Σάββατο, 16 Μαΐου 2020


New data from a large Swedish study show that mammography screening for breast cancer reduces the rate of both advanced and fatal breast cancer.

Three experts who were approached by Medscape Medical News say this is further evidence that regular screening mammography significantly reduces the risk of dying from breast cancer, but one expert questioned the methodology used in the study.

The primary goal of cancer screening is to detect tumors at an early stage, when they are most treatable. The hope is that this will reduce the number of advanced cancers associated with poor prognosis and hence the risk of dying from that cancer.

So far, for mammography, the data have been somewhat conflicting. For example, some evidence suggests that widespread breast cancer screeningmay catch more small, slow-growing tumors that are unlikely to be fatal but will not curb the number of cancers that are diagnosed at a late stage.

The new study, published online in Cancer, refutes this view.

It followed a Swedish cohort of 549,091 women (covering approximately 30% of the Swedish screening-eligible population) who underwent regular mammography.

For the women in this cohort, there was a statistically significant 41% reduction in the risk of dying of breast cancer within 10 years and a 25% reduction in the incidence of advanced disease, compared to women who did not undergo screening. "Even in this age of effective treatments, early detection confers a substantial and significant additional reduction in risk of dying from breast cancer," said lead author Stephen W. Duffy, MSc, from the Center for Cancer Prevention at Queen Mary University, London, United Kingdom.

The current study confirms the findings of a smaller earlier study (Cancer. 2019;125:515-523) from the same investigators. "It finds the same result with an extremely large evidence base, with more than half a million women, and it also adds further to the evidence that screening achieves this reduction in the context of routine healthcare, not only in the research context," Duffy commented. "The results are generalizable to other populations, particularly in North America, Western Europe, and Australasia, where the epidemiology and demographics of breast cancer are similar," said Duffy. "Clearly, more intensive screening is likely to achieve a greater benefit, but a trade-off between costs, both financial and human, and benefits always has to be made specific to each societal and healthcare environment."

In Sweden, the policy regarding breast cancer screening is to screen women aged 40 to 54 years every 18 months. For those aged 55 to 69 years, screening is recommended every 24 months.

"The use of the incidence-based endpoints means that there is accurate classification of both the breast cancer cases and the whole study population in terms of exposure to screening and avoids a number of biases seen in other studies of service screening," Duffy told Medscape Medical News.

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"I have never seen persuasive evidence for the assertion that breast cancer screening does not reduce deaths from metastatic disease — indeed, the randomized trials seem to show the opposite," said Duffy. "This may have arisen from a misunderstanding about the mechanism whereby screening works. It primarily works by diagnosing cancer early so that treatment is successful and recurrence with distant metastases, followed by death, does not occur some years later. I suspect some colleagues have confused this with distant metastases at initial diagnosis," he added.

One Expert Questions Methodology

One of the experts who was approached by Medscape Medical News to comment on the new study, Philippe Autier, MD, MPH, PhD, University of Strathclyde Institute of Global Public Health at the International Prevention Research Institute, Dardilly, France, questioned the methodology of the study." This method is incorrect simply because women attending screening are different from women not attending screening," he said. "The former are more health aware and have healthier behaviors than the latter, and this is a well-known fact and supported by the literature."

Autier emphasized that it is practically impossible to control for that bias, which is known as confounding by indication.

"The statistical methods used for attenuating the so-called self-selection are very approximate and based on unverified assumptions," he said. "For this reason, the Handbook on Breast Cancer Screening produced by the International Agency for Research on Cancer [IARC] clearly stated that 'observational studies based on individual screening history, no matter how well designed and conducted, should not be regarded as providing evidence for an effect of screening,' and the methodology in this paper has never been recommended by the IARC."

A better way of conducting this type of study would have been to show the incidence trends of advanced-stage breast cancer in Sweden for the entire female population aged 40 years and older, he asserts. Autier used that methodology in his own study in the Netherlands, as previously reported by Medscape Medical News. That study found that in the Netherlands, screening mammography over a period of 24 years among women aged 50 to 74 years had little effect on reducing rates of advanced breast cancer or mortality from the disease.

Experts Applaud the New Findings

Three of the experts who were approached by Medscape Medical News to comment on the new findings applauded the efforts of Duffy and colleagues in providing evidence that mammography can reduce breast cancer–related mortality.

Marie Quinn, MD, director of diagnostic radiology at Roswell Park Comprehensive Cancer Center, Buffalo, New York, said this study adds to the growing body of scientific evidence that confirms that women who undergo regular screening mammography significantly reduce their risk of dying from breast cancer.

"Women who underwent regular screening also had a 25% reduction in the incidence of advanced-stage breast cancer," she said. "This is important, because breast cancers are less fatal and often require less treatment when picked up at an earlier stage. We know the risk reduction benefit detected in this well-designed study can be attributed to screening mammography and not advances in cancer treatment, due to the long-term follow-up and outcome of cancer death within 10 years."

The findings from this study support the guidelines recommending routine screening mammography in the United States, Quinn continued, but she pointed out that some aspects of screening (eg, the age at which to begin screening and how often to screen) can vary. "This can be confusing for patients and providers," she said. "Overall, research has shown us that women who undergo regular screening mammograms reduce their risk of dying from breast cancer. For women of average risk, the benefit of mammography is maximized with annual screening beginning at age 40," she said.

Jay A. Baker, MD, FACR, FSBI, chief of the Division of Breast Imaging at Duke University Medical Center, Durham, North Carolina, emphasized that this is yet another study that confirms that the improvement in breast cancer mortality is not the result of improved treatments alone, as some have speculated. "Others have tried to model the benefit of screening vs treatment, but this study is a more direct measurement," he said. "This conclusion is important for both patients and physicians to hear."

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Although the study strongly supports regular screening for all women, it does not specifically address which set of screening guidelines is optimal, Baker commented. "Fortunately, even though some organizations in the US curiously suggest a delayed start to screening, all organizations and professional societies agree that the most lives and the most years of life are saved by yearly screening beginning at age 40," he added. "This new study tells us that new treatments alone aren't enough and confirms that screening saves at least one third more lives."

