Release Date: April 22, 2019
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Pembrolizumab/Cabozantinib Combo Is Well Tolerated, Shows Activity in Metastatic RCC
Pembrolizumab (Keytruda) plus cabozantinib (Cabometyx) has antitumor activity in patients with previously treated metastatic renal cell carcinoma (RCC) and is tolerated at doses indicated for individual use of each agent, according to findings from a dose-escalation cohort of a phase I study. Among 8 patients enrolled with RCC of any histology, the best objective response was a partial response in 2 patients and stable disease in 4 patients; 2 patients experienced progressive disease. The maximum-tolerated dose (MTD) was identified as 60 mg of oral cabozantinib daily plus 200 mg of pembrolizumab intravenously every 3 weeks, said senior study author Elaine Lam, MD, associate professor and medical director of Urologic Oncology Clinics, of the University of Colorado.
No dose-limiting toxicities (DLTs) were observed with 40-mg cabozantinib plus pembrolizumab in patients evaluable for DLTs. One patient required a dose reduction from 60 mg of cabozantinib to 40 mg after cycle 5.
A 2-stage phase II study with the MTD has begun in patients with RCC with either clear cell or non–clear cell histology, with an initial planned enrollment of 20 patients. Treatment-naïve or previously treated patients will also be enrolled.
“If there are 2 more responses, we’ll expand it to an additional 28 patients. It’s too early to say about efficacy from phase I [data]; we hope to enroll quickly into phase II and have results out soon.”
Eligible patients in the phase I study (NCT03149822) had RCC of any histology, measurable or evaluable disease based on RECIST v1.1 criteria, adequate organ function, and an ECOG performance status of 0 or 1. Patients received pembrolizumab and cabozantinib in a standard 3+3 dose escalation to determine the DLTs, MTD, and objective response rate. Cabozantinib was dosed at 40 mg and 60 mg daily in the first and second cohorts, respectively. Pembrolizumab was dosed at 200 mg every 3 weeks in all cohorts.
The original study design included pretreated patients, but after cabozantinib was approved in the first-line setting in patients with interme¬diate- and poor-risk disease, protocol permitted patients with newly diagnosed metastatic RCC, although all 8 patients in the study had prior systemic therapy.
The DLT assessment window was 21 days; dose-escalation patients who did not complete the DLT assessment window for reasons other than a DLT were considered nonevaluable for DLT and replaced. Scans were obtained every 9 weeks, and treatment could continue beyond progression. Two patients in the cabozantinib 40-mg cohort were not evaluable for DLT due to nonadherence and were replaced with 3 patients treated at the 60-mg dose.
In the first cohort (n = 5), 4 patients had clear cell histology and 1 had non–clear cell RCC; all had nephrectomy. Four were intermediate risk and 1 was poor risk by Memorial Sloan Kettering Cancer Center (MSKCC) risk criteria. Three patients in cohort 1 received 1 prior systemic treatment and 2 patients received ≥2. Three patients received prior tyrosine kinase inhibitor (TKI) therapy only, and 2 received prior TKI therapy plus immunotherapy.
In cohort 2 (n = 3), all patients had clear cell histology, prior nephrectomy, and were MSKCC intermediate risk. Two received 1 prior systemic treatment, and 1 received ≥2. Two patients received prior TKI therapy only and 1 received prior TKI therapy and immunotherapy.
Adverse events (AEs) included 1 case of grade 3 reversible leukoencephalopathy syndrome during cycle 4 of the combination therapy at the 60-mg cabozantinib dose. Other grade 3 AEs included 1 instance each of hypertension, anorexia, and confusion; all occurred outside the DLT window and were attributed to cabozantinib. There were no grade 4/5 AEs.
The most common treatment-emergent AEs at either cabozantinib dosage were fatigue (75%), diarrhea (62.5%), weight loss (62.5%), and dysgeusia (50%).
Treatment is ongoing in 2 patients; 1 in cohort 1 who has been treated for >40 weeks and 1 in cohort 2 who has received treatment for >50 weeks.
Patients were not selected for PD-L1 expression. There was no correlation between PD-L1 status and response in all 8 tumor samples tested.
