively [Without randomisation, it is not possible to separate out the role of PARP inhibition and/ or PD-L1 inhibition in these durable objective responses and/or disease stabilisation. Earlier trials examining the safety and efficacy of PARP plus PD-L1 have mostly been histotype-specific and/or limited in their molecular eligibility. In the MEDIOLA basket studies, all cohorts were histotype-limited, with the advanced breast and relapsed ovarian cancer cohorts permitting only germline The first randomised trial of O + D versus durvalumab alone was published recently [All objective responses in this trial were in tumours harbouring Exploratory biological studies compared baseline to week 4 samples after olaparib exposure alone, and then following exposure to O + D. The correlation of high baseline CD38+ B-cell populations with improved clinical outcomes is novel, although we did not observe an effect of olaparib priming on this cell population and cannot delineate histotype-based associations with high baseline levels. B cells can promote anti-tumour immunity through the release of cytokines such as IL-12, IFNγ, granzyme B and TRAIL57 [The strengths of this signal-seeking study are inclusion of less common cancer histotypes and a rich range of correlative biomarkers that add depth to understanding individual responses. As rare and less common cancers account for half of all cancer deaths, their inclusion in clinical trials is vital to improving survival outcomes for patients with cancer as a whole. This however does introduce heterogeneity into the study population based on inherent differences in prognosis between cancer types. Also, the use of archival tissue for dynamic biomarker evaluation can challenge their interpretation.