Another expert, Bonnie N. Joe, MD, PhD, professor in residence and chief of breast imaging in the Department of Radiology and Biomedical Imaging at the University of California, San Francisco, agreed that the study shows the mortality benefits of regular screening mammography. "Notably, these benefits were related to participation in mammography screening and independent of any advances in treatment," she said, "And these findings in this study support regular screening mammography to reduce advanced-stage breast cancers and to reduce a woman's risk of dying from breast cancer."

Joe noted that overall, this was a "well-done, large-scale screening study with long-term outcomes and should be applicable to other populations. In the US, we know that peak cancer incidence is in the 40s for minority women, and the results of this study support regular screening starting at 40."

The study was supported by the American Cancer Society through a gift from the Longaberger Company's Horizon of Hope Campaign. Additional financial support was provided by Brostcancerförbundet, Sweden. Duffy, Autier, Quinn, Joe, and Baker have disclosed no relevant financial relationships. One coauthor of the study has disclosed relationships with industry, as noted in the original article.

Cancer. Published online May 11, 2020. Full text

Follow Medscape Oncology on Twitter for more cancer news: @MedscapeOnc.


Capmatinib produced rapid, deep responses in patients with advanced non–small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations, according to a presentation at the AACR virtual meeting I.

The duration of response was impressive in both treatment-naive and previously treated patients, according to presenter Edward B. Garon, MD, of the University of California, Los Angeles.

In view of these responses, Dr. Garon urged early molecular testing in NSCLC.

He also noted that capmatinib produced responses in patients with brain metastases. However, because of small patient numbers, additional study is needed to validate the intracranial efficacy of capmatinib and ascertain mechanisms of resistance.

Study Rationale and Details

METex14 mutations are reported in up to 4% of patients with NSCLC and portend poor outcomes with chemotherapy and immune checkpoint inhibitors (PLoS One 2014; 9:e107677; Ann Oncol 2018;29:2085-91).

Capmatinib is a highly selective, reversible, and potent inhibitor of MET tyrosine kinase that crosses the blood-brain barrier.

In the phase 2 GEOMETRY mono-1 study, Dr. Garon and colleagues tested capmatinib, given at 400 mg orally twice a day, in patients with METex14-mutated, ALK, and EGFR wild-type, stage IIIB/IV NSCLC. Patients with neurologically stable or asymptomatic brain metastases were eligible.

Dr. Garon presented safety data for all patients enrolled in this study and efficacy data for patients in cohorts 4 and 5b. Cohort 4 enrolled patients who received prior systemic therapy for advanced disease, and cohort 5b enrolled treatment-naive patients. Both cohorts had METex14 gene mutations but not amplification.


There were 97 patients evaluable for efficacy – 69 previously treated and 28 treatment naive. The median age in both cohorts was 71 years, most patients were female (58% of previously treated and 64.3% of treatment-naive patients), and most were never-smokers (58% and 64.3%, respectively). Adenocarcinoma was the predominant histology.

The overall response rate, per an independent review committee, was 40.6% in previously treated patients and 67.9% in treatment-naive patients.

Waterfall plots showed deep responses, with only four cases of disease progression in the previously treated cohort and none in the treatment-naive cohort.

Responses occurred rapidly. Many responses exceeded 1 year and were ongoing at the data cut-off. The median response duration was 9.72 months in previously treated patients and 11.14 months in treatment-naive patients.

There were 13 patients with evaluable baseline brain metastases (3.3 brain lesions per patient [range, 1-8]). Twelve patients had intracranial disease control, and seven patients (54%) had intracranial response. Four patients had complete resolution of all brain lesions.

Intracranial responses were generally seen by the first radiologic evaluation and occurred as rapidly as systemic responses.


With safety data on all 334 patients in the trial, the GEOMETRY mono-1 study is the largest reported experience with capmatinib in NSCLC patients. The median treatment exposure time was 14.9 weeks.

Overall, 35.6% of patients experienced a grade 3/4 adverse event (AE). Grade 4 AEs were observed in 4.5% of patients, and there were no treatment-related deaths.

Peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%) were the most frequent AEs of any grade.

In all, 21.9% of patients required dose adjustments due to treatment-related AEs, and 11.1% of patients stopped treatment because of an AE.

This study was sponsored by Novartis. Dr. Garon disclosed relationships with Novartis, AstraZeneca, Bristol-Myers Squibb, Dracen, Dynavax, Eli Lilly, EMD Serono, Genentech, GSK, Iovance, Merck, Mirati, and Neon.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Garon EB et al. AACR 2020, Abstract CT082.

This story originally appeared on MDedge.com.

Selpercatinib (Retevmo, Loxo/Lilly) becomes the first targeted therapy to be approved by the US Food and Drug Administration (FDA) for use in patients with cancer who have certain tumors that have an alteration (mutation or fusion) in the RET gene.

The drug is indicated for use in RET-positive tumors found in the following:

  • Non–small cell lung cancer (NSCLC) that has spread in adult patients;

  • Advanced medullary thyroid cancer (MTC) or MTC that has spread in adult and pediatric patients (older than 12 years) who require systemic therapy; and

  • Thyroid cancer that requires systemic therapy and that has stopped responding to or is not appropriate for radioactive iodine therapy in adult and pediatric (older than 12 years) patients.

Before initiating treatment, an RET gene alteration must be determined via laboratory testing, the agency emphasized. However, no FDA-approved test is currently available for detecting RET fusions/mutations.

Approval Based on Reponses in Open-Label Trial

This was an accelerated approval based on the overall response rate (ORR) and duration of response (DOR) seen in an open-label clinical trial (the phase 1/2 LIBRETTO-001 study), which involved patients with each of the three types of tumors.

All patients received selpercatinib 160 mg orally twice daily until disease progression or unacceptable toxicity occurred.

The company notes that for this trial, identification of an RET gene alteration was prospectively determined in plasma or tumor tissue by local laboratories using next-generation sequencing, polymerase chain reaction testing, or fluorescence in situ hybridization. Immunohistochemistry was not used in the clinical trial.

Efficacy for NSCLC was evaluated in 105 adult patients with RET fusion-positive NSCLC who were previously treated with platinum chemotherapy. The ORR was 64%.