Keeler ME, Kessler ER, Bernard B, et al. Pembrolizumab (pembro) and cabozantinib (cabo) in patients (pts) with metastatic renal cell carcinoma (mRCC): phase I results. J Clin Oncol. 2019;37 (suppl; abstr 600).
The novel antibody–drug conjugate (ADC) sacituzumab govitecan exhibited clinical activity in patients with heavily pretreated, relapsed/refractory metastatic urothelial cancer in an open-label, single-arm phase I/II basket study (IMMU-132).1
Among the 45 patients with metastatic urothe¬lial cancer enrolled in the phase II portion of the trial, 14 had an objective response to sacitu¬zumab govitecan, for an objective response rate (ORR) of 31.1%, said Scott T. Tagawa, MD, asso¬ciate professor of clinical oncology and medical director, Genitourinary Oncology Research Program, Weill Cornell Medical College in New York, New York, at the 2019 Genitourinary Cancers Symposium.
Sacituzumab govitecan’s activity extended to the post–checkpoint inhibitor setting. Among the 17 patients who received prior checkpoint inhibi¬tion, 4 had responses, for an ORR of 23.5%. The ORR was 33.3% (5 of 15) in patients with liver involvement at study entry.
The median progression-free survival (PFS) was 7.3 months (95% CI, 5.0-10.7), and the median overall survival (OS) was 16.3 months (95% CI, 9.0-31.0).
The responses occurred “in the setting of reasonable drug tolerance,” said Tagawa.
Sacituzumab govitecan was well tolerated, with a manageable and predictable safety profile.
The agent is directed against trophoblast antigen 2 (Trop-2), a cell surface antigen on the surface of multiple types of epithelial tumors, including urothelial carcinoma, in which it is particularly overexpressed in invasive tumors. “The ADC comprises the humanized anti–Trop-2 antibody with a linker that is designed to release the payload inside Trop-2–expressing cells as well as around stroma, and in a high drug-to-antibody ratio, SN-38 is linked to the antibody,” Tagawa said. SN-38, a powerful antineoplastic, is the most active metabolite of irinotecan.
In the initial part of the dose-escalation phase, IMMU-132 investigators enrolled patients with advanced epithelial malignancies of various types that were treatment refractory and unselected for Trop-2 expression. The recommended phase II dosage to emerge was 10 mg/kg given on days 1 and 8 every 21 days. The efficacy signal appeared promising in the subset of patients with advanced urothelial carcinoma.
Tagawa presented data from an expansion cohort of 45 patients with urothelial cancer who had treatment-refractory disease, an ECOG performance status of 0 or 1, and measurable disease. They received sacituzumab govitecan at the recommended phase II dosage until progres¬sion or unacceptable toxicity.
Median patient age was 67 years, 91% were men, 87% were white, 69% had an ECOG perfor-mance status of 1, and 73% had visceral sites of metastatic disease, including 33% with liver metastases. The median number of prior thera¬pies was 2 (range, 1-6); 62% received ≤2 prior lines of therapy, and 38% received ≥3 prior lines. Seventeen patients had prior checkpoint inhib¬itor therapy, 71% of whom had ≥3 prior lines of therapy.
The median duration of follow-up was 15.7 months, and the median number of treat¬ment cycles was 8, with a relative dose intensity of 95.2%. Five patients remained on treatment at the time of data cutoff, 3 of whom had ongoing response.
The most frequent all grade treatment-emer¬gent adverse events (AEs) were diarrhea (69%), nausea (67%), fatigue (58%), and neutropenia (51%), for which, over the duration of the study, 24% of patients received at least 1 dose of granu¬locyte-colony stimulating factor.
Of the 14 responders, there were 2 (4%) complete responses and 12 (27%) partial responses. Most patients had some decrease in tumor burden. Most of the patients who responded did so early, with a median time to onset of response of 1.9 months and 1 patient having an onset of response at 7.4 months. The median duration of response was 12.9 months.
When stratified by number of prior lines of therapy, the ORR was 39.3% in patients receiving ≤2 prior lines and 17.6% in those receiving ≥3 prior lines.
“The grade 3 and 4 adverse events were largely restricted to laboratory-based AEs, including a 38% incidence of grade 3 or 4 neutropenia, but only a 7% rate of febrile neutropenia,” said Tagawa. The most frequent grade ≥3 AEs were neutropenia and anemia (13% each). Five patients discontinued because of potential drug-related AEs, none due to neutropenia. There were no treatment-related deaths.
