Videos

Nurse Practitioners Kathleen Lutz and Kimberly Halla describe the conversations they have with patients with advanced endometrial cancer before and after diagnosis and the common questions they hear.

Conversations with Patients With Advanced Endometrial Cancer Before and After Diagnosis

Certified Nurse Practitioner Kimberly Spickes shares the educational and supportive resources she recommends for patients with newly-diagnosed advanced endometrial cancer.

Resources for Patients With Endometrial Cancer

Kimberly Halla, NP, explains the staging of endometrial cancer and the standards for biomarker testing at her institution.

Initial Consultation of Patients With Advanced Endometrial Cancer

Kimberly A. Spickes, CNP, gives an overview of the typical symptoms women with endometrial cancer present with, discusses how these symptoms are similar and different from those seen with other gynecologic malignancies, and reviews risk factors for endometrial cancer.

Symptoms and Diagnosis of Endometrial Cancer

Extending treatment time with bevacizumab (Avastin) did not improve progression-free survival (PFS) in newly diagnosed patients with stage IIB-IV ovarian cancer, suggesting that 15 months is the optimal treatment duration, according to findings from the phase 3 BOOST trial (NCT01462890) which were published in 

Among 2 cohorts of patients with ovarian cancer receiving bevacizumab, there was no difference in PFS between the treatment arms (HR, 0.99; 95% CI, 0.85-1.15; 

= .90). The median PFS with 15 months of treatment was 24.2 (95% CI, 22.2-26.5), and extended treatment of 30 months yielded a median PFS of 26.0 months. (95% CI, 23.7-29.7). For restricted mean PFS, the outcomes were 39.5 vs 39.3 months, respectively. Overall survival (OS) outcomes were also similar between the 2 arms (HR, 1.04; 95% CI, 0.87-1.23; 

= .68). Moreover, the rates of adverse events (AEs) of interest between 15 months and 30 months of treatment were 29% and 34%. Reported AEs were consistent with previous reports with bevacizumab.

“Extending the duration of maintenance bevacizumab therapy did not significantly improve PFS and therefore, the approved duration of bevacizumab [15 mg/kg once every 3 weeks for 15 months] remains a standard-of-care regimen… in the front-line setting,” study authors wrote.

Two prior trials have demonstrated that early and continuous treatment with bevacizumab, a monoclonal antibody, in addition to carboplatin and paclitaxel chemotherapy, confers a PFS benefit to patients with ovarian cancer. However, prior this this trial, the optimal treatment duration remained unknown.

The BOOST trial was designed to determine the best duration of frontline bevacizumab in this setting and investigators extended treatment length from 15 months (as used in 1 of the 2 trials) to 30 months to assess if longer exposure would improve efficacy.

Enrolled patients had histologically confirmed, newly diagnosed, stage IIB-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer (any grade or histologic subtype). Patients also needed to have received primary cytoreductive surgery at least 8 weeks before starting chemotherapy and more than 4 weeks before the planned start date of bevacizumab treatment. The trial enrolled a total 927 patient between November 11, 2011, and August 6, 2013.

Investigator-assessed PFS represented the trials’ primary end point. Secondary end points included OS, objective response rate, health-related quality of life, safety, and tolerability. The median OS with 15-month and 30-month treatment was 54.3 and 60.0 months, respectively. The restricted mean OS was 60.4 vs 60.8 months, respectively.

No difference in objective response rates were observed; objective responses occurred in 26% and 27% of patients (

AEs of any-grade occurred in great numbers in both treatment arms (99% vs 99%). The rates of grade 3 or worse AEs were also similar between both arms (63% vs 68%), as were the rates of serious AEs (44% vs 46%). A serious AE was defined as any event that resulted in death, inpatient hospitalization, the prolongation of existing hospitalization, was life threatening, or induced a disability.

Extended treatment with bevacizumab was linked to a slight increase in grade 3 or greater hypertension or proteinuria; however, that was the only special AEs of interest to be induced by longer treatment.

Study authors acknowledged that the trial did not assess 

 mutation status and therefore, any potential imbalanced between treatment arms cannot be excluded. Moreover, they noted that the open-label design with no blinded independent review of PFS may represent a limitation; however, investigators noted that patients may not be willing to receive placebo for up to 15 months.

“Longer treatment duration with bevacizumab for up to 30 months did not improve PFS or OS in patients with primary epithelial ovarian, fallopian tube, or peritoneal cancer,” study authors concluded. “A bevacizumab treatment duration of 15 months remains the standard of care.”

Pfisterer J, Joly F, Kristensen G, et al. Optimal treatment duration of bevacizumab as front-line therapy for advanced ovarian cancer: AGO-OVAR 17 BOOST/GINECO OV118/ENGOT Ov-15 open-label randomized phase III trial. 

.Published online November 4, 2022. doi:10.1200/JCO.22.01010

Articles

Increasing the duration of bevacizumab treatment did not improve progression-free survival for patients with ovarian cancer.  