It was also evaluated in 39 patients with RET fusion-positive NSCLC who had not received any previous treatment. The ORR for these patients was 84%.

For both groups, among patients who responded to treatment, the response lasted more than 6 months.

In a company press release, LIBRETTO-001 lead investigator Alexander Drilon, MD, acting chief of early drug development at Memorial Sloan Kettering Cancer Center, New York City, said: "In the clinical trial, we observed that the majority of metastatic lung cancer patients experienced clinically meaningful responses when treated with selpercatinib, including responses in difficult-to-treat brain metastases.

"The approval of selpercatinib marks an important milestone in the treatment of NSCLC, making RET-driven cancers now specifically targetable in the same manner as cancers with activating EGFR and ALK alterations, across all lines of therapy," he added.

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About 1% to 2% of NSCLC tumors are thought to have an RET alteration.

The same trial also included patients with thyroid cancer.

Efficacy for MTC was evaluated in 55 adult and pediatric (older than 12 years) patients with advanced or metastatic RET-mutant MTC who had previously been treated with cabozantinibvandetanib, or both. The ORR was 69%.

In addition, the drug was evaluated in 88 patients with advanced or metastatic RET-mutant MTC who had not received prior treatment with cabozantinib or vandetanib. The ORR for these patients was 73%.

The trial also enrolled 19 patients with RET-positive thyroid cancer whose condition was refractory to radioactive iodine (RAI) treatment and who had received another prior systemic treatment. The ORR was 79%. Eight patients had received only RAI. The ORR for these patients was 100%.

In all the cases of thyroid cancer and lung cancer, among the patients who responded to treatment, the response lasted longer than 6 months.

"RET alterations account for the majority of medullary thyroid cancers and a meaningful percentage of other thyroid cancers," Lori J. Wirth, MD, medical director of head and neck cancers, Massachusetts General Hospital Cancer Center, Boston, noted in the company release.

fact sheet from the company notes that RET mutations are found in about 60% of sporadic MTC cases and in over 90% of familial MTC cases, and that RET fusions are found in approximately 10% to 20% of papillary thyroid cancers.

"For patients living with these cancers, the approval of selpercatinib means they now have a treatment option that selectively and potently inhibits RET," Wirth commented. "Based on the published data for this new medicine, as well as my personal experience treating patients, this may be a good treatment option."

In the LIBRETTO-001 trial, the rate of discontinuations because of adverse reactions (ARs) was 5%, the company reported. The most common ARs, including laboratory abnormalities (≥25%), were increased aspartate aminotransferase level, increased alanine aminotransferase level, increased glucose level, decreased leukocyte count, decreased albumin level, decreased calcium level, dry mouth, diarrhea, increased creatinine level, increased alkaline phosphatase level, hypertension, fatigue, edema, decreased platelet count, increased total cholesterol level, rash, decreased sodium levels, and constipation. The most frequent serious AR (≥2%) was pneumonia.

The FDA warned that selpercatinib can cause hepatotoxicity, elevation in blood pressure, QT prolongation, bleeding, and allergic reactions. It may also be toxic to a fetus or newborn baby so should not be taken by pregnant or breastfeeding women.

The drug is currently being assessed in two phase 3 confirmatory trials. LIBRETTO-431 will test the drug in previously untreated patients with RET-positive NSCLC. LIBRETTO-531 involves treatment-naive patients with RET-positive MTC.

The company that developed selpercaptinib, Loxo Oncology, was acquired by Eli Lilly last year in an $8 billion takeover. This drug was billed as the most promising asset in that deal, alongside oral BTK inhibitor LOXO-305, comments a report in Pharmaphorum.

Loxo developed Vitrakvi (larotrectinib), the first TRK inhibitor to reach the market, as well as the follow-up drug LOXO-195. Both were acquired by Bayer ahead of the Lilly takeover, that report notes.

Follow Medscape Oncology on Twitter for more cancer news: @MedscapeOnc.


On May 15, 2020, the U.S. Food and Drug Administration (FDA) approved the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) as first-line treatment for patients with metastatic non–small cell lung cancer (NSCLC) whose tumors express programmed cell death ligand 1 (PD-L1)  at ≥ 1%, as determined by an FDA-approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

The FDA also approved the PD-L1 IHC 28-8 pharmDx as a companion diagnostic device for selecting patients with NSCLC for treatment with nivolumab plus ipilimumab.


Efficacy was investigated in CheckMate 227, a randomized, open-label, multipart trial in patients with metastatic or recurrent NSCLC and no prior anticancer therapy. In part 1a of the trial, 793 patients with PD-L1 tumor expression ≥ 1% were randomly assigned to receive either the combination of nivolumab plus with ipilimumab (n = 396) or platinum doublet chemotherapy (n = 397).

The trial demonstrated a statistically significant improvement in overall survival for patients with PD-L1 tumor expression ≥ 1% receiving nivolumab plus ipilimumab compared to those treated with platinum doublet chemotherapy. Median overall survival was 17.1 months (95% confidence interval [CI] = 15­–20.1) vs 14.9 (95% CI = 12.7–16.7) (hazard ratio [HR] = 0.79, 95% CI = 0.67–0.94, P = .0066).

Median progression-free survival per blinded independent central review was 5.1 months (95% CI = 4.1–6.3) in the nivolumab plus ipilimumab arm and 5.6 months (95% CI = 4.6–5.8) in the platinum doublet arm (HR = 0.82, 95% CI = 0.69–0.97). Confirmed overall response rate per blinded independent central review was 36% (95% CI = 31%­–41%) and 30% (95% CI = 26%–35%), respectively. Median response duration was 23.2 months in the nivolumab plus ipilimumab arm and 6.2 months in the platinum-doublet chemotherapy arm.

The most common adverse reactions in ≥ 20% of patients receiving the combination of nivolumab plus ipilimumab were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, pruritis, nausea, and hepatitis.

The recommended doses for the combination in patients with metastatic NSCLC are nivolumab at 3 mg/kg every 2 weeks and ipilimumab at 1 mg/kg every 6 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


While upfront autologous transplantation has bested bortezomib-based intensification therapy in a large, randomized multiple myeloma (MM) trial, investigators and observers say more research will be needed to determine the optimal treatment strategy in the era of novel agents.