“Sacituzumab is a new exciting agent poten¬tially for patients with metastatic urothelial cancer, including in the post–checkpoint inhib¬itor space as well as in patients with visceral metastatic disease,” said discussant Matthew Milowsky, MD, section chief, Genitourinary Oncology, University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.
Tagawa S, Faltas B, Lam ET, et al. Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): Results from a phase I/II study. Presented at: 2019 Genitourinary Cancers Symposium; February 14-16; San Francisco, Calif. Abstract 354.
Diane Bartella, MSN, RN, OCN
Oncology Clinical Nurse Educator
Roswell Park Comprehensive Cancer Center
Sacituzumab govitecan shows promise in treating refractory urothelial cancers during phase I and II studies, potentially leading to better outcomes in these patients. It has few adverse events (AEs), most of which are lab related, including myelosuppression and anemia. Febrile neutropenia is rare, and toxicities are manageable.
The research on sacituzumab has a great impact on oncology nurses who are able to offer more effective patient care if they are able to anticipate the potential AEs. With their knowl¬edge and clinical expertise in oncology, nurses are able to readily develop a plan of care to treat these common AEs, including diarrhea, nausea, fatigue, and neutropenia. In addition, having knowledge about the drug, AEs, and treatment plan can ensure that nurses’ practice is more evidence-based, and provide improve care at the bedside.
Nurses can also advocate for patients with metastatic urothelial cancers who qualify to enroll in clinical trials. Being knowledgeable of the response to sacituzumab enables oncology nurses to have a better understanding of research, the research process, and implemen¬tation of clinical trials such as this; stay updated on the latest developments in the field; develop their own conclusions; and become more confident and competent in their roles as a nurse in oncology.
Enzalutamide Extends Radiographic PFS in Metastatic Hormone-Sensitive Prostate Cancer
Enzalutamide (Xtandi) plus androgen depreivation therapy (ADT) prolonged radiographic progression-free survival (rPFS) compared to ADT alone in metastatic hormone-sensitive prostate cancer (mHSPC), according to the phase III ARCHES trial.
At a median follow-up of 14.4 months, median rPFS was not reached in the enzalutamide arm and was 19.45 months in the placebo arm, indicating a 61% reduction in risk of radiographic progression or death with enzalutamide (HR, 0.39; 95% CI, 0.30-0.50; P <.0001),1 lead author Andrew J. Armstrong, MD, reported. Enzalutamide plus ADT was also associated with a reduction in the risk of time to prostate-specific antigen (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).
An interim analysis of overall survival (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 342 deaths.
The international, double-blind ARCHES trial enrolled 1150 patients with histologically verified mHSPC who were randomized to receive enzalutamide at 160 mg daily or placebo. Men with both low- and high-volume disease, and patients who received recent treatment with docetaxel without disease progression, were enrolled.
Patients were allowed to receive prior 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% had a Gleason score ≥8. In the overall study population, approximately 18% of patients had prior docetaxel in the hormone-sensitive setting, and the median duration of prior ADT 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.
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 rPFS that has not been reached for enzalutamide. At the data cutoff date of October 14, 2018, most of the events were radiographic progression events—77 in the enzalutamide arm and 185 in the placebo arm. At a median follow-up of 14.4 months, the median duration of therapy was 12.8 months for enzalutamide/ADT versus 11.6 months for placebo/ADT.
Improvement in rPFS from enzalutamide was observed across all subgroups. For those who had received prior docetaxel, Armstrong said that “this important, nearly 20% subset of patients, had a hazard ratio of 0.53, indicating a 47% improvement in the hazard of progression or death over time.” The 12-month rate of freedom from PSA progression was 91% in the enzalutamide arm versus 63% in the placebo arm. Some 68.1% achieved an undetectable PSA with the combination compared with 17.6% treated with placebo/ADT (P <.0001).
A complete response occurred in 36.7% of enzalutamide-treated patients versus 23.1% in placebo. The overall response rate favored enzalutamide over placebo (83.1% vs 63.7%; P <.0001).
