Darcy Lewis

Superior progression-free survival (PFS) was seen in patients with ovarian cancer who previously had a partial response (PR) to platinum-based therapy when they took Zejula (niraparib). This response was seen in patients with or without germline 

 mutations, according to data from the ENGOT-OV16/NOVA trial presented at the 2017 ASCO Annual Meeting.

Investigators set out to explore the effect of the PARP inhibitor Zejula on PFS in patients with recurrent ovarian cancer who were in response (either complete response [CR] or PR) to their most recent platinum-based therapy after a minimum of our cycles in ENGOT-OV16/NOVA, a phase 3 multicenter, randomized, double-blind, placebo-controlled study.

At the time of unblinding, 45 percent in the Zejula group who were positive for mutant BRCA achieved PFS, compared with 72 percent of patients in the placebo group. In the non-

 mutant cohort, 56 percent of patients had PFS versus 80 percent in the placebo group.

“We had half of the population in both groups who had only partial remission and wanted to know how they were doing. We tried to show the patients who were in partial remission have the same PFS as the whole group,” lead investigator Mansoor Raza Mirza, M.D., chief oncologist in the Department of Oncology in Rigshospitalet, Copenhagen University Hospital, Denmark, and medical director of the Nordic Society of Gynecologic Oncology-Clinical Trial Unit, said in an interview with 

 “PFS is actually better in the non-germline BRCA group because patients with active disease in the placebo group are progressing much faster so you see a better split as a hazard ratio [HR].”

Roughly half of the total study population (272 patients) responded to had a to their last platinum-based therapy. These patients were segregated by 

 mutation status and assigned to either daily 300 mg Zejula daily or placebo until disease progression or unacceptable toxicity. In the germline mutant 

 cohort, 67 out of 138 patients in the Zejula arm (49 percent) and 32 out of 65 patients in the placebo arm (48 percent) entered the trial with a PR. In the non-mutant germline 

 cohort, 117 out of 234 patients in the Zejula arm (50 percent) and 56 out of 116 in the placebo arm (48 percent) entered the trial with a PR.

Randomization was further stratified based on time to progression after completion of the penultimate platinum regimen, the use of Avastin (bevacizumab), and the best response (CR or PR) during the final platinum regimen. Each patient had received at least two prior courses of platinum-based chemotherapy but no prior treatment with a PARP inhibitor.

Disease assessment included imaging performed at baseline every eight weeks through cycle 14, and then every 12 weeks until treatment was discontinued. Disease progression was determined via central review using RECIST v1.1 criteria or clinical assessment. Increased levels of CA-125 alone were not considered to indicate progression.

Researchers determined that the safety profile of Zejula-treated patients with a PR was similar to that of the overall study population. The concluded that, overall, treatment with Zejula provided a statistically significant benefit in patients with a PR, with a treatment effect similar to that observed in the overall study population in both the germline

In March 2017, the FDA approved Zejula for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.

The approval was based on the overall findings from the ENGOT-OV16/NOVA trial, in which Zejula reduced the risk of progression or death by 74 percent compared with placebo for patients with germline 

positive platinum-sensitive, recurrent ovarian cancer.

The median PFS with maintenance Zejula was 21 months compared with 5.5 months for placebo in patients with germline 

 mutations. These findings remained consistent across subgroups of patients, including those without 

Articles

Superior progression-free survival (PFS) was seen in patients with ovarian cancer who previously had a partial response (PR) to platinum-based therapy when they took Zejula (niraparib). This response was seen in patients with or without germline BRCA mutations, according to data from the ENGOT-OV16/NOVA trial presented at the 2017 ASCO Annual Meeting.

Study Shows Zejula's Benefit in Treating Ovarian Cancer

The value of using biomarkers in bladder cancer is compelling, though experts in the field do need to better define the utility and costs, according to Badrinath Konety, M.D., M.B.A., department chair of urology at the University of Minnesota, who spoke at the 2016 Large Urology Group Practice Association (LUGPA) Annual Meeting. 