Autologous hematopoietic stem cell transplantation (HSCT) extended progression-free survival by almost 15 months compared with bortezomib, melphalan, and prednisone (VMP) intensification therapy for the treatment of newly diagnosed multiple myeloma, according to results of the randomized, phase 3 trial of 1,503 patients enrolled at 172 centers in the European Myeloma Network.

That finding could provide more fodder for the ongoing debate over the role of upfront autologous HSCT as a gold-standard intensification treatment for patients who can tolerate myeloablative doses of chemotherapy in light of the proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies that are now available.

However, the study is not without limitations, including the use of bortezomib, cyclophosphamide, and dexamethasone (VCD) as induction therapy, according to the investigators, led by Michele Cavo, MD, with the Seràgnoli Institute of Hematology at Bologna (Italy) University.

The VCD regimen was one of the most frequently used induction regimens back when the trial was designed, but now it's considered "less optimal" versus regimens such as bortezomib, lenalidomide, and dexamethasone (VRD), according to Dr. Cavo and coinvestigators.

Besides, the field is moving forward based on clinical trials of "highly active" daratumumab-based four-drug regimens, which appear to enhance rates of response and minimal residual disease (MRD) negativity when given as induction before autologous HSCT and as consolidation afterward, they said.

"Final results from these studies should be awaited before a shift from routine use of upfront autologous HSCT to delayed HSCT or alternative treatment strategies driven by MRD status can be offered to patients with newly diagnosed multiple myeloma who are fit for high-dose chemotherapy," Dr. Cavo and colleagues noted in their report, available in The Lancet Hematology.

The multicenter, randomized, open-label, phase 3 study by Dr. Cavo and coinvestigators, known as EMN02/HO95, included patients up to 65 years of age with symptomatic multiple myeloma, measurable disease, and WHO performance of 0 to 2. Patients were treated with VCD induction therapy, followed by randomization to either VMP or autologous HSCT after high-dose melphalan. In a second randomization, patients were assigned to either VRD consolidation therapy or no consolidation. All patients then received lenalidomide maintenance therapy until progression.

Median progression-free survival was 56.7 months in patients initially randomized to HSCT, compared with 41.9 months for MP (hazard ratio, 0.73; 95% confidence interval, 0.62-0.85; P = .0001), according to the investigators, who said that finding supports the value of HSCT "even in the era of highly active novel agents."

Turning to results of the second randomization, Dr. Cavo and colleagues said the VRD consolidation strategy resulted in median progression-free survival that was significantly improved versus no consolidation, at 58.9 months and 45.5 months, respectively (P = .014).

While this is an important study, the added benefit of HSCT intensification therapy is in question given the high rates of MRD being reported for potent, daratumumab-based four-drug combination regimens, according to a related commentary by Omar Nadeem, MD, and Irene M. Ghobrial, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

"We are entering an era in which novel combinations have shown unprecedented efficacy and future studies with or without HSCT will be needed to answer these key questions," wrote Dr. Nadeem and Dr. Ghobrial.

Dr. Cavo and colleagues said the estimated 5-year rate of overall survival in EMN02/HO95 was "comparable" between arms, at 75% for the HSCT strategy and 72% for VMP.

"Although this suggests that delaying HSCT to a later time is not harmful, a substantial proportion of patients may become ineligible for high-dose melphalan at first relapse," they said, noting that 63% of VMP-treated patients went on to receive salvage HSCT.

Further follow-up could demonstrate a survival advantage, as seen in other studies, they added.

Dr. Cavo reported that he has received honoraria from multiple pharmaceutical companies, and is a member of speakers bureaus for Janssen and Celgene. Dr. Nadeem and Dr. Ghobrial reported serving on the advisory boards of multiple pharmaceutical companies.

SOURCE: Cavo M et al. Lancet Haematol. 2020 Apr 30. doi: 10.1016/S2352-3026(20)30099-5.

This story originally appeared on MDedge.com.


As we approach the American Society of Clinical Oncology 2020 Annual Meeting — one of the biggest cancer meetings in the world, to be held virtually May 29-31 — it is somewhat sobering to read about "spin" disguising negative results.

Researchers sometimes spin negative results in an ambiguous, or even positive, light in their conclusions sections, say a group of Italian authors. Disseminating conclusions that are unjustified by results could be misleading and, in some cases, even harmful in clinical practice, they warn.

The team undertook a systematic review of oral presentations at two major cancer meetings (held by ASCO and the European Society of Medical Oncology [ESMO]) over 3 years. They found that 13% to 47% of studies with negative results were not reported as such. "Despite the formally negative trial result, the authors' conclusions are not negative," they report.  

The study was published online on April 16 in JAMA Oncology.

"Many slides at important meetings like ASCO and ESMO are tweeted or shared on social media in real-time, and this could contribute to the diffusion of questionable scientific messages," said lead author Massimo Di Maio, MD, from the division of medical oncology at Ordine Mauriziano Hospital in Turin, Italy.

"In our analysis we found that, in several cases, authors defined the experimental treatment as an option for clinical practice," Di Maio said.

Some studies failed to show superiority for the experimental treatment but had similar outcomes for the experimental and standard treatments. However, that does not prove non-inferiority for the experimental treatment compared to standard therapy, and it does not mean the experimental treatment may be an option for clinical practice, Maio commented. Proving noninferiority would require a prespecified, clinically "nonrelevant" margin of difference. Using a post-hoc noninferiority interpretation is methodologically questionable, he added.

"If the drug is already available in clinical practice, as is the case for treatments tested in many academic trials, applying that questionable conclusion to clinical decisions could result in patients potentially receiving an inferior treatment," he said.

He added that he is not against presenting negative results, which may have value and deserve attention.  

"I strongly believe that a formally negative or inconclusive result does not imply that the study deserves less attention compared to a positive result," he said. "Negative trials can represent important evidence. They can be used as part of meta-analyses, and can offer important suggestions for further research."

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Di Maio said he came up with the idea for this study last year while attending oral sessions at the ASCO 2019 annual conference in Chicago, Illinois. He noticed that several trials with a primary analysis that had negative results were presented with ambiguous or non-negative conclusions. So he discussed the issue with his colleagues back in Italy, and they decided to see how big the problem really is.

