Atezolizumab, cobimetinib, and vemurafenib as first-line treatment for unresectable metastatic BRAF V600 mutated melanoma.

INTRODUCTION: The treatment of metastatic melanoma has been revolutionized by the introduction of immune checkpoint inhibitors and BRAF/MEK inhibition. Nevertheless, almost half of patients will progress or show primary resistance to treatment. The combination of BRAF/MEK and immune checkpoint inhibition might achieve higher response rates and improve long-term disease control. The IMspire150 trial investigated the combination of atezolizumab, cobimetinib and vemurafenib versus cobimetinib and vemurafenib alone. AREAS COVERED: This review covers the efficacy and safety of atezolizumab, cobimetinib and vemurafenib for patients with advanced or metastatic BRAF mutant melanoma. The combination is compared with the current standard of care including BRAF/MEK inhibition and treatment with immune checkpoint inhibitors. EXPERT OPINION: Atezolizumab plus cobimetinib and vemurafenib showed superior progression-free survival in metastatic melanoma compared to cobimetinib and vemurafenib alone. Triplet therapy might be an option in situations of urgent need for disease control, when oncologists choose BRAF/MEK inhibition over immune checkpoint inhibition as first line treatment. At this time results are not mature yet, and longer follow-up including overall survival data is needed. The future role of this combination will also be determined by a comparison with the combination of ipilimumab and nivolumab.

Exploring Older Women's Attitudes to and Experience of Treatment for Advanced Ovarian Cancer: A Qualitative Phenomenological Study.

Older women with ovarian cancer more often receive less intensive treatment and early discontinuation compared to younger women. There is little understanding of older women's treatment experience and whether this contributes to declining intensive treatment. We aimed to explore the lived experience of older patients with advanced ovarian cancer undergoing chemotherapy, their treatment preferences and treatment burden. We conducted a phenomenological qualitative study with 15 women who had completed at least three cycles of first-line chemotherapy for advanced epithelial ovarian cancer, aged 65 years or older at the first cycle, at one tertiary cancer centre. We conducted interviews and focus groups and analysed the transcripts using inductive thematic analysis. Women reported a strong preference for active treatment despite treatment burden and toxicities. Participants undertook treatment to lengthen their lives for themselves and their families. Participants did not see age as a barrier to treatment. Patients expressed determination not to let cancer interfere with daily life. Women felt overwhelmed with information and struggled with daily tasks due to fatigue. Logistical issues, such as transportation and ineffective communication between healthcare providers, caused substantial distress. Despite these logistical burdens and toxicities, participants were positive about their care experience and desire for anticancer treatment. Older women may benefit from additional support to facilitate effective communication during the early stages of treatment.

Under-Treatment of Older Patients with Newly Diagnosed Epithelial Ovarian Cancer Remains an Issue.

Older women with ovarian cancer have disproportionately poorer survival outcomes than their younger counterparts and receive less treatment. In order to understand where the gaps lie in the treatment of older patients, studies incorporating more detailed assessment of baseline characteristics and treatment delivery beyond the scope of most cancer registries are required. We aimed to assess the proportion of women over the age of 65 who are offered and receive standard of care for first-line ovarian cancer at two UK NHS Cancer Centres over a 5-year period (December 2009 to August 2015). Standard of care treatment was defined as a combination of cytoreductive surgery and if indicated platinum-based chemotherapy (combination or single-agent). Sixty-five percent of patients aged 65 and above received standard of care treatment. Increasing age was associated with lower rates of receiving standard of care (35% > 80 years old versus 78% of 65-69-year-olds, p = 0.000). Older women were less likely to complete the planned chemotherapy course (p = 0.034). The oldest women continue to receive lower rates of standard care compared to younger women. Once adjusted for Federation of Gynaecology and Obstetrics (FIGO) stage, Eastern Cooperative Oncology Group (ECOG) performance status and first-line treatment received, age was no longer an independent risk factor for poorer overall survival. Optimisation of vulnerable patients utilising a comprehensive geriatric assessment and directed interventions to facilitate the delivery of standard of care treatment could help narrow the survival discrepancy between the oldest patients and their younger counterparts.

