Clinical Insights: December 2019

Monday, December 23, 2019

Release Date: December 22, 2019
Expiration Date: December 22, 2020


This activity is provided free of charge.

STATEMENT OF NEED

This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.

TARGET AUDIENCE

Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may participate in this CE activity.
 
EDUCATIONAL OBJECTIVES

Upon completion, participants should be able to:
  • Describe new preventive options and treatments for patients with cancer
  • Identify options for individualizing the treatment for patients with cancer
  • Assess new evidence to facilitate survivorship and supportive care for patients with cancer
ACCREDITATION/CREDIT DESIGNATION STATEMENT

Physicians’ Education Resource®, LLC is approved by the California Board of Registered Nursing, Provider #16669 for 1 Contact Hour.
 
DISCLOSURES/RESOLUTION OF COI

It is the policy of Physicians’ Education Resource®, LLC (PER®) to ensure the fair balance, independence, objectivity, and scientific objectivity in all of our CE activities. Everyone who is in a position to control the content of an educational activity is required to disclose all relevant financial relationships with any commercial interest as part of the activity planning process. PER® has implemented mechanisms to identify and resolve all conflicts of interest prior to release of this activity.The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial interests pertaining to this activity.

METHOD OF PARTICIPATION
  1. Read the articles in this section in its entirety.
  2. Go to  www.gotoper.com/go/ONN19December
  3. Complete and submit the CE posttest and activity evaluation.
  4. Print your CE Certificate.
OFF-LABEL DISCLOSURE/DISCLAIMER

This CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CE activity is for continuing medical nursing purposes only and is not meant to substitute for the independent medical judgment of a nurse or other healthcare provider relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual authors and do not reflect those of PER®.

Small Cell Lung Cancer

Durvalumab Combo Improves QOL, Reduces New Lesions in Small Cell Lung Cancer

Wayne Kuznar

Durvalumab (Imfinzi) added to etoposide and platinum-based chemotherapy as a first-line treatment for patients with extensive-stage small cell lung cancer (ES-SCLC) delays development of new lesions and improves patient-reported outcomes (PROs) compared with etoposide and platinum-based therapy alone, according to updated results from the CASPIAN study that were presented at the 2019 European Society for Medical Oncology (ESMO) Congress, held in Barcelona, Spain, from September 27 to October 1, 2019.1

In addition, PD-L1 expression was found to be low in this patient setting and did not appear to be a predictive biomarker for the improvement in clinical outcomes observed with the treat-ment combination that included durvalumab, an anti–PD-L1 antibody and checkpoint inhibitor, said Marina Chiara Garassino, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, in a presentation during the meeting.

In the phase III, global, open-label, multi¬center CASPIAN study (NCT03043872), 805 treatment-naïve patients with ES-SCLC were randomized 1:1:1 to 3 different treatment regimens. The results presented at the 2019 ESMO Congress were derived from an interim analysis of 2 of the arms: the durvalumab arm comprised ≤4 cycles of etoposide and plati¬num-based chemotherapy plus durvalumab at 1500 mg every 3 weeks, followed by mainte¬nance durvalumab every 4 weeks (n = 268), and patients in the chemotherapy-only control arm received ≤6 cycles of etoposide and plat¬inum-based chemotherapy every 3 weeks plus optional prophylactic cranial irradiation (PCI) at the investigator’s discretion (n = 269). In the third arm of the trial, patients receive durvalumab, tremelimumab (an antiCTLA-4 antibody), and etoposide plus plati¬num-based chemotherapy (n = 268). Following a preplanned interim analysis by an indepen¬dent data monitoring committee, this arm is continuing blinded to final analysis. The median overall survival increased from 10.3 months with chemotherapy alone to 13.0 months with the addition of durvalumab, trans¬lating to a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.591-0.909; P = .0047) at a median follow-up of 14.2 months.2

The data also showed that the median progres¬sion-free survival (PFS) was 5.1 months with durvalumab versus 5.4 months without (HR, 0.78; 95% CI, 0.645-0.936); this result was not formally tested for statistical significance. Analysis of the 12-month PFS rate showed an advantage of durvalumab (17.5% vs 4.7%, respectively).