How Big Is the Problem?

The team reviewed oral presentations of phase 3 randomized controlled trials (excluding noninferiority trials) presented at ASCO and ESMO from 2017 through 2019. They separated trials based on whether the primary endpoint had positive or negative results. Then they evaluated the wording of the conclusions sections. Conclusions were considered non-negative when the authors "more or less explicitly" brought up the idea of using the experimental treatment in a clinical setting and did not provide clear conclusions about the negative results.

The analysis included 208 trials, of which 91 had negative primary endpoint results. Among trials with negative results, 29% had non-negative conclusions, of which 22% were presented in 2017, 13% in 2018, and 47% in 2019.

Among the studies with negative results and non-negative conclusions:

The team also compared for-profit and academic (nonprofit) studies and found similar percentages of non-negative conclusions among studies with negative results: 30% (17/57) among nonprofit studies and 26% (9/34) among for-profit studies.

"One could hypothesize that the tendency to present results in a non-negative way is related to economic interests of the study sponsor. However, our results tell us that this is not the case," Di Maio said. "Many researchers tend to present their study as positive, maybe because they are 'in love' with the hypothesis and truly convinced of the efficacy of the treatment they have tested."

Overall, the results imply the need for caution when listening to oral presentations, whether or not the study is sponsored by "big pharma" or a nonprofit.

"Practicing physicians should not read authors' conclusions as pure gold, but should question whether the conclusions are actually supported by the results. I suggest always looking carefully at the study design, primary objectives, and hypothesis," he said.

"We believe that more attention should be paid to the statements included in the conclusions of oral presentations at meetings, and the discussants' role is crucial," the team concludes. In addition, "when the primary endpoint is not met, the word negative should be explicitly used."

Di Maio has reported receiving personal fees from AstraZeneca, Eli Lilly, Bristol Myers Squibb, MSD, Eisai, Takeda, Pfizer, and Janssen. Several coauthors have also reported receiving fees from various pharmaceutical companies.

JAMA Oncol. Published online April 16, 2020. Letter

Follow Medscape Oncology on Twitter for more cancer news: @MedscapeOnc.

The cost of cancer drugs continues to escalate with each new product that comes on the market, often presenting formidable challenges to both patients and healthcare systems. But a new analysis suggests these high costs cannot be justified with respect to clinical benefit.

The analysis considered 65 oncology drugs launched in the past decade and found no association between clinical benefit and monthly treatment cost.

The study was published online May 1 in the Lancet Oncology.

"Prices of cancer drugs should be better aligned with their clinical benefit to improve access to beneficial medicines and enable limited resources to be used for treatments that offer patients improved outcomes," said lead author Kerstin Noëlle Vokinger, MD, JD, PhD, LLM, assistant professor for public law and digitalization, health law, and regulatory sciences at the University of Zurich, Switzerland.

Clinician "Tough Discussions" With Patients

The findings of this study are similar to findings of previous studies, noted an expert who was approached for comment.

There is already considerable evidence that the price of new drugs does not reflect the drug's value, said Yousuf Zafar, MD, MHS, FASCO, associate professor of medicine and public policy at Duke University in Durham, North Carolina.

"Because price is not linked to value, manufacturers are incentivized to develop more drugs in an existing class or drugs with limited benefit," he told Medscape Medical News. "If value played a role in the drug pricing and approval process, we could disincentivize the production of the tenth checkpoint inhibitor or the drug that improves survival by just weeks."

Existing value frameworks (such as those used in the current study) provide a good start for this process, he noted, but payers will ultimately need to make difficult decisions about coverage.

"But that responsibility does not end with payers," Zafar emphasized. "Clinicians should have the tough discussion with patients about how much benefit is actually expected from the drugs we prescribe.

"In many instances, I have had patients decline drugs like regorafenib [Stivarga, Bayer] for colorectal cancer when I explain the magnitude of expected benefit vs the potential for toxicity ― both physical and financial," he added.

Details of the Findings

Drug prices have been a hot topic of discussion for some time, especially in the United States, where they are the highest in the world. Determining the value of a drug by pegging cost to benefit has been proposed by experts and the two major professional organizations.

The American Society of Clinical Oncology (ASCO) developed a value framework (ASCO-VF) that defines the value of a drug on the basis of clinical benefit, toxicity, and cost. The European Society of Clinical Oncology (ESMO) released a Magnitude of Clinical Benefit Scale (MCBS), which offers a "rational, structured, and consistent approach" to stratifying drugs' clinically meaningful benefits.

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The new study used both of these frameworks to assess the association between the clinical benefit of approved cancer drugs and their cost in the United States and four European countries (England, Switzerland, Germany, and France).

The researchers identified all new drugs indicated for adult cancers that were approved by the US Food and Drug Administration between January 1, 2009, and December 31, 2017, and by the European Medicines Agency through September 1, 2019. Because the ESMO-MCBS tool can only be used with regard to solid tumors, the evaluation of clinical benefit was restricted to drugs indicated for nonhematologic cancers.

The median monthly treatment costs for the included cancer drugs was highest in the United States ($13,179), followed by England ($6202), Switzerland ($5696), Germany ($5121), and France ($4866).

When the team assessed the 46 drugs approved for solid tumors, there was no significant difference in monthly treatment costs between drugs that had high clinical benefit and those of low benefit (using the ASCO-VF, two-sided = .25; using the ESMO-MCBS, = .25).

As an example, for the treatment of prostate cancercabazitaxel (Jevtana, Sanofi-Aventis) had lower clinical benefit scores than abiraterone (Zytiga, Janssen) (ESMO-MCBS score, 2 vs 4), yet the cost of the two drugs was similar in the United States ($10,531 vs $10,887) and Germany ($3311 vs $3340) and was slightly higher in England ($4554 vs $3568) and Switzerland ($5292 vs $3475).

With regard to individual countries, no significant associations were observed between cost and clinical benefit using the ESMO-MCBS (for the United States, = .16; for England, = .98; for Switzerland, = .54; for Germany, = .52; and for France, P =.40). The same was true when the team used the ASCO-VF except for France, where there was a correlation (for the United States, = .56; for England, = .47; for Switzerland, = .26; for Germany, = .23; and for France, = .037).