15 Months of Bevacizumab Remains Ideal Length for Patients With Ovarian Cancer

The FDA has granted mirvetuximab soravtansine-gynx (Elahere) accelerated approval on the indication of folate receptor alpha (Frα)– positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients may have been treated with 1 to 3 prior therapies to be eligible for treatment.

The accelerated approval is backed by findings from the phase 3 SORAYA trial (NCT04296890), which showed that patients who received mirvetuximab soravtansine achieved an objective response rate of 31.7% (95% CI, 22.9%-41.6%), including 5 complete responses. In addition, the median duration of response was 6.9 months (95% CI, 5.6%-9.7%).

The FDA has also approved the companion diagnostic, VENTANA FOLR1 (FOLR-2.1), to help identify patients for whom this treatment is suitable. Testing can be done on fresh or archived tissue, and patients can be tested at diagnosis to determine if this treatment would be appropriate at the time of platinum resistance.

"The approval of ELAHERE is significant for patients with FRα-positive platinum-resistant ovarian cancer, which is characterized by limited treatment options and poor outcomes," Ursula Matulonis, MD, chief of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute, professor of medicine at the Harvard Medical School, and SORAYA co-principal investigator, stated in a press release. “ELAHERE’s impressive anti-tumor activity, durability of response, and overall tolerability observed in SORAYA demonstrate the benefit of this new therapeutic option, and I look forward to treating patients with ELAHERE."

In the United States, ovarian cancer represents the leading cause of death from gynecologic cancers. Approximately 20,000 patients are diagnosed with this disease, and 13,000 die from it, annually.

The current standard of care for ovarian cancer is surgery followed by platinum-based chemotherapy. However, most patients eventually develop platinum-resistant disease, and effective treatment options in this disease setting are limited. Many patients end up receiving single-agent chemotherapies that yield low response rates, short response times, and high toxicity burdens.

The SORAYA trial was a single-arm study which enrolled 106 patients with platinum-resistant ovarian cancer and Frα-positive tumors. All patients were allowed to have had at least 3 prior lines of therapy, and all were required to have received bevacizumab. Mirvetuximab soravtansine is an antibody-drug conjugate directed against Frα, a cell surface protein which is highly expressed in ovarian cancer. The new agent is the first antibody-drug conjugate to be approved in this setting.

The recommended dose is 6 mg/kg adjusted ideal body weight every 3 weeks.

Mirvetuximab soravtansine comes with a boxed warning for ocular toxicity, including visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis. In the trial, 61% of patients experienced an ocular toxicity, 9% of which were grade 3. The median time to first ocular adverse event was 1.2 months (range, 0.03-12.9).

Prior to treatment with mirvetuximab soravtansine, patients should receive an ophthalmic exam, including visual acuity and slit lamp exam. These exams should continue every other cycle for the first 8 cycles and then as clinically indicated.

It is recommended to premedicate patients with lubrication and ophthalmic topical steroids during treatment. In addition, patients should be advised to avoid contact lenses, unless directed by a healthcare providers. For patients who experience ocular toxicity, prophylactic artificial tears and ophthalmic topical steroids may be administered. Treatment should be withheld until toxicities improve. If grade 4 ocular toxicities occur, treatment should be discontinued.

Patients who receive mirvetuximab soravtansine are also at an increased risk pf pneumonitis and peripheral neuropathy. These adverse effects (AEs) occurred in 10% and 36% of treated patients, respectively. Patients should be monitored for signs of pulmonary symptoms, or neuropathy. If pulmonary signs develop, infectious, neoplastic, and other causes for symptoms should be excluded through appropriate investigations.

Overall, serious AEs occurred in 31% of patients. The most common AEs include intestinal obstruction (8%), ascites (94%), infection (3%), and pleural effusion (3%). Two percent of patients experienced fatal AEs. The most common any grade AEs included vision impairment, fatigue, increased aspartate aminotransferase, nausea, increased alanine aminotransferase, keratopathy, abdominal pain, decreased lymphocytes, peripheral neuropathy, diarrhea, decreased albumin, constipation, increased alkaline phosphatase, dry eye, decreased magnesium, decreased leukocytes, decreased neutrophils, and decreased hemoglobin.

In addition, 20% of patients needed dose reduction because of toxicities. The toxicities which contributed to dose reductions included intestinal obstruction (2%) and thrombocytopenia (2%). One patient discontinued because of visual impairment.

Moreover, 39% of patients required dose delays. The AEs which were responsible for dose delays were visual impairment (15%), keratopathy (11%), neutropenia (6%), dry eye (5%), cataracts (3%) and increased gamma-glutamyltransferase (3%).

Continued approval will be contingent on the findings from the phase 3 MIRASOL trial (NCT04209855), a confirmatory randomized trial designed to confirm the findings of SORAYA. The trial is fully enrolled and top-line data are anticipated in early 2023.

