The FDA has granted a priority review designation to a supplemental new drug application for enzalutamide (Xtandi) for the treatment of men with metastatic hormone-sensitive prostate cancer (mHSPC), according to Astellas Pharma Inc. and Pfizer Inc., the codevelopers of the androgen receptor inhibitor.

The designation, which will expedite the development and review of enzalutamide in this setting, is based on data from the phase III ARCHES and ENZAMET trials. The ARCHES study showed that at a median follow-up of 14.4 months, median radiographic progression-free survival (rPFS) in men with mHSPC was not reached in the enzalutamide arm and was 19.45 months in the placebo arm, translating to a 61% reduction in risk of radiographic progression or death with enzalutamide (HR, 0.39; 95% CI, 0.30-0.50; P <.0001).

In the phase III ENZAMET trial, the 3-year overall survival (OS) rate in men with mHSPC was 80% in patients treated with enzalutamide plus standard of care (SOC) compared with 72% among those who received a different nonsteroidal antiandrogen (NSAA; HR, 0.67; 95% CI, 0.52-0.86; P = .002).

"The complementary data from the ARCHES and ENZAMET trials in men with mHSPC take us another step closer to understanding Xtandi's full potential in helping address unmet needs in prostate cancer," said Andrew Krivoshik, MD, PhD, senior vice president and oncology therapeutic area head at Astellas, said in a press release. "Xtandi is a current standard of care in castration-resistant prostate cancer and we look forward to working with the FDA to potentially make Xtandi available to men earlier in their prostate cancer journey."

The international, double-blind ARCHES trial enrolled 1150 patients with histologically verified mHSPC across North America, Europe, and the Asia-Pacific region who were randomized to receive enzalutamide at 160 mg daily or placebo. Men with both low- and high-volume disease, as well as patients who received recent treatment with docetaxel but did not have disease progression were enrolled.

Patients were allowed to receive prior androgen deprivation therapy (ADT) ≤3 months; those who received prior docetaxel could have had ADT for up to 6 months. The primary endpoint was rPFS, defined as the time to radiographic progression of disease either by soft tissue or confirmed bone scan criteria or death from any cause within 24 weeks of treatment discontinuation, whichever occurred first.

At initial diagnosis, 70% in the enzalutamide arm and 63% in the placebo arm had distant metastasis; 62% and 65%, respectively, had high disease volume; and 67% and 65%, respectively, had a Gleason score ≥8. Across the overall study population, approximately 18% of patients received prior docetaxel in the hormone-sensitive setting and the median duration of prior ADT at study entry was 1.6 months. Of those with confirmed metastases at screening, nearly half had bone only metastases with about 9% having soft tissue only metastases.

Enzalutamide plus ADT was also associated with a reduction in the risk of time to PSA progression by 81% (HR, 0.19; 95% CI, 0.13-0.26; P <.0001) and the time to initiation of new antineoplastic therapy by 72% (HR, 0.28; 95% CI, 0.20-0.40; P <.0001) compared with ADT alone.

An interim analysis of OS showed that the median OS has not been reached in either arm, with 39 deaths in the enzalutamide arm and 45 in the placebo arm. A final OS analysis will be conducted after approximately 342 deaths.

The 12-month event-free rate estimate for rPFS was 84% in the enzalutamide/ADT arm and 64% in the placebo/ADT arm, with a median that has not been reached for enzalutamide. At the data cutoff date of October 14, 2018, the majority of the events were radiographic progression events—77 in the enzalutamide arm and 185 in the placebo arm. With a median follow-up of 14.4 months, the median duration of therapy was 12.8 months for enzalutamide plus ADT versus 11.6 months for placebo plus ADT.

A complete response (disappearance of all lesions on imaging) was attained by 36.7% of enzalutamide-treated patients versus 23.1% of placebo recipients. The overall response rate favored enzalutamide over placebo (83.1% vs 63.7%; P <.0001).