The authors conclude that the prices of cancer drugs should correspond more closely with their clinical importance, "such as by prioritizing drugs with low or uncertain benefit for price negotiations, to improve access to beneficial medicines and enable finite resources to be used for treatments that offer patients improved outcomes and optimal value."

"I recognize two explanations for the lack of strong association between price and clinical benefit seen in this paper," said Scott Huntington, MD, MPH, of Yale School of Medicine, New Haven, Connecticut, who was approached for comment.

"First, this work and others provide compelling evidence that prices of recent cancer therapeutics are not strongly tied to clinical utility, particularly in the US, where payers have little leverage over coverage or pricing of cancer drugs," he told Medscape Medical News.

In countries such as the United Kingdom, formal cost-effectiveness analyses do inform negotiations, drug prices, and ultimately coverage decisions, thus, "we would expect cancer drug prices in the UK to be more closely associated with clinical benefit, but that is not seen in this analysis," Huntington pointed out. "It is likely that the cost measure — using monthly drug cost — and clinical utility — framework composite scores — in this study is less precise than what is typically used in formal cost-effectiveness analyses."

The bottom line, he added, is that it is probably safe to conclude that there's a long way to go before cancer drug prices are strongly associated with their clinical benefit.

"Incorporating the spirit of available value-based oncology frameworks, particularly concepts of treatment-related toxicity and degree of innovation, alongside traditional cost-effectiveness modeling is likely an important step towards value-based pricing of cancer therapeutics," he said.

The study was funded by the Swiss Cancer Research Foundation (Krebsforschung Schweiz). Vokinger received grants from Swiss Cancer Research Foundation during the conduct of the study. Several coauthors also report receiving various grants. Huntington is employed at an academic medical center with 340B status; he has consulted for Celgene, Bayer, Genentech, Pharmacyclics, and AbbVie and has received research (institutional) funding from DTRM Biopharma, Celgene, and TG Therapeutics. Zafar has relationships with Shattuck Labs, AIM Specialty Health, Copernicus WCG, Discern Health, Family Reach Foundation, McKesson, RTI Health Solutions, Vivor, and AstraZeneca (institutional).

Lancet Oncol. Published online May 1, 2020. Abstract

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Adding the immune-checkpoint inhibitor durvalumab and the PARP inhibitor olaparib to standard neoadjuvant chemotherapy may improve outcome in women with high-risk, HER2-negative breast cancer, according to results of the I-SPY 2 trial.

The benefit was apparent in both the hormone-receptor-positive (HR+) and triple-negative breast cancer (TNBC) subgroups.

The I-SPY 2 study enrolled women with high-risk, HER2-negative stage-II/III tumors measuring 2.5 cm or greater. The 73 women randomized to the experimental arm (21 with TNBC and 52 with HR+ tumors with high-risk features on MammaPrint) received neoadjuvant durvalumab and olaparib concurrent with paclitaxel followed by doxorubicin and cyclophosphamide. The 299 women in the control arm received paclitaxel followed by doxorubicin and cyclophosphamide.

The results showed that adding durvalumab and olaparib to standard chemotherapy increased rates of pathologic complete response (pCR) for the overall HER2-negative group (from 20% to 37%) and in HER2-negative/HR+/high-risk status (from 14% to 28%) and TNBC (27% to 47%) subtypes.

"Immune-rich cancers showed higher pCR rates in all subtypes and in both treatment arms," Dr. Lajos Pusztai of Yale Cancer Center in New Haven, Connecticut, reported April 27 at the American Association for Cancer Research (AACR) virtual annual meeting.

"The estimated probability that the experimental (treatment) is superior to chemotherapy alone is greater than 98% in all subsets," he said.

Exploratory analysis suggested several potential predictive markers of benefit of durvalumab/olaparib over chemotherapy alone. These include ultra-high MammaPrint status in HR+ cancers, as well as low CD3/CD8 ratio, high macrophage/Tc-class 2 ratio and high proliferation signature in the TNBC subtype.

There were no unexpected safety signals. Adverse events were consistent with known side effects of these drugs. Overall 19% of patients in the durvalumab/olaparib arm experienced immune-related grade-3 adverse events compared with 1.6% in the control arm.

Dr. Pamela Munster of the University of California, San Francisco, who was invited to discuss the study at the AACR meeting, said it shows "promising activity of durvalumab and olaparib in addition to paclitaxel. This combination may be of particular interest for a subgroup of women with tumors expressing ultra-high MammaPrint" molecular profile.

"The toxicity as presented appears incomplete and one should consider the financial toxicity from this combination," she added.

"Placing this trial in context with other studies, the contribution of PARP inhibitors to immunotherapy in early-stage breast cancer remains uncertain. Thus we should await confirmatory, randomized controlled trials . . . before using combined immune-checkpoint inhibitors and PARP inhibitors in early-stage breast cancer," Dr. Munster concluded.

Dr. Pusztai and Dr. Munster have disclosed financial relationships with AstraZeneca, which makes durvalumab and olaparib.

SOURCE: https://bit.ly/3fqil5b AACR 2020 annual meeting, presented April 27, 2020.


Two MEK inhibitors were tested against recurrent low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum, but only one inhibitor offered clinical benefit over standard care, investigators from two randomized trials reported.

Trametinib improved progression-free survival (PFS) when compared with standard care, while binimetinib conferred no PFS benefit.

In a phase 2/3 trial, the median PFS was 13 months for patients treated with trametinib and 7.2 months for patients who received an aromatase inhibitor or chemotherapy (P < .0001).

"Our findings suggest that trametinib represents a new standard-of-care treatment option for women with recurrent low-grade serous carcinoma," said investigator David M. Gershenson, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In contrast, in the phase 3 MILO/ENGOT-ov11 trial, there was no significant difference in PFS between patients treated with binimetinib and those who received physician's choice of chemotherapy. The median PFS was 11.2 months with binimetinib and 14.1 months with chemotherapy (P = .752).