ImmunoGen announces FDA accelered approval of Elahere (mirvetuximab soravtansine-gynx) for the treatment of platinum-resistant ovarian cancer. News release. ImmunoGen Inc. November 14, 2022. Accessed November 14, 2022. http://bit.ly/3GgrCwL

FDA grants accelerated approval to mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer. News release. FDA. November 14, 2022. Accessed November 14, 2022. http://bit.ly/3UP742w

Elahere (mirvetuximab soravtansine-gynx). Prescribing information; ImmunoGen Inc; 2022. Accessed November 14, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761310s000lbl.pdf

Mirvetuximab soravtansine-gynx, an antibody drug conjugate, has received accelerated approval for platinum-resistant ovarian cancer. The prescribing label comes with warnings for visual toxicities, pneumonitis, and peripheral neuropathy. 

Mirvetuximab Soravtansine-gynx Gets Go Ahead in Platinum-Resistant Ovarian Cancer

For patients with advanced ovarian cancer, the homologous recombination and 

mutation status of their tumor may clue providers into whether a PARP inhibitor is appropriate as maintenance therapy for that individual, according to Eirwen M. Miller, MD.

 CFS®, Miller outlined findings from 5 clinical trials that evaluated the safety and efficacy of PARP inhibition therapy: SOLO-1 (NCT01844986), PRIMA (NCT02655016), ATHENA-MONO (NCT03522246), PAOLA-1 (NCT02477644), and Ovario (NCT03326193).

“Each of these studies evaluated PARP inhibitor maintenance either as a single agent or in combination with bevacizumab [Avastin] for patients with stage III to IV ovarian cancer following a complete or partial response to platinum-based chemotherapy,” Miller, a gynecologic oncologist at Allegheny Health Networks in Pittsburgh, Pennsylvania, said during the presentation. “The inclusion criteria vary somewhat across these studies. [Although] cross-trial comparison is really tempting, it’s not valid.”

In the phase 3 SOLO-1 trial, investigators examined the efficacy of olaparib (Lynparza) maintenance therapy in patients with newly diagnosed stage III or IV ovarian cancer harboring a mutation in 

, or both. Patients were randomly assigned 2:1 to oral olaparib 300 mg twice daily (n = 260) or placebo (n = 131). The primary end point of the study was progression-free survival (PFS).

In the overall study population, most patients (83%) had stage III disease. A majority of patients (82%) achieved a complete response (CR) after treatment with chemotherapy. Nearly all patients had high-grade serous ovarian cancer (HGSOC; 97%). All patients had homologous recombination deficiency (HRD)-positive disease.

Findings from the trial showed that olaparib maintenance therapy provided a clear PFS benefit over placebo; the median PFS was 56.0 months vs 13.8 months, respectively (HR, 0.33; 95% CI, 0.25-0.43). Additionally, the median overall survival (OS) was not reached (95% CI, NR-NR) in the olaparib arm compared with 75.2 months (95% CI, 65.4-NR) in the placebo arm (HR, 0.55; 95% CI, 0.40-0.76).

Miller highlighted key safety findings from SOLO-1. Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) were adverse effects (AEs) of special interest. In the primary PFS analysis, 3 patients treated with olaparib eventually developed MDS or AML vs no patients in the placebo arm. After a 7-year follow-up, in the final OS analysis, 4 cases of MDS/AML were reported in the investigational arm and 1 case was reported in the placebo arm.

The phase 3 PRIMA trial compared the efficacy of niraparib (Zejula) maintenance therapy with placebo in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy. Patients were randomly assigned 2:1 to receive either niraparib or placebo once daily. The primary end point was PFS.

A slight majority of patients (50.8%) were HRD positive. Patients were HRD positive with 

mutations at a rate of 30.4%. HRD positivity and 

 wild-type status was reported in 20.5% of patients. Stage IV disease was reported in 35% of patients. Most experienced a CR after chemotherapy (70%), and had HGSOC histology (94%).

In regard to the primary outcome, patients with 

-mutant disease treated with niraparib had a median PFS of 22.1 months compared with 10.9 months with placebo (HR, 0.40; 95% CI, 0.27-0.62).5 Patients with HRD-positive disease had a median PFS of 21.9 months vs 10.4 months, respectively (HR, 0.43; 95% CI, 0.31-0.59). Among those with HRD-positive, 

 wild-type disease, the median PFS was 19.6 months compared with 8.2 months, respectively (HR, 0.50; 95% CI, 0.31-0.83). Those with HRD-negative disease experienced a median PFS of 8.1 vs 5.4 months, respectively (HR, 0.68; 95% CI, 0.49-0.94). In the overall intention-to-treat (ITT) population, patients who received niraparib (n = 487) achieved a median PFS of 13.8 months vs 8.2 months for patients in the placebo arm (n = 246; HR, 0.62; 95% CI, 0.50-0.76).

Additionally, treatment with niraparib had an effect on OS: The 24-month OS rate was 84% in the investigational arm compared with 77% in the placebo arm (HR, 0.70; 95% CI, 0.44-1.11). More specifically, patients with HRD-positive disease experienced 24-month OS rates of 91% vs 85%, respectively (HR, 0.61; 95% CI, 0.27-1.39). Patients with HRD-negative disease had a 24-month OS of 81% vs 59%, respectively (HR, 0.51; 95% CI, 0.27-0.97). Miller noted that these figures were based on 11% maturity at interim analysis.