In the findings presented during the 2019 ESMO Congress, progression patterns for the 2 arms were shown. Although no data on statis¬tical significance were presented, the 2 arms appeared to have possible similar patterns with the exception of new lesion development at first progression (41.4% vs 47.2% in the durvalumab and control arms, respectively). The incidence of total progression events was 84.3% in the durvalumab arm versus 86.6% in the chemo-therapy-alone arm, and progression—as defined by RECIST criteria—occurred in 71.6% and 72.1%, respectively. The rates of target lesion progression were 42.9% and 39.4%, and the rates of nontarget lesion progression were 24.6% and 22.7%, respectively. Death in the absence of progression occurred in 12.7% and 14.5% of patients in the durvalumab and control arms, respectively.

New lesions appeared in 41.4% of the durvalumab arm and 47.2% of the control arm. Specifically, there were fewer new lesions in the lung (8.6% vs 15.2%, respectively), liver (5.6% vs 8.9%), and bone (4.5% vs 7.1%) in the durvalumab arm.

In the PRO analysis, patients’ symptoms, health-related quality of life (QOL), and func¬tioning were assessed using 2 QOL questionnaires developed by the European Organisation for Research and Treatment of Cancer: QLQ-C30 (general oncology) and QLQ-LC13 (lung cancer-specific). Time to deterioration, which was defined as the time from randomization until the first clinically meaningful deterioration confirmed at the following visit or death, was analyzed using a Cox proportional hazards model. Baseline scores were comparable between the durvalumab and control arms across all symptom scales.

REFERENCES
1. Paz-Ares L, Goldman JW, Garassino MC, et al. PD-L1 expression, patterns of progression and patient-reported outcomes (PROs) with durvalumab plus platinum-etoposide in ES-SCLC: results from CASPIAN. Presented at: 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA62. bit.ly/2qgHVoh.

2. Paz-Ares L, Chen Y, Reinmuth N, et al. Overall survival with durvalumab plus etoposide-platinum in first-line extensive-stage SCLC: results from the CASPIAN study. Presented at: International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract PL02.11.https://library.iaslc.org/virtual-library-search?productid=15&author=Paz-Ares&category=
 
Breast Cancer

Adding Abemaciclib to Fulvestrant Improves Survival in HR-positive Advanced Breast Cancer

Gina Columbus

The addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to the estrogen receptor antagonist fulvestrant (Faslodex) led to a median 9.4-month overall survival (OS) benefit compared with fulvestrant plus placebo in patients with hormone receptor– positive, HER2-negative advanced breast cancer who had progressed on prior endocrine therapy, according to results of the phase III MONARCH 2 trial that were presented at the 2019 European Society for Medical Oncology (ESMO) Congress, held in Barcelona, Spain, from September 27 to October 1, 2019.1,2

“With further follow-up we have overall survival data showing a statistically signifi¬cant and clinically meaningful improvement in overall survival with the combination,” said lead study investigator George W. Sledge Jr, MD, in a press conference during the meeting.

The FDA approved abemaciclib in combina¬tion with fulvestrant in this patient population in September 2017, based on progression-free survival (PFS) data from the MONARCH 2 study. The earlier findings showed that adding abemaciclib to fulvestrant led to a 45% reduction in the risk of disease progression or death compared with fulvestrant alone.3

In the MONARCH 2 trial (NCT02107703), 669 pre-, peri-, or postmenopausal patients with hormone receptor–positive, HER2- negative advanced breast cancer resistant to endocrine therapy were randomized 2:1 to receive abemaciclib and fulvestrant (n = 446) or placebo and fulvestrant (n = 223). Abemaciclib was administered at 150 mg twice daily on a continuous schedule, and fulvestrant was given at 500 mg, per label. Enrollment occurred between August 7, 2014, and December 29, 2015.

