Impulse control disorders are common in Parkinson's disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a 'Sure' choice and a 'Gamble' choice of moderate risk. To commence each trial, in the 'Gain' condition, individuals started at $0 and in the 'Loss' condition individuals started at -$50 below the 'Sure' amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk ('Gamble Risk'). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the 'Gain' relative to the 'Loss' condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals.

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Immunohistochemical markers have traditionally guided treatment decisions in breast cancer. However, advances in gene-expression profiling and availability of gene-based assays have launched these newer tests into everyday clinical practice. Luminal A-subtype tumors are a unique subset that may have favorable tumor biology. Properly defining this tumor subtype is important and may identify a subset of patients for whom endocrine therapy alone is sufficient.

On March 8, 2019, the FDA granted accelerated approval to atezolizumab in combination with paclitaxel protein-bound for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 [PD-L1 stained tumor-infiltrating immune cells (IC) of any intensity covering ≥1% of the tumor area], as determined by an FDA-approved test. Approval was based on data from IMpassion130, which randomized patients to receive atezolizumab or placebo in combination with paclitaxel protein-bound. Investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) and PD-L1-positive populations were coprimary endpoints. After 13-month median follow-up, the estimated median PFS in the PD-L1-positive population was 7.4 months in the atezolizumab arm and 4.8 months in the placebo arm [HR ¼ 0.60; 95% confidence interval (CI), 0.48-0.77]. Overall survival (OS) results were immature with 43% deaths in the ITT population, representing 59% of the OS events required to perform the final OS analysis. Adverse reactions occurring in ≥20% of patients receiving atezolizumab with paclitaxel protein-bound were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite. Accelerated approval was appropriate taking into account the unmet medical need along with the immaturity of the OS results and potential for PFS in the PD-L1-expressing population to predict clinical benefit.

On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.1 in the cohort of trial participants whose tumors had a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11 months [95% confidence interval (CI), 7.5–14.5] compared with 5.7 months (95% CI, 3.7–7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50–0.85; two-sided P = 0.001). The median overall survival was not yet reached for the alpelisib plus fulvestrant arm (95% CI, 28.1–NE) and was 26.9 months (95% CI, 21.9–NE) for the fulvestrant control arm. No PFS benefit was observed in trial participants whose tumors did not have a PIK3CA mutation (HR, 0.85; 95% CI, 0.58–1.25). The most common adverse reactions, including laboratory abnormalities, on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia.

On December 19, 2018, the U.S. Food and Drug Administration (FDA) granted approval to olaparib monotherapy for first-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer and, on May 8, 2020, expanded the indication of olaparib to include its use in combination with bevacizumab for first-line maintenance treatment of homologous recombination deficient (HRD)-positive advanced ovarian cancer. Both these approvals were based on randomized, double-blind, placebo-controlled trials. Approval for olaparib monotherapy was based on the SOLO-1 trial, comparing the efficacy of olaparib versus placebo in patients with BRCAm advanced ovarian, fallopian tube, or primary peritoneal cancer after surgical cytoreduction and first-line platinum-based chemotherapy. Two companion diagnostic (CDx) tests were approved with this indication: BRACAnalysis CDx, for germline BRCA1/2 alterations, and FoundationOne CDx, for BRCA1/2 alterations in tissue specimens. Approval for olaparib in combination with bevacizumab was based on the results of the PAOLA-1 trial that compared olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced highgrade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer after first-line platinum-based chemotherapy and bevacizumab. Myriad myChoice CDx was designated as a companion diagnostic device for use of olaparib plus bevacizumab combination for ovarian cancer associated with HRD-positive status. Both trials demonstrated clinically meaningful improvements in progression-free survival and favorable benefit-risk profiles for the indicated populations. This article summarizes the FDA thought process and data supporting the approval of olaparib as monotherapy and in combination with bevacizumab for maintenance therapy in this setting. The Oncologist 2021;26:e164-e172 Implications for Practice: These approvals represent the first poly (ADP-ribose) polymerase inhibitor, alone or in combination with bevacizumab, approved in first-line maintenance treatment of women with advanced ovarian cancer after cytoreductive surgery and chemotherapy. In patients with BRCA-mutated tumors, olaparib monotherapy demonstrated a 70% reduction in the risk of disease progression or death compared with placebo, and olaparib in combination with bevacizumab demonstrated a 67% reduction in the risk of disease progression or death compared with bevacizumab alone in homologous recombination deficient-positive tumors. These approvals represent a major advance for the treatment of women with advanced ovarian cancer who are in complete or partial response after their initial platinum-based chemotherapy.

PURPOSE Many older women will be treated with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and an aromatase inhibitor (AI), given US Food and Drug Administration approval of three agents in this class. The current pooled analysis examines the efficacy and safety of this combination in older women. PATIENTS AND METHODS We pooled data from three randomized controlled studies (N = 1,827) of different CDK4/6 inhibitors in combination with an AI for initial treatment of postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer. The effect of age on progression-free survival was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model. RESULTS For patients age 75 years or older (n = 198) who were treated with a CDK4/6 inhibitor and an AI, hazard ratio was 0.49 (95% CI, 0.31 to 0.76) with an estimated median progression-free survival of 31.1 months (95% CI, 20.2 months to not reached) versus 13.7 months (95% CI, 10.9 months to 24.9 months) for those treated with an AI. Incidence of grade 3 to 4 adverse events was 88.8% in patients age 75 years and older and 73.4% in patients younger than age 75 years. Patients age 75 years or older reported a decline in quality-of-life measures using the EQ-5D regardless of treatment with AI alone or with the addition of a CDK4/6 inhibitor. CONCLUSION There was similar efficacy with a CDK4/6 inhibitor in combination with an AI compared with AI alone for first-line treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer in older women compared with younger patients. Patients older than age 75 years experienced higher rates of toxicity, dose modifications, and a decrease from baseline in quality-of-life measures.

On June 29, 2020, the FDA approved pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection (Phesgo) for the treatment of patients with HER2-positive early-stage and metastatic breast cancer. Patients should be selected for therapy based on an FDA-approved companion diagnostic test. Approval was primarily based on the FeDeriCa trial, a randomized, open-label, multicenter comparability study of pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection compared with intravenous pertuzumab and intravenous trastuzumab administered in the neoadjuvant and adjuvant settings with chemotherapy for the treatment of patients with early breast cancer. The pharmacokinetic endpoints were, first, to demonstrate that the exposure of subcutaneous pertuzumab was not inferior to that of intravenous pertuzumab, and then to demonstrate that the exposure of subcutaneous trastuzumab was not inferior to that of intravenous trastuzumab. The primary endpoints were met with the observed lower limit of the two-sided 90% confidence intervals above the prespecified noninferiority margins. The most common adverse reactions were alopecia, nausea, diarrhea, anemia, and asthenia. The totality of the evidence demonstrated comparability of the subcutaneous product to intravenous, allowing for extrapolation and approval of all breast cancer indications for which intravenous trastuzumab and pertuzumab are approved.