Rucaparib (Rubraca) maintenance therapy was compared to placebo for patients with stage III to IV high-grade ovarian cancer undergoing surgical cytoreduction in the phase 3 ATHENA-MONO trial. Patients were randomly assigned 4:1 to received oral rucaparib 600 mg twice daily (n = 427) or placebo (n = 111). The primary end point was PFS.

In the overall population, patients had HRD-positive disease, HRD-positive disease with 

wild-type disease, and HRD-negative disease at a rate of 43.5%, 21.4%, 22.1%, and 44.2%, respectively. Most patients had HGSOC histology (91%), stage III disease (75%), and experienced a CR following chemotherapy (75%).

In the ITT population, patients experienced a median PFS of 20.2 months vs 9.2 months in the investigational and placebo arms, respectively (HR, 0.52; 95% CI, 0.40-0.68). Patients with 

-mutant disease achieved a median PFS of NR vs 14.7 months, respectively (HR, 0.40; 95% CI, 0.21-0.75). Among patients with HRD-positive disease, the median PFS was 28.7 months compared with 11.3 months, respectively (HR, 0.47; 95% CI, 0.31-0.72). Patients with 

 wild-type, HRD-positive disease experienced a median PFS of 20.3 months vs 9.2 months, respectively (HR, 0.58; 95% CI, 0.33-1.01). Finally, patients who were HRD negative had a median PFS of 12.1 vs 9.1 months, respectively (HR, 0.65; 95% CI, 0.45-0.95).

Miller noted that the OS figures in ATHENA-MONO are to be determined.

Investigators combined olaparib with bevacizumab as maintenance therapy for patients withnewly diagnosed, advanced, high-grade ovarian cancer who responded to first-line chemotherapy in the phase 3 PAOLA-1 trial. Patients were eligible irrespective of surgical outcome or 

 mutation status. Patients were randomly assigned 2:1 to receive olaparib 300 mg twice daily (n = 537) or placebo (n = 269). Every patient received bevacizumab 15 mg/kg every 3 weeks for up to 15 months.

Patients in PAOLA-1 had HRD-positive disease, HRD-positive disease with a 

wild-type disease, and HRD-negative disease at a rate of 48.0%, 29.4%, 18.6%, and 34.3%, respectively. Most patients had HGSOC histology (96%) and stage III disease (70%), and had no evidence of disease (53%) after treatment with chemotherapy.

In the overall population, the median PFS was 22.1 months in the investigational arm compared with 16.6 months in the control arm (HR, 0.59; 95% CI, 0.49-0.72). Patients with 

-mutant disease experienced a median PFS of 37.2 months compared with 21.7 months, respectively (HR, 0.31; 95% CI, 0.20-0.47). Patients with HRD-positive disease achieved a median PFS of 37.2 months vs 17.7 months (HR, 0.33; 95% CI, 0.25-0.45). Those with HRD-positive, 

 wild-type ovarian cancer registered a median PFS of 28.1 months vs 16.6 months (HR, 0.43; 95% CI, 0.28-0.66). Finally, those with HRD-negative disease experienced a median PFS of 16.6 months vs 16.2 months, respectively (HR, 1.00; 95% CI, 0.75-1.35).

Regarding OS, the median in the overall population was 56.5 months vs 51.6 months in the combination and placebo arms, respectively (HR, 0.92; 95% CI, 0.76-1.12). For patients with 

-mutant disease, the median OS was 75.2 months vs 66.9 months, respectively (HR, 0.60; 95% CI, 0.39-0.93). Those with HRD-positive disease experienced a median OS of 75.2 vs 57.3 months, respectively (HR, 0.62; 95% CI, 0.45-0.85).

Notably, for patients with HRD-positive, 

 wild-type disease the median OS was NR vs 52 months, respectively (HR, 0.71; 95% CI, 0.45-1.13). No OS benefit was observed with the combination for patients with HRD-negative disease; the median OS was 36.8 months in the combination arm compared with 40.4 months in the placebo arm (HR, 1.19; 95% CI, 0.88-1.63).

Miller also presented safety findings for the AEs of special interest from PAOLA-1. At the primary PFS analysis, 7 patients in the combination arm experienced MDS/AML compared with 3 in the placebo arm. At the final OS analysis these figures were 22 patients vs 8 patients, respectively.

In the phase 2 Ovario trial, niraparib plus bevacizumab was evaluated as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer. The primary end point was PFS.

Patients in Ovario had HRD-positive disease, HRD-positive disease with 

 wild-type, and HRD-negative disease at a rate of 46.7%, 27.6%, 15.2%, and 36.2%, respectively. Most patients had HGSOC histology (95%) and stage III disease (78%), and achieved a CR after treatment with chemotherapy (58%).