To be eligible for enrollment in MONARCH 2, patients must have relapsed on endocrine therapy (in the neoadjuvant setting or within 1 year of receiving adjuvant treatment) or have progressed on frontline endocrine therapy for advanced breast cancer. Prior chemotherapy or >1 line of endocrine treatment for advanced disease was not permitted. All enrolled patients had an ECOG performance status ≤1.

The primary end point was investigator-as¬sessed PFS. Patients were stratified by site of metastasis and type of endocrine therapy resis¬tance (primary or secondary). The data cutoff date was June 20, 2019.

The OS benefit was consistent across subgroups, including in patients with poor prognostic factors such as visceral metastasis (HR, 0.675; 95% CI, 0.511-0.891) and primary endocrine therapy resistance (HR, 0.686; 95% CI, 0.451-1.043).

Sledge also provided updated findings on PFS, with 297 events occurring on the abemaciclib arm versus 193 events on placebo. The median PFS was 16.9 months for abemaciclib versus 9.3 months for placebo (HR, 0.536; 95% CI, 0.445-0.645; P <.0001). Moreover, the 3-year PFS rates were 29.9% and 10.1%, respectively.

The time to second disease progression also improved with the addition of abemaci¬clib, with a median 23.1 months versus 20.6 months with placebo (HR, 0.675; 95% CI, 0.558-0.816).

Additionally, the abemaciclib arm showed a statistically significant improve¬ment in median chemotherapy-free survival compared with placebo, at 25.5 months and 18.2 months, respectively (HR, 0.638; 95% CI, 0.527-0.773).

Regarding safety, Sledge noted that the toler¬ability and adverse events (AEs) associated with abemaciclib were consistent with those observed in the primary analysis.

Common hematologic grade ≥3 AEs in patients who received abemaciclib included neutropenia (29.9%), anemia (9.1%), and leukopenia (11.1%). No new cases of febrile neutropenia were reported relative to the primary analysis (n = 6). The most frequent nonhematologic AE reported was diarrhea (grade ≥3, 14.5%); most cases occurred during the first 4 weeks after abemaciclib initiation and were effectively managed using loperamide or dose adjustments. Only 1.4% of patients discontinued treatment due to diarrhea.

Moreover, at the median 47.7-month follow-up, 17% of patients on abemaciclib remained on treatment compared with 4% of those on placebo. This data highlights the long-term tolerability of this agent. 1. REFERENCES Sledge Jr GW, Toi M, Neven P, et al. MONARCH 2: overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2 advanced breast cancer. Presented at: 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA6PR. academic.oup.com/annonc/article/30/Supplement5/mdz394.006/5577645.

2. Sledge Jr GW, Toi M, Neven P, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor–positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: a randomized clinical trial [published online September 29, 2019]. JAMA Oncol. doi: 10.1001/jamaoncol.2019.4782.

3. Sledge GW, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy. J Clin Oncol. 2017;35(suppl 15; abstr 1000). doi: 10.1200/JCO.2017.73.7585. .

Nurse Perspective

Lisa Hineman, MSN, AOCN, PHN, ANP-C
Lead Nurse Practitioner Good Samaritan Hospital Los Angeles, California


AS AN ONCOLOGY NURSE since 1984 and a nurse practitioner since 2002, I have seen over a thousand patients with breast cancer. The first time I treated these patients made me realize that while breast cancer could be a curable or deadly disease, it can also be a chronic disease. Many of our patients with hormone receptor–positive breast cancer can live decades with the use of different versions of hormone blockades. However, results of some of the early studies of tamoxifen showed only 56% adherence, an early indication that even in a curative setting, patient medication adherence can be poor.