In particular, Konety singled out biomarkers’ diagnostic consistency and the ways they can aid cystoscopy. “I use them to arbitrate atypicals and for post-intravesical therapy,” he said. He added that they also show potential in the areas of screening for bladder cancer, revealing other, unrelated cancers, and in distinguishing among bladder cancer grades.

These benefits contrast with the drawbacks associated with cytology, which include the need to send samples out to a lab, readings that can vary by pathologist and a low degree of sensitivity, he said.

According to Konety, the use of bladder cancer biomarkers among urologists increased from 11 percent to 26 percent between 2000 and 2015. Among the more commonly used biomarker assays are the BTA/BTA Stat, NMP22 (BladderChek), UroVysion FISH, ImmunoCyt and CxBladder.

But do biomarkers actually improve tumor detection?

Konety summarized a study from 2010 led by Madelon N. van der Aa published in the 

, noting that it was a single-blind, randomized study using microsatellite markers. In the control arm, cystoscopy was performed at 3, 12 and 24 months without the positive or negative urine test results being communicated to the urologist. In the intervention arm, the urologist knew the marker result so that cystoscopy was performed on patients who tested positive on their urine test. At follow-up visits, recurrences were detected in 14.5 percent of patients in the intervention arm, versus in 10 percent of control-arm patients. The false positive rate in the intervention arm was 15 percent, compared to 20 percent in the control, showing a meaningful difference.

Konety described the BTA test as an in-office assay that identifies a complement H-related factor present in urine. Its sensitivity is 68 percent, while its specificity is 74 percent. He also noted that the NMP22 test detects nuclear mitotic apparatus protein (NuMA) with a sensitivity of 67 percent and a specificity of 75 percent. He noted that situations in which patients shed large numbers of benign cells can yield a high rate of false positives.

He then turned to Urovysion’s FISH test, which identifies the number of copies of chromosomes or regions of chromosomes with a sensitivity of 79 percent and a specificity of 88 percent. The ImmunoCyt assay consists of three monoclonal antibodies (19A211, M344 and LDQ10) labeled with two fluorescent markers. It has a sensitivity of 77 percent and a specificity of 76 percent.

There can be problems related to the FISH test. For example, false negatives can be caused by degenerated cells, presence of a hyphal fungus, contaminated squamous cells present only, excessive lubricant or autofluorescent bacteria.

False positives, on the other hand, can appear due to umbrella cells, polyoma virus infection with inclusions, and, rarely, seminal vesicle cells. Tetraploidy in reactive cells can also confound the results. Fortunately, correlation with cytology findings can exclude false positives caused by these complicating factors. Additionally, FISH testing is insufficient for the upper tract and situations with urinary diversion.

According to Konety, FISH testing is also useful after Bacillus Calmette-Guerin (BCG) treatment. “A post-BCG FISH predicts for both recurrence and prognosis,” he said. “FISH is also useful if post-BCG cytology is equivocal.”

Konety also discussed what he called “second-level” biomarker assays, those that are most helpful after atypical cytology to guide further care. One example is CxBladder, developed by New Zealand’s Pacific Edge, which Konety said has been validated in patients with hematuria. Using mRNA expression by PCR, CxBladder tests for CDC2, HOXA13, MDK, IGFBP5 and CXCR2. The test has shown a sensitivity of 97 percent for high-grade tumors and 69 percent for low-grade tumors, making it “better than cytology” (83 percent for high-grade and 28 percent for low-grade tumors): “CxBladder has a couple papers in review so it will be interesting to see how those data pan out.”

Methylation profiling is another area with the potential for clinical applicability. In a 23-gene set, it was effective on four: APC alpha, TERT alpha, TERT beta and EDNRB, with an area under the curve (AUC) between 0.69 and 0.82, a sensitivity of 63 percent and a specificity of 58 percent. Other genes that have been studied include RASSF1A, p14, TWIST1, and NID2.