Among 105 efficacy-evaluable patients the median PFS of 19.6 months (95% CI, 16.5-25.1). The median PFS was 28.3 months, 28.3 months, and 14.2 months in the HRD-positive, HRD-positive/

 wild-type, and HRD-negative subgroups, respectively.

OS data for Ovario was not available, said Miller.

“There remains a significant unmet need for HRD-negative tumors,” Miller said. “We anxiously await the results from FIRST [NCT03602859], DUO-O [NCT03737643], and KEYLYNK [NCT03740165], in which PARP inhibitors have been combined with immunotherapy in the maintenance setting. There are also ongoing trials evaluating novel maintenance therapy agents including an anti-Ca125 monoclonal antibody and antibody drug conjugates targeting the folate receptor alpha and NaPi2b.”

Miller EN. Evolving Landscape of frontline maintenance therapy for advanced ovarian cancer. Presented at: 

 CFS®: November 9-11, 2021; New York, NY.

Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. 

. 2018;379(26):2495-2505. doi:10.1056/NEJMoa1810858

DiSilvestro P, Banerjee S, Colombo N, et al. Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 Trial. 

. 2022;JCO2201549. doi:10.1200/JCO.22.01549

González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. 

. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962

Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45) 

. 2022;JCO2201003. doi:10.1200/JCO.22.01003

Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. 

. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361

Ray-Coquard I, Leary A, Pignata S, et al. Final overall survival (OS) results from the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib (ola) plus bevacizumab (bev) in patients (pts) with newly diagnosed advanced ovarian cancer (AOC). 

. 2022;33(suppl 7):S1396-1397. doi:10.1016/j.annonc.2022.08.025

Hardesty MM, Krivak TC, Wright GS, et al. OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab. 

. 2022;166(2):219-229. doi:10.1016/j.ygyno.2022.05.020

During the 40th Annual Chemotherapy Foundation Symposium,  Eirwen M. Miller, MD, evaluated the safety and efficacy profiles of different PARP inhibitor therapies for patients with advanced ovarian cancer.  

HRD, BRCA Status May Inform PARP Inhibitor Suitability in Advanced Ovarian Cancer

Several immunotherapy agents have received FDA approval across numerous malignancies since ipilimumab (Yervoy) a decade ago and, in many ways, the effect of immunotherapy in certain populations is equitable to magic, according to Melinda S. Weber, DNP, APN, AOCN-C. However, the unique mechanism of action associated with immunotherapy is also linked to adverse events (AEs) for patients receiving treatment.

In a presentation during the Nursing track at the 

 Weber who is the director of care transformation and a charge APN in the Skin and Sarcoma Division at John Theurer Cancer Center at Hackensack University Medical Center Weber, touched on the marked success of the treatment in the field in melanoma and outlined the tenets of early recognition, appropriate grading, and best management practices for these immune-related adverse events (irAEs).

Immunotherapeutic Agents Usher in a Wave of Hope

“Prior to the advent of ipilimumab [Yervoy] in 2011, [a diagnosis of] metastatic melanoma was a death sentence,” said Weber in an interview with 

 ahead of a presentation. “No radiation touched [the melanoma], no chemotherapy touched it, [and approximately] less than 1% of patients might survive [treatment with] high-dose IL-2 therapy, but that was very rare.”

In November 2022, approved immune-checkpoint inhibitors include atezolizumab (Tecentriq), avelumab (Bavencio), cemiplimab-rwlc (Libtayo), dostarlimab-gxly (Jermperli), durvalumab (Imfinzi), nivolumab (Opdivo), and pembrolizumab (Keytruda). Each of these regiments are approved across multiple indications.

Weber said that the efficacy that immunotherapy wielded in certain populations has been nothing short of astounding, and that it drastically changed her clinical practice.

“They’ve changed the face of oncology…I never thought in a million years that I would see PET scans, that were once lit up like a Christmas tree, become normal and stay normal over months, and then years. Now we have people that are survivors 10 years [or longer]….Our focus for those patients [with] late-stage disease was about palliative care, preserving their dignity, and optimizing their comfort. It was very sad.”

Weber said that the availability of these drugs is exciting because they are helping many patients achieve remission, and for those who do not, immunotherapeutic agents may help individuals reach partial remission, prolonged duration of responses, and superior overall survival rates.

“I never take for granted when we bring in our patients for follow-up visits, because I will never forget what it was like before these drugs,” Weber said. “To see people now go on to live their lives, enjoy their families, watch their children and grandchildren grow, is incredible.”

However, Weber noted the start of the immunotherapy integration was not a smooth journey and shared that when immunotherapy first hit the scene, she had patients who chose not to continue treatment because the irAEs were so severe. According to Weber, as clinicians, you must do everything in your power to avoid that possibility, because patients could be forfeiting a chance at a partial or full remission.

The most common irAEs associated with immune-checkpoint inhibitors include fatigue, asthenia, musculoskeletal pain, decreased appetite, diarrhea, nausea, vomiting, pyrexia, cough, dyspnea, constipation, abdominal pain, rash, peripheral neuropathy, mucosal inflammation, alopecia and stomatitis.

