Inflammation is a hallmark of cancer¹. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities^2–5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b⁺HLA-DR^loCD15⁺CD14⁻ myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.

Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management.

A deep understanding of the tumor microenvironment and the recognition of tumor-infiltrating lymphocytes as a prognostic factor have resulted in major milestones in immunotherapy that have led to therapeutic advances in treating many cancers. Yet, the translation of this knowledge to clinical success for ovarian cancer remains a challenge. The efficacy of immune checkpoint inhibitors as single agents or combined with chemotherapy has been unsatisfactory, leading to the exploration of alternative combination strategies with targeted agents (e.g., poly-ADP-ribose inhibitors (PARP)and angiogenesis inhibitors) and novel immunotherapy approaches. Among the different histological subtypes, clear cell ovarian cancer has shown a higher sensitivity to immunotherapy. A deeper understanding of the mechanism of immune resistance within the context of ovarian cancer and the identification of predictive biomarkers remain central discovery benchmarks to be realized. This will be critical to successfully define the precision use of immune checkpoint inhibitors for the treatment of ovarian cancer.

Radiomics is an emerging field of research that aims to find associations between quantitative information extracted from imaging examinations and clinical data to support the best clinical decision. In the last few years, some papers have been evaluating the role of radiomics in gynecological malignancies, mainly focusing on ovarian cancer. Nonetheless, cervical cancer is the most frequent gynecological malignancy in developing countries and endometrial cancer is the most common in western countries. The purpose of this narrative review is to give an overview of the latest published papers evaluating the role of radiomics in cervical and endometrial cancer, mostly evaluating association with tumor prognostic factors, with response to therapy and with prediction of recurrence and distant metastasis.

Purpose: This phase 1 study evaluated safety, tolerability, pharmacokinetics and preliminary activity of the PI3K/mTORC1/2 dual inhibitor gedatolisib combined with carboplatin and paclitaxel. Experimental design: Patients with advanced solid tumors treated with less than or equal to 2 prior chemotherapies received intravenous gedatolisib on days 1, 8, 15, 22 (95, 110 or 130 mg according to dose level), carboplatin (AUC5) on day 8 (day 1 following protocol amendment), paclitaxel at 80 mg/m² on days 8, 15, 22 (1, 8, 15 after amendment), every 28 days. Patients without progressive disease after cycle 6 received maintenance gedatolisib until progression. Results: Seventeen patients were enrolled (11 ovarian [10 clear cell (CCOC)], 4 endometrial, 2 lung cancers). Median number of prior chemotherapies was 1 (range 0-2). Median number of administered cycles was 6 (range 2-16). Dose limiting toxicities occurred in 4 patients: 2 (cycle 2 delay due to G2-G3 neutropenia) at 110 mg leading to a change in the treatment schedule, 2 at 130 mg (G2 mucositis causing failure to deliver greater than or equal to 75% of gedatolisib at cycle 1). The recommended phase II dose is gedatolisib 110 mg on days 1, 8, 15, 22 with carboplatin AUC 5 on day 1 and paclitaxel 80 mg/m² on days 1, 8, 15. The most frequent greater than or equal to G3 TEAEs were neutropenia (35%), anemia (18%) and mucositis (12%). The overall response rate was 65% (80% in CCOC). Pharmacokinetic parameters of gedatolisib were consistent with single agent results. Conclusions: Gedatolisib combined with carboplatin and paclitaxel is tolerable and preliminary efficacy was observed especially in CCOC.