“But there are issues with methylation profiling due to their small discovery and validation sets,” Konety said. “Most have focused on hematuria evaluation and seem to be more closely associated with grade and stage.”

Konety, who served on the American Urological Association's International Consensus Panel, discussed its recommendations. Marker-guided follow-up and screening of patients with low-grade non-muscle invasive bladder cancer (NMIBC) were both deemed “attractive,” but not recommended at this time. The panel does not recommend biomarkers in the surveillance of high-grade NMIBC. “Consider that 75 percent of patients want a test with a sensitivity of at least 95 percent in order to be willing to forego cystoscopy, as uncomfortable as that test is,” he said.

Konety also reviewed the recently updated guidelines from the American Urological Association (AUA).

In surveillance of NMIBC, a clinician should not use urinary biomarkers in place of cystoscopic evaluation.

In a patient with a history of low-risk cancer and a normal cystoscopy, a clinician should not routinely use a urinary biomarker or cytology during surveillance.

In a patient with NMIBC, a clinician may use biomarkers to assess response to intravesical BCG (UroVysion FISH) and adjudicate equivocal cytology (UroVysion FISH and ImmunoCyt). 

“The AUA is most concerned with specificity and the issue of false positives,” he said. “Biomarkers’ false positive rate is unclear and we want to avoid additional harms to our patients.”

As for what’s in the pipeline, Konety mentioned several promising biomarkers. These include Genomic Health, MDx (Assure MDx), Genome Dx, CertNDx (Predictive Biosciences), COXEN, Foundation Medicine and Xpert (Cepheid), which has already been released in Germany. “We’re clearly headed toward more complicated tests that will give us a more sophisticated view of what’s happening with our patients,” he said. “We’re currently waiting to see which genes pan out. The bottom line is that new markers need large studies, and we’re not there yet.”

Biomarkers have value in the diagnosis and monitoring of bladder cancer, but their use is still being perfected.

Using Biomarkers in Bladder Cancer Diagnosis and Monitoring

Lynparza (olaparib) was found to significantly increase overall survival (OS) when given as a maintenance therapy for patients with platinum-sensitive, relapsed serous ovarian cancer, according to the third survival analysis of 265 patients from the phase 2 Study 19 trial. These data were presented at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO), a gathering of 30,000 oncology professionals in Chicago.

Results of the study's extension showed that the PARP inhibitor demonstrated the greatest OS advantage in women who had a 

 mutation, according to lead author Jonathan Ledermann, professor of Medical Oncology at the University College London Cancer Institute and director of the Cancer Research UK & UCL Cancer Trials Centre. However, this survival advantage did not meet the criterion for statistical significance.

Additional key findings were that both time to first subsequent therapy or death (TFST) and time to second subsequent therapy or death (TSST) were substantially prolonged in patients taking Lynparza; again, the greatest benefit was seen in those with a 

 mutation. Additionally, the unprecedented long-term exposure meant that 13 percent of all trial patients (15 percent of 

-mutated patients) received maintenance Lynparza for at least five years. In three years of follow-up since the 2012 analysis, there were no new safety findings.

Study 19 assessed patients with platinum-sensitive, recurrent high-grade serous ovarian cancer. They had received two or more prior regimens of platinum-based chemotherapy and experienced complete response (CR) or partial response (PR) to their most recent regimen. In a double-blind, one-to-one randomization, half the patients received Lynparza 400 mg capsules twice daily as maintenance therapy (136 patients) and half received placebo capsules twice daily (129 patients).

 testing occurred for all patients in the form of case reports that contained the results of previous local germline 

 testing. The division between patients was nearly even between those 

 mutations (136 patients) and those with wild type 

 findings (118 patients), meaning that they either did not have a detected 

The primary endpoint was progression free survival (PFS) as measured by RECIST 1.0. Secondary endpoints included OS, safety and tolerability. Exploratory endpoints included TFST and TSST.