Imaging in the pre-operative staging of ovarian cancer.

The main prognostic factor in ovarian cancer is the stage of disease at diagnosis. The staging system in use (FIGO classification, updated in 2014) is based on the surgical-pathological findings. Although surgical staging is the gold standard in ovarian cancer, the initial patient management depends on the imaging-based pre-surgical staging assessment, in order to identify unresectable or difficult to resect disease. Radiologists need to be aware of the strengths of the available imaging modalities, as well as the imaging pitfalls. Clear understanding of pattern of disease spread and review areas are critical for accurate staging and treatment planning. The current standard of care for pre-surgical staging is CT of the thorax, abdomen, and pelvis. This allows a rapid evaluation of disease extent and is fairly accurate in identifying bulky disease but has definite limitations in assessing the extent of small volume disease and in the confirmation of certain sites of disease beyond the abdomen. Functional MRI has been reported to be superior in detecting small peritoneal deposits. PET/CT may be used as a problem-solving tool in some patients where determination remains unclear, particularly in confirmation of advanced stage beyond the abdomen.

PARP inhibitors in older patients with ovarian and breast cancer: Young International Society of Geriatric Oncology review paper.

Breast and ovarian cancer are common malignancies among older adults, causing significant morbidity and mortality. Although most cases of breast and ovarian cancer are sporadic, a significant proportion is caused by mutations in cancer susceptibility genes, most often breast cancer susceptibility genes (BRCA) 1 and 2. Furthermore, some breast and ovarian tumors are phenotypically similar to those with BRCA mutations, a phenomenon known as "BRCAness". BRCA mutations and "BRCAness" lead to defects in DNA repair, which may be a target for therapeutic agents such as Poly ADP-Ribose Polymerase (PARP) inhibitors. PARP inhibitors are novel medications which lead to double-strand breaks resulting in cell death due to synthetic lethality, and which have been shown to be effective in patients with advanced breast and ovarian cancers with or without BRCA mutations. Three different PARP inhibitors (olaparib, niraparib, and rucaparib) have been approved for the treatment of ovarian cancer and one (olaparib) for breast cancer harboring BRCA mutations. Here, we review the currently available evidence regarding the use of PARP inhibitors for the treatment of patients with breast and ovarian cancer, with a particular focus on the inclusion of older adults in clinical trials of these therapies. Additionally, we provide an overview of currently ongoing studies of PARP inhibitors in breast and ovarian cancer, and include recommendations for increasing the evidence-base for using these medications among older patients.

Improving outcomes for older women with gynaecological malignancies.

The incidence of most gynaecological malignancies rises significantly with increasing age. With an ageing population, the proportion of women over the age of 65 with cancer is expected to rise substantially over the next decade. Unfortunately, survival outcomes are much poorer in older patients and evidence suggests that older women with gynaecological cancers are less likely to receive current standard of care treatment options. Despite this, older women are under-represented in practice changing clinical studies. The evidence for efficacy and tolerability is therefore extrapolated from a younger; often more fit population and applied to in every day clinical practice to older patients with co-morbidities. There has been significant progress in the development of geriatric assessment in oncology to predict treatment outcomes and tolerability however there is still no clear evidence that undertaking a geriatric assessment improves patient outcomes. Clinical trials focusing on treating older patients are urgently required. In this review, we discuss the evidence for treatment of gynaecological cancers as well as methods of assessing older patients for therapy. Potential biomarkers of ageing are also summarised.

Targeted agents and combinations in ovarian cancer: where are we now?

Epithelial ovarian cancer is a heterogeneous disease with distinct histological subtypes characterized by different patterns of clinical behaviour. The identification of molecular pathways associated with individual subtypes has fuelled enthusiasm for the development of targeted therapies directed at specific subtypes of ovarian cancer. To date, the most successful targeted therapies in ovarian cancer to have undergone clinical development include anti-angiogenic agents and PARP inhibitors. Other promising areas of development include folate receptor antagonists, MEK and BRAF inhibitors in low-grade serous carcinoma, and immunotherapy. These novel therapeutic agents have the potential to maximize tumor efficacy, minimize toxicity and improve outcomes for women with epithelial ovarian cancer.