The safety profile of enzalutamide was consistent with prior studies of the androgen receptor inhibitor. The proportion of patients who had to discontinue study was similar between enzalutamide and placebo (7.2% vs 5.2%) and the rate of grade ≥3 adverse events (AEs) was also similar (24.3% vs 25.6%).

Following the unblinding at the end of double-blind treatment and the significant positive outcome on the primary endpoint, all patients in the placebo group are being offered enzalutamide in an open-label extension protocol.

The international, randomized phase III ENZAMET trial was led by the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group. The trial enrolled 1125 men with mHSPC between March 2014 and March 2017. These men were randomized 1:1 to receive either enzalutamide or 1 of 3 first-generation NSAAs (bicalutamide [Casodex], nilutamide [Nilandron], or flutamide [Eulexin]) plus a testosterone-suppressing medicine. Less than half of the men (n = 503) received early doses of docetaxel. Patients were evaluated every 12 weeks and at progression could receive therapy for castration-resistant prostate cancer at the investigator’s discretion.

ADT was allowed in the study up to 120 days prior to randomization, but intermittent ADT dosing was not allowed.

Randomization was stratified by volume of disease, planned early docetaxel use, planned anti-resorptive therapy, comorbidity score, performance status, and study site. A high volume of disease was considered the existence of visceral metastases and/or ≥4 bone metastases, with at least 1 of these beyond the pelvis and vertebral column.

The study authors noted that the 2 treatment arms were well balanced at baseline. The median age was 69 years across the 2 treatment arms.

As of the first interim analysis on February 28, 2019, when the criteria of 235 deaths had been met, patients had been followed for a median of 33 months. At 3 years, 64% of patients assigned to receive enzalutamide were still on the study treatment compared with 36% in the other NSAA arm.

The time until clinical prostate-specific antigen (PSA) rise, clinical progression or death was significantly increased with enzalutamide compared to the other NSAAs (HR, 0.39; 95% CI, 0.33-0.47; P <.001). Looking only at clinical progression also showed a significant benefit with enzalutamide (HR, 0.40; 95% CI, 0.33-0.49; P <.001). There was a 60% decreased rate of progression at any one time.

Among men with a high volume of disease on imaging scans (n = 596), those who received enzalutamide had a 3-year OS rate of 71% compared with 63% with another NSAA (HR, 0.74; 95% CI, 0.55-1.01). The 3-year OS rates were 89% and 82% (HR, 0.48; 95% CI, 0.28-0.80), respectively, in men with a low volume of disease (n = 529).

In the subgroup of men who received planned concurrent docetaxel, the OS rates were similar regardless of treatment (HR, 0.90; 0.62-1.31). Of these patients, 71% had a high volume of disease. There was a more significant difference in survival in men who did not receive planned early docetaxel (HR, 0.53; 95% CI, 0.37-0.75). Only 37% of these patients had a high volume of disease.

Selected AEs included hypertension of grade 2 seen in 4% of those treated with another NSAA and in 8% treated with enzalutamide and of grade 3 in 5% versus 11%, respectively. Grade 2 (14% vs 25%) and grade 3 (1% vs 6%) fatigue, grade 2 (1% vs 5%) and grade 3 (<1% vs 1%) falls, grade 1/2 concentration impairment (1% vs 4%), syncope (1% vs 4%), and seizure (0% vs 1%) were also noted. The rate of selected AEs per year of treatment exposure was 34% (95% CI, 29%-40%) with enzalutamide compared with 33% (95% CI, 28%-39%) with other NSAAs.

1. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. Phase 3 study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial. J Clin Oncol. 2019;37(suppl 7, abstr 687). doi: 10.1200/JCO.2019.37.7_suppl.687.

2. Sweeney C, Martin AJ, Zielinski RR, et al. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. J Clin Oncol. 2019;37(suppl; abstr LBA2). doi: 10.1200/JCO.2019.37.18_suppl.LBA2.