In Study 19, the median PFS for patients taking maintenance Lynparza was 8.4 months, compared to 4.8 months for the control group. The difference in the 

 mutation subgroup was even more pronounced: 11.2 months with Lynparza and 4.3 months with placebo.

The third data analysis of Study 19, with data cut-off at September 30, 2015, was performed with data at 77 percent maturity, OS in the overall study population (265 patients) was a median 29.8 months in the Lynparza group and 27.8 months in the placebo group. In the 

 mutation group (136 patients), where the data were at 70 percent maturity, median OS was 34.9 months for the Lynparza group and 30.2 months for placebo.

“Statistical tests did not provide sufficient evidence to dismiss the proportional hazards assumption for OS, so a restricted means analysis was performed to compare mean survival,” Ledermann said. “The difference in mean survival adds further support to the OS advantage of Lynparza.” In the overall study population, the restricted mean OS was 40.1 for the Lynparza group and 34.9 for the control group, for a difference of 5.2 months. In the 

 subgroup, the restricted mean OS was 44.3 months on Lynparza (74 patients) versus 36.9 months with placebo (62 patients), a difference of 7.4 months.

 wild type subgroup. Of these, 47 (82 percent) experienced TFST events. The median TFST was 12.9 months. Of the 61 women who received placebo, 60 (98 percent) experienced TFST events; for them, the median TFST was 6.9 months. These data were at 91 percent maturity.

The updated exploratory analysis also examined TSST events. Of the 57 patients in the 

 wild type subgroup treated with maintenance Lynparza, 47 (82 percent) experienced TSST. The median TSST was 17.0 months. In the placebo group, 59 (97 percent) experienced a TSST; the median TSST was 14.7 months. These data were at 90 percent maturity.

 mutation consisted of 20 patients. Their OS data were inconsistent with the overall study population, but conclusions were limited by the small group size.

With a median follow-up interval of 5.9 years, 15 patients (11 percent) were still receiving Lynparza (eight with 

-mutated patient was still receiving placebo. Twelve percent of 

 wild-type patients on Lynparza achieved median follow-up of between five and six years.

The adverse events (AEs) and dose modifications remained consistent from 2012 and included three cases of myelodysplastic syndrome/acute myeloid leukemia. Two of these patients were in the Lynparza group (on treatment for 57 and 10 months) and one was on placebo for 44 months. In women receiving Lynparza for at least two years, frequencies of common AEs (nausea, fatigue, vomiting, anemia) were consistent with the overall population. AEs were generally reported during the first two years of treatment.

In the overall study population, 59 patients (43 percent) experienced an AE of grade 3 or above, while only 28 (22 percent) of those on placebo did. Those percentages remained fairly consistent among patients who remained on trial for two years or more: 15 (47 percent) in the Lynparza arm and one (20 percent) in the control arm. Likewise, the percentages of dose reductions due to AEs were consistent over time: 34 (25 percent)/five (4 percent) active versus control in the overall study population and eight (25 percent) and 0, respectively, among those on treatment for two years or longer. There were few treatment discontinuations due to AEs: eight active and two control patients overall and three Lynparza patients from the long-term treatment group. No patients from the long-term placebo group discontinued treatment due to AEs.

Patients with relapsed serous ovarian cancer saw a survival benefit with Lynparza (olaparib) in a phase 2 trial. 

PARP Inhibitor Increases Survival for Subset of Patients With Ovarian Cancer

Pretreated patients with recurrent ovarian cancer had a 2.5-month progression-free survival (PFS) benefit when receiving the vascular disrupting agent (VDA) fosbretabulin plus Avastin (bevacizumab) compared with Avastin alone, according to data from the phase 2 GOG186i study; however, hypertension rates were double in patients receiving the combination regimen.

In the phase 2 trial, the risk of disease progression was reduced by 31.5 percent with fosbretabulin/Avastincompared with single-agent Avastin (7.3 versus 4.8 months). At the time of the analysis, data on overall survival (OS) were not yet mature.