Additionally, immune-checkpoint inhibition is also associated with pneumonitis, colitis, hepatitis, encephalitis, endocrinopathies, dermatologic adverse events, nephritis, renal dysfunction, solid organ transplant rejection, infusions-related reactions, and embryo-fetal toxicity.

According to the National Comprehensive Cancer Network (NCCN), a comprehensive baseline assessment of a patient’s current emotional, physical, and spiritual status, with attention to a patient’s social determinants of health, financial toxicity burden, and health literacy are important for early recognition and prompt intervention for irAEs. These factors may influence how and when patients report irAEs, and can influence whether a patient needs to be admitted following the emergence of irAEs. 

According to Weber, the key with irAEs is to catch them early and intervene as soon as possible, because the sooner that the reactions dissolve and therapy can continue, the greater the outcome the patient can expect to achieve.

Weber noted that nurses today may be able to leverage novel technologies such as mobile applications or software programs to track irAEs. Prior to the advent of these applications, research nurses would carry around binders with the common terminology criteria for adverse events (CTCAE) information when assessing patients.

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only, intervention not indicated.

Gradw 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL).

Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.

Grade 4: Life-threatening consequences; urgent intervention indicated.

Although CTCAE provides this broad overview of irAE grading, Weber also provided an example of what the clinical presentation looks like for a common irAE, diarrhea.

Grade 1: Increase of < 4 stools per day over baseline; mild increase in ostomy output compared with baseline.

Grade 2: Increase of 4 to 6 stools per day over baseline; moderate increase in ostomy output compared with baseline; limiting instrumental ADL.

Grade 3: Increase of > 7 stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared with baseline limiting self-care ADL.

According to Weber, CTCAE criteria offer clear guidance into appropriate handling of various irAEs, and with early intervention, management is possible. However, she repeatedly stressed that these irAEs are not to be taking lightly, as they can represent a serious barrier to treatment for many patients.

“If I can get anything across, it is that irAEs represent real suffering. [They are] different from chemotherapy adverse reactions,” Weber said. “For example, immunotherapy-induced colitis is horrific, and patients, depending on the grade, may be frightened to leave their homes. Besides the abdominal cramping, the discomfort, the risk of dehydration malnutrition, for many patients, there may be embarrassment or fear of living a normal life, and they may not want to leave their house.”

Moreover, irAEs are different from chemotherapy-related toxicities, because they can occur at unexpected time intervals. These toxicities have varying onset times—they can appear as early as within the first 2 weeks of treatment, or 12 weeks in, they can even occur over 22 months past the last cycle of immunotherapy. Thus, the gravity of these toxicities, the threat they pose to patients, and the need for patient education, cannot be overemphasized.

“irAEs are profoundly debilitating for many, many patients,” she added. “Our job as nursing professionals, besides [providing] great patient education, must be knowing the patient’s baseline to where they are right now, teaching patients to call us early when anything is out of ordinary that’s didn’t not occur before these drugs to call us, and intervening as swiftly as possible.”

Nurses Play a Vital Role in irAE Management

Therefore, when a patient is embarking on immunotherapy, the oncology nurse adopts a unique role as a patient cheerleader.

“We have to be the person who provides knowledge and comfort to that patient,” Weber said. She noted that patients are often afraid of the AEs of their treatments, but nurses can help reassure them and let them know that there is a plan to manage their irAEs.…We tell patients ‘We are going to get you through this,’” Weber said. She added that she likes to tell patients that immunotherapy makes their immune system similar to hungry sharks.

“It’s important for patients to understand what’s happening to them and how we are going to intervene,” she said. “We use a multidisciplinary group, we need our nutritionist, our psychotherapist, we need [individuals] that can provide globally comprehensively care for that patient.”

When it comes to symptom management, there is an arsenal of strategies that clinicians can utilize to help their patients; however, the most important thing, according to Weber, is recognizing the effect these symptoms can have on a patient’s quality of life and reassure them that it can be diminished.

“You can do old-fashioned things. For example, with diarrhea you can [advise patients] to use the BRAT diet, given its within your institutions policies. You can give Imodium [loperamide], Lemotil [atropine and diphenoxylate], Bentyl [dicycloverine], etc. Teach them appropriate dosing of prednisone as ordered, and to get the [irAE] behind them so they can move on.

Weber stressed that there must be awareness alongside action. Nurses have a responsibility to recognize the anguish, pain, and sometimes embarrassment, that patients experienced with these therapies. In managing the patients’ physical symptoms, it is important to recognize the turmoil they can induce on the whole person.

“They are not just clinical symptoms; they really change the face of the patient’s and the family member’s perception of their treatment,” Weber emphasized. “We have to really inspire hope that it's not going to be this way forever,” she said.

Weber MS. Monitoring and managing toxicities associated with immune checkpoint inhibitors. Presented at: 

 CFS®; November 9-11, 2022; New York, NY.