This article originally appeared on OncLive as, "

FDA Grants Enzalutamide Priority Review for Metastatic Hormone-Sensitive Prostate Cancer

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FDA Granted Enzalutamide Priority Review to Treat Metastatic Hormone-Sensitive Prostate Cancer

The FDA has approved the combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) for the frontline treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The approval is based on findings from the phase III CLL14 trial, in which the venetoclax combination reduced the risk of disease progression or death by 67% versus obinutuzumab plus chlorambucil in patients with treatment-naïve CLL and co-existing medical conditions (HR, 0.33; 95% CI, 0.22-0.51; P<.0001).

The overall response rate (ORR) was 85% (95% CI, 79%-89%) with venetoclax/obinutuzumab versus 71% (95% CI, 65%-77%) in the control arm (P = .0007). The complete response or complete response with incomplete hematologic recovery rates were 50% versus 23% respectively (P <.0001).

The rate of minimal residual disease (MRD)-negativity in the bone marrow was 57% in the venetoclax arm compared with 17% in the obinutuzumab/chlorambucil arm. The MRD-negativity rates in the peripheral blood were 76% versus 35%, respectively.

“Venclexta plus Gazyva is the only chemotherapy-free option of fixed duration that provides durable responses to help people live longer without progression of their disease, compared to a standard of care,” Sandra Horning, MD, chief medical officer and head of Global Product Development, at Roche (Genentech), which manufactures venetoclax and obinutuzumab, said in a press release.

In the phase III CLL14 trial (NCT02242942), the combination of fixed-duration venetoclax and obinutuzumab was compared with obinutuzumab and chlorambucil in 432 treatment-naïve patients with CLL and coexisting medical conditions. Patients were randomized to receive 12 months of venetoclax alongside 6 months of obinutuzumab (arm A) or 6 months of obinutuzumab followed by 6 months of chlorambucil (arm B).

Complete results of the study are scheduled to be presented early next month at the 2019 ASCO Annual Meeting.

This article was originally published on 

FDA Approves Venetoclax/Obinutuzumab Combo for Frontline CLL

The FDA has approved the combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) for the frontline treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
 

FDA Approves Venetoclax Plus Obinutuzumab for CLL Treatment

The FDA has granted an accelerated approval to the frontline combination of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) for patients with unresectable locally advanced or metastatic PD-L1—positive triple-negative breast cancer (TNBC).

The approval is based on the phase III IMpassion130 trial, in which the addition of the PD-L1 inhibitor atezolizumab to nab-paclitaxel reduced the risk of progression or death by 40% compared with nab-paclitaxel alone in this patient population.

The double-blind IMpassion130 study evaluated the efficacy and safety of the PD-L1 inhibitor plus chemotherapy versus nab-paclitaxel alone in treatment-naïve patients with metastatic TNBC. Patients were randomized 1:1 to receive nab-paclitaxel at 100 mg/m

 intravenously on days 1, 8, and 15 of the 28-day cycle with atezolizumab at 840 mg intravenously (n = 451) on days 1 and 15 of a 28-day cycle or with placebo (n = 451). Treatment was given until disease progression or unacceptable toxicity.

The coprimary endpoints were progression-free survival (PFS) and overall survival (OS) in both the intent-to-treat (ITT) and PD-L1—positive populations; secondary endpoints were overall response rate, duration of response, and safety. Patients were stratified by prior taxane use, liver metastases, and PD-L1 expression, which was defined as at least 1% on tumor-infiltrating immune cells to be positive.

Results of the primary PFS analysis in the PD-L1—positive population demonstrated a clinically meaningful median PFS of 7.4 months with atezolizumab/nab-paclitaxel and 4.8 months with chemotherapy (HR, 0.60; 95% CI, 0.48-0.77; 

 <.0001). Moreover, the 1-year PFS rates were 29% (95% CI, 22%-36%) and 16% (95% CI, 11%-22%) with atezolizumab/nab-paclitaxel and nab-paclitaxel, respectively.