This is a critical issue in oncology, which has seen a substantial increase in oral therapies, including CDK4/6 inhibitors. Although patients receiving palbociclib (Ibrance) are monitored for neutropenia, and those receiving ribociclib (Kisqali) for occasional neutropenia, mildly elevated test results, or mild cardiac abnormalities, a big chal¬lenge with abemaciclib has been diarrhea. With a 47.7-month overall survival when given with fulves¬trant, abemaciclib plays a role in the metastatic, hormone receptor–positive breast cancer arena. As abemaciclib crosses the blood-brain barrier, as shown in the preclinical setting, management of the adverse effects is critical. Our ability as advanced nursing providers to foresee and prevent expected symptoms is critical.

The first patient we treated had severe diarrhea and discontinued therapy after 4 days. When the patient returned dehydrated with weight loss, a sig¬nificant discussion on prevention versus treatment of diarrhea ensued. Loperamide was prophylactically prescribed for this woman with metastatic breast cancer with pulmonary effusion and brain metastasis post radiation. She has since tolerated the agent well and has remained in stable condition for 18 months. We have subsequently started all patients on lopera¬mide prophylactically without further incident. br />  
Gastrointestinal Stromal Tumors

Ripretinib Shows Dramatic PFS Improvement for Heavily Pretreated GISTs

Silas Inman

Treatment with the novel switch-control inhibitor ripretinib (DCC-2618) reduced the risk of progression or death by 85% compared with placebo in heavily pretreated patients with advanced gastrointestinal stromal tumors (GISTs), according to findings from the phase III INVICTUS trial presented at the 2019 European Society for Medical Oncology (ESMO) Congress, held in Barcelona, Spain, from September 27 to October 1, 2019.

In the double-blind study, the median progression-free survival (PFS) was 6.3 months with ripretinib compared with 1.0 month for placebo (HR, 0.15; 95% CI, 0.09- 0.25; P <.0001). Additionally, ripretinib was associated with a 64% reduction in the risk of death, which was a secondary end point. The median overall survival (OS) was 15.1 months for ripretinib versus 6.6 months for placebo (HR, 0.36; 95% CI, 0.20-0.62; P = .0004). However, due to the lack of a statistically significant objective response rate (ORR; see below) and the hierarchical testing procedures used in the study’s statistical analysis, the significance of the OS difference could not be conclusively established.

“Ripretinib represents a potential new stan¬dard of care with broad activity in fourth-line GISTs, a patient population with advanced refractory disease and no other approved options,” said lead investigator Margaret von Mehren, MD, a member of the Department of Hematology/Oncology of the Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“The OS data are clinically meaningful. Patients with disease progression on placebo were allowed to cross over to receive ripretinib. Patients who [crossed] over had a substantial benefit in OS compared with those who did not and experi¬enced rapid deterioration.”

Primary mutations in the KIT or PDGFRA (platelet-derived growth factor receptor alpha) genes drive GISTs in more than 85% of cases, according to von Mehren. KIT and PDGFRA proteins with oncogenic mutations in the activa¬tion loop (or “switch”) region of the juxtamem¬brane domain show constitutive kinase activity. By binding to this region, ripretinib stabilizes the kinase in the inactive state, thus func¬tioning as a switch-control inhibitor.

At this time, no FDA-approved therapies are available in the fourth-line setting following first-, second-, and third-line treatment with imatinib (Gleevec), sunitinib (Sutent), and regorafenib (Stivarga). The INVICTUS trial (NCT03353753) aimed to address this unmet need in patients with heavily pretreated GISTs. The investigators randomized patients in a 2:1 ratio to receive ripretinib at 150 mg daily (n = 85) or placebo (n = 44).

The median patient age was 60 years, with more patients aged 75 years or older in the placebo group (9% vs 23%). Nearly two-thirds of patients had received 3 prior therapies, and one-third had received 4 or more (range, 4-7). The most common mutation was in KIT exon 11 (58%), followed by KIT exon 9 (16%).