"Although this study did not meet its primary endpoint, binimetinib showed activity in low-grade serous ovarian cancer across the efficacy endpoints evaluated, with a response rate of 24% and a median PFS of 11.2 months on updated analysis. Chemotherapy responses were better than predicted, based on historical retrospective data," said investigator Rachel N. Grisham, MD, of Memorial Sloan Kettering Cancer Center in New York.

The binimetinib trial and the trametinib trial were both discussed during a webinar on rare tumors covering research slated for presentation at the Society of Gynecologic Oncology's Annual Meeting on Women's Cancer. The meeting was canceled because of the COVID-19 pandemic.

Chemoresistant Cancers

Low-grade serous ovarian or peritoneal cancers are rare, accounting for only 5% to 10% of all serous cancers, Dr. Gershenson noted.

"[Low-grade serous cancers are] characterized by alterations in the MAP kinase pathway, as well as relative chemoresistance, and prolonged overall survival compared to high-grade serous cancers. Because of this subtype's relative chemoresistance, the search for novel therapeutics has predominated over the last decade or so," he said.

MEK inhibitors interfere with the MEK1 and MEK2 enzymes in the MAPK pathway. Alterations in MAPK, especially in KRAS and BRAF proteins, are found in 30%-60% of low-grade serous carcinomas, providing the rationale for MEK inhibitors in these rare malignancies.

Trametinib Study

In a phase 2/3 study, Dr. Gershenson and colleagues enrolled 260 patients with recurrent, low-grade serous carcinoma of the ovary or peritoneum. Patients were randomized to receive either trametinib at 2 mg daily continuously until progression (n = 130) or standard care (n = 130).

Standard care consisted of one of the following: letrozole at 2.5 mg daily; pegylated liposomal doxorubicin at 40-50 mg IV every 28 days; weekly paclitaxel at 80 mg/m2 for 3 out of 4 weeks; tamoxifen at 20 mg twice daily; or topotecan at 4 mg/m2 on days 1, 8, and 15 every 28 days. Patients randomized to standard care could be crossed over to trametinib at progression.

Σελίδα 2 από 2

All patients had at least one prior line of platinum-based chemotherapy, and nearly half had three or more prior lines of therapy. The median age was 56.6 years in the trametinib arm and 55.3 years in the control arm.

At a median follow-up of 31.4 months, median PFS, the primary endpoint, was 13 months with trametinib vs. 7.2 months with standard care. The hazard ratio (HR) for progression on trametinib was 0.48 (P < .0001).

The overall response rates were 26.2% in the trametinib arm and 6.2% in the standard care arm. The odds ratio for response on trametinib was 5.4 (P < .0001).

For 88 patients who crossed over to trametinib, the median PFS was 10.8 months, and the overall response rate was 15%.

Trametinib was also associated with a significantly longer response duration, at a median of 13.6 months, compared with 5.9 months for standard care (P value not shown).

The median overall survival was 37 months with trametinib and 29.2 months with standard care, with an HR favoring trametinib of 0.75, although this just missed statistical significance (P = .054). Dr. Gershenson pointed out that the overall survival in the standard care arm included patients who had been crossed over to trametinib.

Grade 3 or greater adverse events included hematologic toxicities in 13.4% of patients on trametinib and 9.4% on standard care; gastrointestinal toxicity in 27.6% and 29%, respectively; skin toxicities in 15% and 3.9%, respectively; and vascular toxicities in 18.9% and 8.6%, respectively.

Binimetinib Study 

The phase 3 MILO/ENGOT-ov11 study enrolled 341 patients with low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum. Patients were randomized on a 2:1 basis to receive either binimetinib at 45 mg twice daily (n = 228) or physician's choice of chemotherapy (n = 113). Chemotherapy consisted of pegylated liposomal doxorubicin at 40 mg/m2 on day 1 of each 28-day cycle; paclitaxel at 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle; or topotecan at 1.25 mg/m2 IV on days 1-5 of each 21-day cycle.

The efficacy analysis included 227 patients assigned to binimetinib and 106 assigned to chemotherapy.

A planned interim analysis was performed in 2016 after the first 303 patients were enrolled. At that time, the median PFS by blinded central review was 9.1 months in the binimetinib arm and 10.6 months in the physician's choice arm (HR, 1.21; P = .807), so the trial was halted early for futility. Patients on active treatment at the time could continue until progression and were followed by local radiology.

At the interim analysis, secondary endpoints were also similar between the arms. The overall response rate was 16% in the binimetinib arm and 13% in the chemotherapy arm.

The most common grade 3 or greater adverse events with binimetinib were blood creatinine phosphokinase increase (26%) and vomiting (10%).

Dr. Grisham also reported updated follow-up results through January 2019.

The median PFS in the updated analysis was 11.2 months with the MEK inhibitor and 14.1 months with chemotherapy, a difference that was not statistically significant (HR, 1.12; P = .752). Updated overall response rates were the same in both arms, at 24%.

A post hoc molecular analysis of 215 patients suggested a possible association between KRAS mutation and response to binimetinib.

Two MEKs, One 'Meh' 

Discussant Jubilee Brown, MD, of the Levine Cancer Institute at Atrium Health in Charlotte, N.C., said that "with a 2% to 5% chance of response in patients with low-grade serous ovarian cancer, there is a low bar for any compound to demonstrate success."

Regarding the MILO/ENGOT-ov11 trial, she noted that "this study did not meet its primary endpoint, but perhaps the endpoint is not reflective of the importance of the study."

A different outcome might have occurred had investigators stratified patients by KRAS status upfront, comparing patients with KRAS mutations treated with binimetinib to KRAS wild-type patients treated with either a MEK inhibitor or physician's choice of care, Dr. Brown said.

She agreed with the assertion by Dr. Gershenson and colleagues that improved PFS qualifies trametinib to be considered a new option for standard care, "especially in a rare tumor setting with limited options. This is a huge win for patients."

The trametinib study was sponsored by NRG Oncology and the UK National Cancer Research Institute. Dr. Gershenson disclosed relationships with NRG Oncology, Genentech, Novartis, Elsevier, and UpToDate, as well as stock in several companies.

The binimetinib study was sponsored by Pfizer. Dr. Grisham disclosed relationships with Clovis, Regeneron, Mateon, Amgen, AbbVie, OncLive, PRIME, MCM, and Medscape. MDedge News and Medscape are owned by the same parent organization.