Avastin is known to be active as a single agent against recurrent ovarian cancer, while fosbretabulin selectively targets pre-existing tumor vasculature with a resulting vascular shutdown that leads to cell death and necrosis. Given this mechanism of action, the rates of cardiac events were expectedly higher with the combination. The rate of moderate to severe hypertension was 35 percent with the combination versus 16% with single-agent Avastin.

Bradley J. Monk, presented findings during at the 2015 Society of Gynecologic Oncology’s (SGO) Annual Meeting on Women’s Cancer.

“Based on the progression-free survival and tolerability of these two anti-vascular therapies, further evaluation is warranted for this chemotherapy-free regimen, with the understanding that fosbretabulin may increase the frequency of hypertension,” said Monk, professor of gynecologic oncology at the University of Arizona Cancer Center. “Overall survival data are currently too early in the timeline to warrant any conclusions, because this was a hypothesis-generating trial. But, in general, we now know that vascular disruption is highly significant.”

In the trial, 107 patients with persistent or recurrent epithelial ovarian, fallopian tube or peritoneal carcinoma, measurable or detectable disease, and 1 to 3 prior regimens of chemotherapy were randomized to Avastin or Avastin plus fosbretabulin. Patients received treatment every three weeks until disease progression or unacceptable levels of toxicity occurred.

The randomization was stratified by disease status (measurable versus nonmeasurable), prior Avastin and platinum-free interval. The study’s primary objective was to assess whether the addition of fosbretabulin to Avastin prolongs the duration of PFS. Two secondary objectives were to compare response rates and OS and to evaluate AEs in each study arm.

The objective response rate (ORR) with Avastin alone was 28.2 percent among 39 patients with measurable disease. The ORR with the combination regimen was 35.7 percent  in 42 patients. The odds ratio for responding to the combination arm relative to the Avastin arm was 1.41.

Both regimens were well tolerated enough for patients to complete a relatively high number of cycles. The median number of cycles with bevacizumab was 7 versus 6 with the combination. Grade 3 hypertension in the Avastin arm was 19.6 percent compared with 32.7 percent in the combination arm. There was one grade 3 thromboembolic AE.

No grade 5 treatment-related AEs occurred in either study arm. One grade 4 AE occurred in each treatment arm: a metabolism/nutrition-related AE in the Avastin group and a hypertension-related AE in the bevacizumab and fosbretabulin group. Additionally, one bowel perforation occurred in the Avastin arm, but all adverse events were manageable.

Fosbretabulin is a potent and reversible tubulin depolymerizing agent. It selectively affects immature endothelial cells typically seen in solid tumors, which lack smooth muscle and pericytes and rely more on tubulin to maintain the vessel wall’s flat shape. Tubulin inhibition causes rounding in the affected epithelial cells, obstructing the blood vessel lumen. A blockage at any point in a vessel segment will shut off blood flow upstream and downstream, which leads to rapid death of cells.

“It’s possible that anti-angiogenesis agents like bevacizumab might prevent revascularization during and after VDA treatment,” Monk, professor of gynecologic oncology at the University of Arizona Cancer Center, said at the conference.

Although a phase 3 study to explore the combination of fosbretabulin and Avastin has not yet been initiated, a phase 2 study is exploring fosbretabulin in patients with gastrointestinal neuroendocrine tumors. Patients in this study are required to have elevations in specific biomarkers, such as serotonin, 5-hydroxyindoleacetic acid, chromogranin A, neurokinin A, and neuron-specific enolase.

Pretreated patients with recurrent ovarian cancer had a 2.5-month progression-free survival benefit when receiving fosbretabulin plus Avastin  compared with Avastin alone; however, hypertension rates doubled.


Darcy Lewis

Study Shows Zejula's Benefit in Treating Ovarian Cancer

Using Biomarkers in Bladder Cancer Diagnosis and Monitoring

PARP Inhibitor Increases Survival for Subset of Patients With Ovarian Cancer

Fosbretabulin and Avastin Combo Delays Progression, But Doubles Hypertension in Ovarian Cancer

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