The ORR with ripretinib was 9.4% compared with 0% in the placebo group (P = .0504). This finding narrowly missed achieving statistical significance. Median duration of response had not yet been reached at the data cutoff on May 31, 2019, with 7 of the 8 patients with confirmed responses continuing to respond at that time.

The 6-month PFS rate was 51.0% (95% CI, 39.4%-61.4%) for the novel targeted therapy compared with 3.2% for placebo (95% CI, 0.2%- 13.8%). PFS benefit was observed across all assessed patient subgroups. In patients treated with 3 therapies, the HR for PFS was 0.15 in favor of ripretinib (95% CI, 0.08-0.29). In those treated with ≥4 therapies, the HR was 0.24, also in favor of the switch-control inhibitor (95% CI, 0.12-0.51).

The 6-month OS rate with ripretinib was 84.3% (95% CI, 74.5%-90.6%) compared with 55.9% for placebo (95% CI, 39.9%-69.2%). The 12-month OS rates were 65.4% (95% CI, 51.6%-76.1%) and 25.9% (95% CI, 7.2%-49.9%), respectively. A further analysis of OS was added to assess the benefit of crossover. The results showed that the median OS in the placebo arm without crossover was 1.8 months (95% CI, 0.9-4.9) compared with 11.6 months (95% CI, 6.3 to not estimable) for patients who crossed over to the investigational arm.

Any-grade treatment-emer¬gent adverse events (TEAEs), regardless of causality, were experienced by 98.8% of patients in the ripretinib arm and 97.7% with placebo. Grade 3-4 TEAEs, regard¬less of cause, were experienced by 49.4% and 44.2%, respectively. The most common any-grade TEAEs in the ripretinib and placebo groups, respectively, were alopecia (51.8% vs 4.7%), fatigue (42.4% vs 23.3%), nausea (38.8% vs 11.6%), abdominal pain (36.5% vs 30.2%), constipation (34.1% vs 18.6%), and myalgia (31.8% vs 11.6%). The most common grade 3-4 TEAEs were anemia (9.4% vs 14%), hypertension (7.1% vs 0%), and abdominal pain (7.1% vs 4.7%).

TEAEs led to a dose reduction for 7.1% of patients in the ripretinib group versus 2.3% in the placebo arm. Treatment discontinuation due to TEAEs occurred in 8.2% and 11.6%, respec¬tively. There were more TEAEs leading to death in the placebo arm than in the ripretinib group (5.9% vs 23.3%).

“Ripretinib, a novel switch-control inhib¬itor, improves PFS and very likely also overall survival in a GIST patient population whose tumor has progressed on all 3 stan¬dard therapeutic agents,” said ESMO discus¬sant Heikki Joensuu, MD, PhD, research director at the Comprehensive Cancer Center, Helsinki University Hospital, in Finland. Enrollment is ongoing in the phase III random¬ized INTRIGUE study, which is evaluating ripretinib versus the multi-tyrosine kinase inhibitor sunitinib for patients with GISTs following prior imatinib therapy.

“Results from the ongoing INTRIGUE trial that [is comparing] ripretinib with sunitinib as the second-line treatment of advanced GISTs are awaited with much interest,” said Joensuu. “Switch-control inhibitors of tyrosine kinases other than KIT/PDGFRA seem an interesting field for further drug development. The current results are further good news to GIST patients.” REFERENCE

von Mehren M, Attia S, Bauer S, et al. INVICTUS: A phase 3, international, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as ≥4th line therapy In patients with AdvanCed gastrointestinal stromal TUmorS (GIST) who have received treatment with prior anticancer therapies (NCT03353753). Presented at: ESMO Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA87. https://oncologypro.esmo.org/Meeting-Resources/ESMO-2019-Congress/INVICTUS-A-Phase-3-INterVentional-Double-Blind-Placebo-Controlled-Study-to-Assess-the-Safety-and-Efficacy-of-Ripretinib-as-4th-Line-Therapy-In-Patients-With-AdvanCed-Gastrointestinal-Stromal-TUmorS-GIST-Who-have-Received-Treatment-With-Prior-Antica