In the ITT population, the median PFS with atezolizumab/nab-paclitaxel and nab-paclitaxel was 7.2 months (95% CI, 5.6-7.5) and 5.5 months (95% CI, 5.3-5.6), respectively (HR, 0.80; 95% CI, 0.69-0.92; 

 = .0025). Moreover, the 1-year PFS rates were 24% (95% CI, 20%-28%) in the combination arm and 18% (95% CI, 14%-21%) in the nab-paclitaxel arm.

At a 12.9-month follow-up, an interim OS analysis of the PD-L1—positive population showed a clinically meaningful improvement with added atezolizumab at 25.0 months versus nab-paclitaxel alone at 15.5 months (HR, 0.62; 95% CI, 0.45-0.86). Two-year OS rates were 54% and 37% in the immunotherapy/chemotherapy and chemotherapy arms, respectively. In the ITT population, the P value for OS was .0840 (HR, 0.84; 95% CI, 0.69-1.02). However, OS was not formally tested in a statistical design in the PD-L1–positive subgroup, but was tested in the overall study population.

To be eligible for enrollment, patients must have had metastatic or inoperably locally advanced TNBC with no prior therapy for their advanced disease with an ECOG performance status of 0 or 1. Prior chemotherapy in the curative setting, including taxanes, were permitted if the treatment-free interval was longer than 12 months.

Regarding safety, most all-grade adverse events (AEs) were similar between arms. The most common grade 3/4 AEs with atezolizumab/nab-paclitaxel and nab-paclitaxel were neutropenia (8% vs 8%), decreased neutrophil count (5% vs 3%), peripheral neuropathy (6% vs 3%), fatigue (4% vs 3%), and anemia (3% vs 3%), respectively.

FDA Approves Atezolizumab Combo for Frontline TNBC

The Food and Drug Administration has granted an accelerated approval to the frontline combination of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) for patients with unresectable locally advanced or metastatic PD-L1–positive triple-negative breast cancer (TNBC)

The FDA has approved romiplostim (Nplate) for the treatment of pediatric patients aged ≥1 year with immune thrombocytopenia (ITP) for at least 6 months who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The approval is based on 2 double-blind, placebo-controlled trials in this patient population. The first study (NCT01444417) randomized 62 patients with relapsed/refractory disease following ≥1 previous ITP treatment in a 2:1 ratio to either romiplostim (n = 42) or placebo (n = 20).1

Fifty-two percent (n = 22) of patients in the romiplostim arm achieved durable platelet response compared with 10% (n = 2) of the placebo arm (P <.05). According to the FDA, the trial design defined durable platelet response as “at least 6 weekly platelet counts ≥50 × 109/L during weeks 18 through 25 of treatment.” Seventy-one percent (n = 30) versus 20% (n = 4) of patients in the 2 arms, respectively, had overall platelet response (P <.05), which the FDA explained that the trial defined as “a durable or a transient platelet response.” In the romiplostim group, patients had platelet counts ≥50 x 109/L for a median of 12 weeks versus 1 week in the control arm (P <.05).

The second trial (NCT00515203) randomized 22 patients in a 3:1 ratio to romiplostim (n = 17) or placebo (n = 5). In the romiplostim group 88% (n = 15; 95% CI, 64%-99%) of patients during the treatment period reached a platelet count ≥50 x 109/L for 2 consecutive weeks and an increase in platelet count of ≥20 × 109/L above baseline for 2 consecutive weeks. Neither outcome measure was reached by any patient treated with placebo.

The FDA noted that all-grade adverse events (AEs) that occurred in ≥25% of patients were contusion, upper respiratory tract infection, and oropharyngeal pain.

Data were recently presented at the 2018 ASH Annual Meeting for an integrated analysis of data from 5 clinical trials that showed that most pediatric patients with ITP had rapid and durable platelet responses when treated with romiplostim.2

Nearly 90% of 282 evaluable patients had platelet responses, which occurred after a median treatment duration of 6 weeks. Patients remained in response for a median of 76% of months during follow-up.

In general, romiplostim was well tolerated; 3% of patients discontinued treatment because of AEs.