Dr. Brown disclosed consulting for Biodesix, Caris, Clovis, Genentech, Invitae, Janssen, Olympus, OncLive, and Tempus.

SOURCE: Gershenson DM et al. SGO 2020, Abstract 42; Grisham RN et al. SGO 2020, Abstract 41.

This article originally appeared on MDedge.com.


The Food and Drug Administration has announced a new approved indication for olaparib (Lynparza) in adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Olaparib is now FDA-approved for use in combination with bevacizumab as maintenance therapy in patients who responded to first-line platinum-based chemotherapy and whose cancer is homologous recombination deficiency positive, as defined by a deleterious or suspected deleterious BRCA mutation and/or genomic instability.

The FDA also approved the Myriad myChoice CDx test as a companion diagnostic for olaparib.

Trial results

The efficacy of olaparib and the myChoice CDx test were assessed in patients in the phase 3 PAOLA-1 trial (NCT02477644). The study enrolled patients with advanced high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received first-line platinum-based chemotherapy and bevacizumab.

Patients were stratified by first-line treatment outcome and BRCA mutation status, as determined by prospective local testing. All available clinical samples were retrospectively tested with the Myriad myChoice CDx test.

The patients were randomized to receive olaparib at 300 mg orally twice daily in combination with bevacizumab at 15 mg/kg every 3 weeks (n = 537) or placebo plus bevacizumab (n = 269). Patients continued bevacizumab in the maintenance setting and started olaparib 3-9 weeks after their last chemotherapy dose. Olaparib could be continued for up to 2 years or until disease progression or unacceptable toxicity.

The median progression-free survival among the 387 patients with homologous recombination deficiency-positive tumors was 37.2 months in the olaparib arm and 17.7 months in the placebo arm (hazard ratio, 0.33), according to the prescribing information for olaparib.

Serious adverse events occurred in 31% of patients in the olaparib arm. The most common were hypertension (19%) and anemia (17%).

Dose interruptions from adverse events occurred in 54% of patients in the olaparib arm, and dose reductions from adverse events occurred in 41%.

This article originally appeared on MDedge.com.

For the first time, overall survival has been improved with maintenance therapy involving a poly (ADP-ribose) polymerase (PARP) inhibitor in patients with platinum-sensitive recurrent ovarian cancer associated with BRCA1/2 mutations.

“A median overall survival improvement of nearly 13 months is impressive in ovarian cancer and brings a substantial benefit to our patients.” 
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In the final, preplanned, overall survival analysis in the randomized phase III SOLO2/ENGOT-ov211 trial, maintenance treatment with the PARP inhibitor olaparib extended overall survival by “an unprecedented 12.9 months,” compared with placebo in women, reported Andres Poveda, MD, of Initia Oncology, Hospital Quirónsalud, Valencia, Spain, at a press briefing in advance of the ASCO20 Virtual Scientific Program.1

“A long-term treatment benefit was seen with olaparib vs placebo, with an overall survival hazard ratio [HR] of 0.74 in the full-analysis set, which was unadjusted for crossover,” Dr. Poveda announced.

“SOLO2 is the first phase III trial to provide final overall survival data on maintenance PARP inhibitor therapy. A median overall survival improvement of nearly 13 months is impressive in ovarian cancer and brings a substantial benefit to our patients,” he commented.

Olaparib is approved as maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer, regardless of BRCA mutation status, in numerous countries.

ASCO Chief Medical Officer and Executive Vice President Richard L. Schilsky, MD, FACP, FSCT, FASCO, commented in a press briefing, “These results, while they will not change access to the drug because it’s already approved, are comforting in showing that the treatment confers a significant survival benefit. That’s good news for women with ovarian cancer harboring BRCA1/2 mutations, which generally has a poor prognosis.”

“These results, while they will not change access to the drug because it’s already approved, are comforting in showing that the treatment confers a significant survival benefit.”
— Richard L. Schilsky, MD, FACP, FSCT, FASCO

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SOLO2 Details

The current report is the preplanned, final, overall survival analysis of the study, which was conducted in the germline BRCA-mutated subset and finalized February 3, 2020, with data maturity of 61%. SOLO2 had already shown that maintenance treatment with olaparib significantly improved median progression-free survival by 13.6 months vs placebo (hazard ratio [HR] = 0.30; P < .0001).2 The time to second disease progression or death significantly improved as well, and a quality-adjusted progression-free survival benefit was observed.

The study enrolled 295 patients with relapsed BRCA-related ovarian high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer. All had received at least two prior lines of therapy and were in response to their most recent platinum-based regimen. Women were randomly assigned to receive maintenance olaparib (300 mg twice daily) (n = 195) or placebo (n = 99), continued until disease progression.

Crossover was noted for 39% of the placebo arm; 11% of the olaparib arm received a subsequent PARP inhibitor. Patients were followed for a median of 65 months.

Survival Benefit Shown

Olaparib extended overall survival, which was a secondary endpoint, by approximately 13 months, compared with placebo, and this was consistent across three analyses: the full-analysis set, which was unadjusted for crossover; the full, prespecified sensitivity analysis of germline BRCA-mutated patients; and the post hoc sensitivity analysis that used stratification variables based on electronic case reports to correct for patients who had been erroneously stratified at randomization (Table 1). At 5 years, 42% of the olaparib arm was alive, compared to 33% of the placebo arm (HR = 0.74; P = .0537), Dr. Poveda reported.

The toxicity was consistent with the known side effects of olaparib. The most common grade ≥ 3 treatment-emergent adverse event was anemia, which led to dose interruptions in 50% of patients (vs 19% with placebo), dose reduction in 28% (vs 3%), and treatment discontinuations in 17% (vs 3%). 

DISCLOSURE: This study was funded by AstraZeneca and Merck Sharp & Dohme Corp. Dr. Poveda has consulted or advised for AstraZeneca, Clovis Oncology, PharmaMar, Roche, and Tesaro and has received travel funding from PharmaMar. Dr. Schilsky has received institutional research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech/Roche, Lilly, Merck, and Pfizer and has been reimbursed for travel, accommodations, or other expenses by Varian.