Prostate Cancer

Apalutamide Is Linked to OS Benefit in nmCRPC

Gina Columbus

The next-generation androgen receptor inhibitor apalutamide (Erleada), in combination with androgen deprivation therapy (ADT), demonstrated a 25% reduction in the risk of death compared with placebo plus ADT in patients with nonmetastatic castration-resistant prostate cancer (CRPC), according to updated findings from the phase III SPARTAN trial that were presented at the 2019 European Society for Medical Oncology (ESMO) Congress, held in Barcelona, Spain, from September 27 to October 1, 2019.1,2

At a recent data analysis at a median 41 months of follow-up, median overall survival (OS) was not reached in either arm, with the results favoring apalutamide (HR, 0.75; 95% CI, 0.59-0.96; P = .0197). However, due to a prespecified P value boundary of .0121, these data were not considered statistically significant.

“The P value was .0197; although close, this value was higher than the prespeci¬fied O’Brien-Fleming boundary of .0121. Accordingly, the study follow-up will continue per protocol, and the final analysis will occur after 427 deaths,” lead study author Matthew R. Smith, MD, PhD, director of the Genitourinary Malignancies Program at the Massachusetts General Hospital Cancer Center, stated in a presentation during the meeting.

The FDA approved apalutamide in this setting in February 2018, based on data from SPARTAN’s primary end point, metastasis-free survival (MFS). These data showed that apalut¬amide reduced the risk of metastasis or death by 72% in patients with nonmetastatic CRPC. The median MFS was 40.5 months in the apalut¬amide arm versus 16.2 months in the placebo arm (HR, 0.28; 95% CI, 0.23-0.35; P <.0001).3

In the international SPARTAN study (NCT01946204), investigators evaluated the safety and efficacy of apalutamide versus placebo in 1207 patients who had nonmetastatic CRPC and a rapidly rising prostate-specific antigen (PSA) level despite continuous ADT. Nonmetastatic status was determined by a nega¬tive bone scan, as well as a negative computed tomography (CT) of the pelvis, abdomen, chest, and brain. Patients were required to have a PSA doubling time (PSADT) ≤10 months.

Patients were randomized 2:1 to receive ADT plus either 240 mg of apalutamide daily (n = 806) or placebo (n = 401). The average baseline PSADT was <5 months in both arms. Stratification factors included PSADT >6 months versus ≤6 months, use of bone-sparing agents, and locoregional disease (N0 vs N1).

The primary end point was MFS; secondary end points included time to metastasis, progres¬sion-free survival, time to symptomatic progres¬sion, and OS. For patients who developed metastases, the investigators also evaluated the time to the initiation of cytotoxic chemo¬therapy for metastatic CRPC and subsequent progression-free survival (PFS2). After the first interim data analysis in 2017, patients who developed metastases were permitted to receive abiraterone acetate (Zytiga) plus prednisone.

At the first interim analysis, which occurred after a median 20.3 months of follow-up, 61% of the apalutamide arm remained on treatment compared with 30% of the placebo group. After reviewing the preliminary data, an inde¬pendent data monitoring committee recom¬mended unblinding the trial and allowing the remaining patients on the placebo arm to cross over and receive open label apalutamide (19%; n = 76), Smith said.

The first interim OS analysis (after 24% of events required for final OS analysis had occurred) revealed a trend favoring apalut¬amide (P = .07), although the data were immature. Additionally, at this primary anal¬ysis, apalutamide was found to improve the time to symptomatic progression compared with placebo (HR, 0.45; 95% CI, 0.32-0.63; P <.0001). The updated analysis presented at the 2019 ESMO Congress included data on the effects of apalutamide on OS, time to initiation of chemotherapy, PFS2, and safety.