The findings from 5 clinical trials of children with ITP treated with romiplostim included randomized and placebo-controlled trials, single-arm trials, open-label trials, and extension studies. The 282 children included in the analysis had a median age of 10, median ITP duration of 1.9 years, and median baseline platelet count of 14.3 x 109/L.

The patients received a median of 2 prior ITP therapies before initiating romiplostim, and 46% of patients had 3 or more prior treatments. Treatment history most often included corticosteroids (88%), intravenous immunoglobulin (87%), anti-D antibody (23%), and rituximab (Rituxan; 21%).

Patients began romiplostim treatment at a dose of 1 µg/kg weekly, titrated to a maximum dose of 10 µg/kg weekly as needed to maintain a platelet count of 50,000 to 200,000/mL. The 282 patients had a median treatment duration of 65 weeks, including 62% of patients treated for at least 48 weeks, and the median dose was 6.6 µg/kg.

Overall, 89% of patients treated with romiplostim achieved a platelet response, defined as platelet count ≥50 x 109/L. Patients maintained responses for a median of 11 months and for 75.6% of all months on treatment. When response was calculated from initial response (N = 232), patients maintained the response for a median of 14 months and for 92.3% of treatment months.

Among the 19 patients who had prolonged treatment-free responses, the median duration of the treatment-free intervals was 12 months.

A summary of the safety data showed that 24% of patients had a serious AE during romiplostim treatment, but no fatal AEs occurred. One patient had thrombocytosis associated with a platelet count of 1462 x 109/L at week 14 that persisted for 1 week. Another patient had elevated platelet counts on 10 different occasions during weeks 20 and 172, reaching a maximum of 872 x 109/L but without a thrombotic event.

The most commonly reported AEs in romiplostim-treated patients were headache (40%), epistaxis (39%), pyrexia (32%), and nasopharyngitis. Sixty-eight percent of patients had bleeding AEs, most of which were mild or moderate in severity. The most frequent bleeding AEs were epistaxis (39%), contusion (28%), petechiae (24%), and hematoma (15%). The most common serious AE was epistaxis (6%).

Data for 1 patient who had a bone marrow biopsy at investigator request showed an increase in modified Bauermeister bone marrow grade from 0 to 2 without any associated AE. In an ongoing open-label trial, bone marrow biopsies in 32 patients showed no collagen or bone marrow abnormalities.

FDA Approves Romiplostim for Pediatric ITP

FDA Approves Romiplostim for Pediatric Immune Thrombocytopenia

The Food and Drug Administration (FDA) has granted a priority review to the XPO1 inhibitor selinexor for the treatment of patients with penta-refractory multiple myeloma.

In its announcement, Karyopharm Therapeutics, manufacturer of the therapy, cited results from the phase IIb STORM trial as the basis for its new drug application (NDA). The trial examined the combination of selinexor and dexamethasone in patients with penta-refractory multiple myeloma. Updated data from the study presented at the 2018 Society of Hematologic Oncology (SOHO) Annual Meeting showed that the doublet regimen was associated with an overall response rate (ORR) of 26.2% and a median overall survival (OS) of 8.6 months in patients with penta-refractory disease.

Sundar Jagannath, MD, director of the Multiple Myeloma Program and professor of medicine at The Tisch Cancer Institute, Mount Sinai Health System, delivered the STORM findings at SOHO. He explained that patients who had a response to treatment, even a minor response, did significantly better, with a median OS of 15.6 months. Historically, the median OS in this patient population is an estimated 3.6 months.

According to Karyopharm, the study defined 

as “patients who have previously received at least one alkylating agent, glucocorticoids, two immunomodulatory drugs (IMiDs; lenalidomide [Revlimid] and pomalidomide [Pomalyst]), two proteasome inhibitors (PIs; bortezomib [Velcade] and carfilzomib [Kyprolis]), and daratumumab (Darzalex), and whose disease is refractory to glucocorticoids, at least one PI, at least one IMiD, and daratumumab, and whose disease has progressed following their most recent therapy.”