Clinical practice guidelines in oncology. National Comprehensive Cancer Network. Management of Immune-Related Toxicities. Version 1.2022 February 28, 2022. Accessed November 9, 2022. bit.ly/3UK0VnZ

Common terminology criteria for adverse events (CTCAE) v5.0. November 27, 2017. Accessed November 9, 2022. bit.ly/3TlJF7n 

Immunotherapy has changed the face of cancer treatment, but requires appropriate irAE management to reach full potential. 

Maximizing Potential of Immunotherapy Requires Appropriate irAE Management

For a downloadable version that you can print at home, check out our 

» As maintenance therapy for patients with recurrent ovarian epithelial, fallopian tube, and primary peritoneal cancer who have a complete or partial response (CR/PR) to platinum-based chemotherapy regardless of 

» As maintenance therapy for patients with deleterious or suspected deleterious germline or somatic 

-mutated advanced ovarian epithelial, fallopian tube, and primary peritoneal cancer who have a complete or partial response to frontline platinum-based chemotherapy. 

» In combination with bevacizumab (Avastin) maintenance treatment of patients with advanced ovarian cancer who have a CR/PR to first-line platinum-based chemotherapy with bevacizumab and whose cancer is associated with homologous recombination deficiency (HRD). Positive HRD status is defined by either a deleterious or suspected deleterious 

» Patients with germline BRCA-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy. Patients with hormone receptor-positive disease must also have had prior endocrine therapy. 

-mutated, HER2-negative, highrisk early breast cancer who have undergone chemotherapy before or after surgery. Patients with hormone receptorpositive disease must also have had prior endocrine therapy. 

-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed after at least 16 weeks of a first-line platinum-based chemotherapy regimen. 

» Patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) genemutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga).

Olaparib has been studied in several phase 2 and 3 trials across various malignancies. 

In the phase 3 SOLO-1 trial (NCT01844986), patients with 

 mutation–positive advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer achieved a 70% reduction in risk of disease progression or death in patients with frontline maintenance olaparib than with placebo. In the phase 3 SOLO-2 trial (NCT01874353), maintenance treatment with olaparib yielded a 70% reduction in the risk of progression or death compared with placebo for patients with platinumsensitive, relapsed, 

-mutant ovarian cancer. The phase 3 PAOLA-1 trial (NCT02477644) revealed that the combination of olaparib and bevacizumab led to a 41% reduction in the risk of disease progression or death compared with bevacizumab alone in patients with HRD-positive advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have CR/PR to platinum-based chemotherapy plus bevacizumab (HR, 0.59; 95% CI, 0.49-0.72;

 < .001). After a median follow-up of 22.9 months, the median PFS was 22.1 vs 16.6 months, respectively. In the subgroup of patients with 

 gene mutation–positive cancers, the PFS benefit was even more profound (HR, 0.31; 95% CI, 0.20-0.47). 

-positive, HER2-negative metastatic breast cancer, patients who received olaparib monotherapy experienced a 42% improvement in invasive disease-free survival in the phase 3 OlympiAD trial (NCT02000622) compared with standard therapy (HR, 0.58; 95% CI, 0.46- 0.74; 

 < .0001). In March 2022, findings from the phase 3 OlympiA (NCT02032823) trial found that olaparib reduced the risk of death by 32% compared with placebo (HR, 0.68; 98.5% CI, 0.47-0.97; 

= .009) in BRCA-mutated, HER2-negative, high-risk early breast cancer. Furthermore, the 3-year survival rate was 92.8% with the PARP inhibitor compared with 89.1% for placebo. 

In the phase 3 POLO trial (NCT02184195), patients with germline 

-mutated metastatic pancreatic cancer achieved a median progression-free survival (PFS) of 7.4 months with olaparib compared with 3.8 months on placebo (HR, 0.53; 95% CI, 0.35-0.81; 

= .0035). Moreover, after 2 years, 22.1% of patients in the olaparib group had no disease progression vs 9.6% in the placebo group.

Findings from the phase 3 PROfound trial (NCT02987543) showed that olaparib induced a 66% reduction in the risk of disease progression or death compared with abiraterone acetate or enzalutamide (HR, 0.34; 95% CI, 0.25-0.47; 

PARP enzymes are involved in DNA repair and are specifically responsible. Olaparib is a potent oral PARP inhibitor which induces synthetic lethality in 

 deficient tumor cells through the formation of double-stranded DNA breaks which cannot be accurately repaired, leading to cell death. 

Olaparib is an oral drug manufactured in 150-mg and 100-mg tablets. Olaparib is taken by mouth, twice daily. It can be taken without or without food. Olaparib should be taken as prescribed, and capsules should be swallowed whole. Do not crush, dissolve, or open capsules. 

The recommended dosing for metastatic breast cancer is 300 mg by mouth every 12 hours. 