The second interim OS analysis was conducted using a preplanned group sequential testing procedure with an O’Brien–Fleming-type alpha-spending function, a common means of controlling the overall type I error when moni¬toring efficacy in clinical trials. This assessment was performed after 285 OS events (67% of the required number) had occurred, with a P value boundary of .0121 for statistical significance.

Additional results showed that the 4-year OS rates for the apalutamide and placebo arms were 72.1% and 64.7%, respectively. The beneficial effect of apalutamide on OS was observed across patient subgroups, especially in those with an age <65 years (HR, 0.33; 95% CI, 0.14-0.74), regional lymph node metastasis (N1); (HR, 0.52; 95% CI, 0.29-0.94), prior bone-sparing therapy (HR, 0.55; 95% CI, 0.27-1.11), and PSADT >6 months (HR, 0.57; 95% CI, 0.34-0.95). The OS benefit with apalutamide was also seen despite patient crossover from the placebo arm.

Of the patients who initiated cytotoxic chemotherapy (n = 197), 115 were on apalut¬amide and 82 were on placebo. Median time to initiation of chemotherapy was not reached in either arm (HR, 0.60; 95% CI, 0.45-0.80).

Moreover, apalutamide was found to signifi¬cantly extend PFS2 compared with placebo, with median PFS2 values of 55.6 months and 43.8 months, respectively (HR, 0.55; 95% CI, 0.45-0.68; P <.0001). Sixty-nine percent of patients in the placebo arm and 40% on apalut¬amide received subsequent life-prolonging therapy, which mainly consisted of abiraterone acetate plus prednisone.

In the second interim analysis, the safety profile of apalutamide was consistent with that in the primary analysis. The median duration of treatment was 31.4 months with apalutamide and 11.5 months with placebo. Adverse events (AEs) were reported in 97.3% and 93.7% of apalutamide- and placebo-treated patients, respectively. Grade 3-4 AEs were reported in 53.1% of patients in the apalutamide arm and 36.7% of those on placebo, and serious AEs occurred in 33.5% and 24.9%, respectively. The incidence of AEs leading to treatment discon¬tinuation on apalutamide (13.6%) was nearly double that of placebo (7.3%). AEs that led to death occurred in 2.1% and 0.5% of patients on apalutamide and placebo, respectively.

Karim Fizazi, MD, PhD, head of the Department of Cancer Medicine at the Institut Gustave Roussy in Villejuif, France, commented on the OS data as an invited discussant following Smith’s presentation. “At the moment, we cannot say that apalutamide prolongs survival in this setting. [With PFS2], there is a more meaningful difference we are seeing; this is utterly important because abiraterone was provided as a potential salvage treatment in both arms. In other words, [the data analysis] is comparing deferred AR [androgen receptor] targeting, at least in some patients, and at the same time, it is making a difference in [extending PFS2].”

REFERENCES

1. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in patients with nonmetastatic castration-resistant prostate cancer: updated results from the phase III SPARTAN study. Presented at: 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract 843O. bit.ly/2MicQcw.

2. Small EJ, Saad F, Chowdhury S, et al. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer [published online September 27, 2019]. Ann Oncol. 2019; 0:1-8 doi: 10.1093/annonc/mdz397.

3. Small EJ, Saad F, Chowdhury S et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2018;36(suppl 6s; abstract 161). doi: 10.1200/JCO.2018.36.6suppl.161.
 
Ovarian Cancer

Niraparib Improves PFS as Frontline Maintenance in Ovarian Cancer


Silas Inman

Frontline maintenance therapy with the PARP inhibitor niraparib (Zejula) improved median progression-free survival (PFS) by 5.6 months compared with placebo for patients with newly diagnosed advanced ovarian cancer who had responded to platinum-based chemotherapy, according to findings from the phase III PRIMA study presented at the 2019 European Society for Medical Oncology (ESMO) Congress, held in Barcelona, Spain, from September 27 to October 1, 2019, and simultaneously published in the New England Journal of Medicine.1,2

In the overall population of the PRIMA study (NCT02655016), the median PFS in the niraparib arm was 13.8 months compared with 8.2 months in the placebo group, representing a 38% reduction in the risk of progression or death (HR, 0.62; 95% CI, 0.50-0.76; P <.001) with the addition of the PARP inhibitor (TABLE).1 In patients with tumors that tested positive for homologous recombi¬nation deficiency (HRD), the median PFS was 21.9 months with niraparib compared with 10.4 months for placebo (HR, 0.43; 95% CI, 0.31-0.59; P <.001).