Under the Prescription Drug User-Fee Act, the FDA is scheduled to make a decision on the NDA by April 6, 2019.

"As a potential new therapy with a novel mechanism and compelling clinical profile, we believe oral selinexor, if approved, will provide a meaningful therapeutic option for patients battling highly resistant, penta-refractory myeloma," Sharon Shacham, PhD, MBA, founder, president and chief scientific officer of Karyopharm, said in a statement. "The acceptance of this NDA for review and grant of Priority Review mark significant milestones for the selinexor program, and further underscores the high level of unmet need in this patient population.  We look forward to working with the FDA during the review process."

The STORM trial included 122 patients with penta-refractory multiple myeloma at 38 sites in the United States; 85 patients were treated per-protocol. The median patient age was 65 years (range, 40-85). Eligible patients had to have received prior treatment with bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, an alkylator, and glucocorticoids.

Patients had undergone a median of 7 prior treatments (range, 3-18), and all were refractory to proteasome inhibitor/immunomodulatory drugs/ daratumumab/glucocorticoid. Ninety-six percent were refractory to carfilzomib/pomalidomide/daratumumab. Eighty-four percent had undergone stem cell transplant, and 28% had undergone ≥2 transplants.

Patients received 80 mg of oral selinexor plus 20 mg of oral dexamethasone twice weekly until progression. The primary endpoint was ORR.

Two patients, both of whom were negative for minimal residual disease, achieved stringent complete response. Two patients who relapsed following chimeric antigen receptor T-cell therapy achieved a partial response.

The median progression-free survival (PFS) was 3.7 months for the entire cohort. For partial responders, the median PFS was 5.3 months, and 4.6 months for those who had at least minimal response.

Duration of response was 4.4 months (range, <1-12.2). Jagannath said responses typically occurred in the first 4 weeks of treatment. The clinical benefit rate was 39.3% and the disease control rate was 78.7%.

“If you’re able to arrest the growth of the tumor, you’re able to get a survival benefit for these patients,” Jagannath said.

The most common grade 3/4 treatment-related hematological adverse event (AE) was thrombocytopenia (53.7%), followed by anemia (29.3%), neutropenia (17.9%), leukopenia (13.8%), and lymphopenia (8.9%). There was only 1 instance of grade 4 anemia and no grade 4 leukopenias recorded.

There were no grade 4 non-hematological AEs observed. The most common grade 3 non-hematological AEs were fatigue/asthenia (22.8%), hyponatremia (16.3%), and nausea (9.8%).

Selinexor links to and inhibits XPO1 (CRM1), a nuclear export protein. There is an accumulation of tumor suppressor proteins in the cell nucleus as a result of this activity, and, subsequently, the cell’s tumor suppressor function is regained and amplified, which investigators hypothesize induces apoptosis.

Jagannath J, Vogl DT, Dimopoulos MA, et al. Phase 2b results of the STORM study: oral selinexor plus low dose dexamethasone (sd) in patients with penta-refractory myeloma (penta-MM). 

. 2018;18(suppl; Abstract MM-255). doi: 10.1016/j.clml.2018.07.149.

Karyopharm Completes Rolling Submission of New Drug Application to U.S. Food and Drug Administration for Selinexor as a Treatment for Patients with Penta-Refractory Multiple Myeloma. Published August 6, 2018. Accessed October 6, 2018. https://bit.ly/2zVwIfi.

The FDA has granted a priority review to the XPO1 inhibitor selinexor for the treatment of patients with penta-refractory multiple myeloma.

OncLive Staff

Articles

FDA Granted Enzalutamide Priority Review to Treat Metastatic Hormone-Sensitive Prostate Cancer

FDA Approves Venetoclax Plus Obinutuzumab for CLL Treatment

FDA Approves Atezolizumab Combo for Frontline TNBC

FDA Approves Romiplostim for Pediatric Immune Thrombocytopenia

FDA Grants Priority Review to Selinexor for Penta-Refractory Multiple Myeloma