The most common types of adverse events (AEs) associated with olaparib are hematologic and gastrointestinal (GI). Anemia is the most common hematologic toxicity and occurs in up to 45% of patients. Neutropenia and thrombocytopenia are less common. A dose reduction should be considered for recurrent anemia (hemoglobin < 8 mg/dL) and/or to avoid multiple blood transfusions. Olaparib is considered moderately emetogenic, and 5-HT3 receptor antagonists (eg, ondansetron) are recommended as prophylaxis. Consider reducing dose for persistent nausea requiring daily antiemetics and/or resulting in greater than 5% weight loss. Rare but serious AEs include secondary myelodysplastic syndrome/acute myeloid leukemia (< 2%) and pneumonitis. If prolonged hematologic toxicity is observed (≥ grade 2 or > 4 weeks), further evaluation is warranted. Interrupt treatment and evaluate promptly for new or worsening respiratory symptoms (eg, cough, dyspnea, wheezing) or radiographic abnormalities. Olaparib should be permanently discontinued if pneumonitis is confirmed. The dose should be continued until disease progression unless there is toxicity, in which case it can be reduced to 200 mg every 12 hours or 100 mg every 12 hours. A dose adjustment is recommended for a creatinine clearance (CrCl) of 31 to 50 mL/min. The medication has not been studied in patients with CrCl below 30 mL/min or end-stage renal disease. No adjustment is needed for hepatic impairment. 

Patients about to begin treatment with olaparib should be advised to avoid grapefruit juice and Seville oranges as both may increase the level of olaparib in the blood. 

ADVICE FOR NURSES WHO ADMINISTER THIS AGENT 

Prior to initiating olaparib, health care professionals should rule out pregnancy, kidney dysfunction, and lung and breathing problems. Safety and monitoring parameters include obtaining a pregnancy test at baseline in female patients, complete blood count with differential at baseline and monthly thereafter, and ongoing monitoring for signs and symptoms of thromboembolism. 

Olaparib should be stored in its original container and in a cool and dry environment to protect it from moisture. 

In August 2022, AstraZeneca voluntarily withdrew the indication for the treatment of adult patients with deleterious or suspected germline 

-mutant advanced ovarian cancer who have been treated with 3 or more lines of chemotherapy. New treatment of patients who meet these criteria should not be initiated and patients who are receiving olaparib in this setting should consult their physician to make an informed decision on their ongoing care.

1. Lynparza. Prescribing information. AstraZeneca Pharmaceuticals LP, 2022. Accessed August 15, 2022. bit.ly/3AfVZyC 

2. Important prescribing information: Lynparza. AstraZeneca. August 26, 2022. Accessed September 29, 2022. https://bit.ly/3C4k4ud

Olaparib is an oral drug manufactured in 150-mg and 100-mg tablets. Olaparib is taken by mouth, twice daily. It can be taken without or without food.

Oncology Drug Crash Course: Olaparib (Lynparza)

Durable clinical outcomes were observed in heavily pretreated patients with clear cell gynecologic cancer (CCGC) following treatment with pembrolizumab monotherapy in the phase 2 PEACOCC trial (NCT03425565), according to findings published in the 

Forty-eight patients were included in the analysis. The progression-free survival (PFS) rate was 43.8% (n = 21/48; 90% CI, 31.5%-56.6%) at 12 weeks, exceeding the established lower bound of 15%. Eighteen (37.5%) patients had progressive disease, and 6 (12.5%) progressed and died.

Translational sample analysis is ongoing. Investigators said these results justify further evaluation of pembrolizumab as the new standard of care for advanced CCGC.

At a median follow-up of 2.1 years, the median PFS was 12.2 weeks (95% CI, 5.9-23.9). The 1-year PFS rate was 22.0% (95% CI, 11.5%-34.7%).

The median overall survival (OS) was 71.0 weeks (95% CI, 29.1-137.6). The OS rate was 54.8% (95% CI, 39.3%-67.8%) at 1 year and 37.2% (95% CI, 22.4%-52.0%) at 2 years.

Prognosis is poor for patients with advanced CCGC. The objective response rate (ORR) for standard second-line chemotherapy ranges from 0% to 8% in ovarian pure clear cell cancer.

Previous data have shown that PD-L1 and PD-L2 are highly expressed in CCGC. Furthermore, PD-L1­–positive tumor infiltrating lymphocytes, proinflammatory cytokine signaling, high tumor mutational burden are associated with CCGC and investigators have observed preclinical activity with PD-1 inhibitors in CCGC. Investigators in PEACOCC sought to assess the safety and efficacy of the PD-1­ inhibitor pembrolizumab in this patient population.

Eligible patients were diagnosed with advanced clear cell ovarian cancer, including primary peritoneal and fallopian tube disease; endometrial, vaginal, vulval or cervical cancer. They needed to have measurable disease based on RECIST v1.1 criteria as well as evidence of radiological disease progression. Patients had an ECOG performance status of 0 or 1 and received at least 1 prior line of chemotherapy.

Those who received prior therapy with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent were excluded.

Patients in the trial received 200 mg of pembrolizumab every 21 days for a maximum of 2 years or until progression, unacceptable toxicity, or clinical/patient decision. Four patients remain on treatment.

Patients with heavily pretreated clear cell gynecologic cancer achieved encouraging responses with single-agent pembrolizumab. 

Gynecologic Cancers