“Niraparib therapy in patients with advanced ovarian cancer provided a clinically significant improvement in PFS after response to first-line platinum-based chemotherapy in all patients,” said study author Antonio Gonzalez-Martin, MD, head of the Medical Oncology Department of Clinica Universidad de Navarra in Madrid, Spain.

The study randomized 733 patients in a 2:1 ratio to receive niraparib (n = 487) or placebo (n = 246). Patients were randomized within 12 weeks of finishing the last cycle of chemo¬therapy. At the initiation of the study, niraparib was given at a fixed dose of 300 mg, which was adjusted to 200 mg for patients who weighed less than 77 kg or had platelet counts below 150,000/μL. The median relative dose intensity in the study was 63%.

According to International Federation of Gynecology and Obstetrics (FIGO) staging guidelines, about two-thirds of patients had stage III disease, and one-third had stage IV disease. The primary tumor locations were the ovary, fallopian tube, and peritoneum. Most patients had serous histology (approximately 95%), and most had achieved a complete response to prior platinum-based chemo¬therapy (70%). Two-thirds of patients had received neoadjuvant chemotherapy, and none had received bevacizumab (Avastin), as the study was designed prior to approval of the VEGF inhibitor in the frontline setting.

At the interim analysis, median overall survival (OS) was not yet reached, at just 10.8% data maturity. At this early time point, however, the 24-month OS rates in the overall population were 84% in the niraparib group and 77% in the placebo arm (HR, 0.70; 95% CI, 0.44-1.11). In the HRD-positive cohort, the 24-month OS rates were 91% and 85%, respectively (HR, 0.61; 95% CI, 0.27-1.39).

Analysis of the HRD-positive group was further stratified by tumor BRCA status. For HRD-positive patients with a BRCA mutation, the median PFS was 22.1 months with niraparib compared with 10.9 months for placebo (HR, 0.40; 95% CI, 0.27-0.62). In patients with HRD-positive tumors who were negative for BRCA mutations, the median PFS was 19.6 versus 8.2 months, respectively (HR, 0.50; 95% CI, 0.31-0.83).

Niraparib outperformed placebo for PFS across several patient subgroups, including those with HRD-negative tumors. In this group, the median PFS was 8.1 months with niraparib and 5.4 months for placebo (HR, 0.68; 95% CI, 0.49-0.94). Interim OS data for patients with HRD-negative tumors showed 24-month OS rates of 81% and 59%, respectively (HR, 0.51; 95% CI, 0.27-0.97).

More patients experienced treatment-re¬lated adverse events (TRAEs) of any grade in the niraparib arm compared with placebo (96.3% vs 68.9%). Grade ≥3 TRAEs were experienced by 65.3% of patients in the niraparib arm compared with 6.6% of those in the placebo group. Anemia (31.0% vs 1.6% STET), thrombocytopenia (28.7% vs 0.4%), platelet count decrease (13.0% vs 0%), and neutropenia (12.8% vs 1.2%) were the most common grade ≥3 AEs in the niraparib and placebo groups, respectively.

Overall, 70.9% of patients in the niraparib arm required a dose reduction, and 12.0% discontinued therapy due to AEs. The main AEs related to discontinuation were myelosuppres¬sive in nature. REFERENCE

1. Gonzalez-Martin A, Pothuri B, Vergote I, et al. Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study). Presented at: ESMO Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA1. bit.ly/2qhks6p.

2. Gonzalez-Martin A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer [published online September 28, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1910962.

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