The 12-month event-free rate estimate for time to initiation of new antineoplastic therapy was 94% versus 80% in the enzalutamide and placebo arms, respectively. The most common next therapy was docetaxel followed by abiraterone and then enzalutamide.
At data cutoff, enzalutamide plus ADT did not have a significant impact on time to deterioration of urinary symptoms (HR, 0.88; 95% CI, 0.72- 1.08; P = .2162) or the Functional Assessment of Cancer Therapy—Prostate total score compared with placebo.
The proportion of patients who discontinued study was similar between enzalutamide and placebo (7.2% vs 5.2%), as was the rate of grade ≥3 adverse events (24.3% vs 25.6%).
After double-blind treatment and the positive outcome on the primary endpoint, patients in the placebo group are being offered enzalutamide in an open-label extension protocol. REFERENCES
Meredith Morgan, MSN, ACNP-BC
- 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. Presented at: 2019 Genitourinary Cancers Symposium; February 14-16; San Francisco, CA. Abstract 687.
- Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352-360. doi: 10.1056/NEJMoa1704174.
- James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377(4):338-351. doi: 10.1056/NEJMoa1702900.
Michigan Medicine Urology Oncology Clinic- Rogel Cancer Center
Ann Arbor, MI
AT THE BEGINNING OF MY CAREER (which was only 7 years ago), there were not any additional approved treatments for metastatic hormone-sensitive prostate cancer (mHSPC) other than androgen deprivation therapy (ADT). We currently have options including abiraterone and docetaxel. Just 1 of these is an oral therapy (abiraterone) and therefore, easy for patients to administer at home. Although it is not yet FDA approved in this space, as this article demonstrates, the addition of enzalutamide early (in the mHSPC space) extends the time men have until additional metastatic sites show up on scans.
Currently, enzalutamide is approved for metastatic, castration-resistant prostate cancer, which includes patients with metastatic disease who have a rising prostate-specific antigen (PSA) on ADT. Enzalutamide is also currently approved for non-metastatic castrate-resistant prostate cancer, meaning patients who did not have visible disease on scans, but have a rising PSA on ADT.
When educating patients and families about enzalutamide, there are several important factors to remember. The starting dose is 160 mg, which is administered by 4 tablets of 40 mg each. Patients will need to take all 4 tabs at 1 time, once daily, with or without food. The rationale for the medication being admin¬istered with 4 tablets is for dose-reduction purposes. If a patient experiences intolerable adverse events (AEs), the medication can be reduced by 25% (down to 3 tablets) or even by 50% (down to 2 tablets). The most common AE I see is fatigue. Many of these men already have some level of fatigue caused by the ADT they are currently on. Other possible AEs are hot flashes, muscle aches, diarrhea, and hypertension. It may only be a matter of time before we have 3 or more options for men with mHSPC. It is key to choose the right drug for the right patient while keeping potential AEs in mind.
Darolutamide Improves Metastasis-Free Survival in Nonmetastatic CRPC
Darolutamide plus androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS) compared with placebo plus ADT in patients with nonmetastatic castration-resistant prostate cancer (CRPC) enrolled in the phase III ARAMIS trial.
At a median follow-up of 17.9 months, median MFS was 40.4 months in the darolutamide arm versus 18.4 months in the placebo arm (HR, 0.41; 95% CI, 0.34-0.50; P <.0001),1 Karim Fizazi, MD, announced at the 2019 Genitourinary Cancers Symposium. This improvement in MFS with darolutamide occurred across patient subgroups.
At an interim analysis for overall survival (OS), the 3-year rates of OS were 83% in the darolutamide arm versus 73% in the placebo arm, corresponding to a 29% reduction in the risk of death (HR, 0.71; 95% CI, 0.50-0.99, P = .0452). Median OS was not yet reached in either arm.
The median time to pain progression, using the Brief Pain Inventory (Short Form) or by opioid use, also favored darolutamide, at a median of 40.3 months compared with 25.4 months with placebo, consistent with a 35% risk reduction (HR, 0.65; 95% CI, 0.53-0.79; P <.0001).
“Darolutamide also has a very favorable safety profile,” said Fizazi, head of the Gard Inpatient Unit in the Department of Medical Oncology at the Institut Gustave Roussy in Villejuif, France, and professor of oncology at the University of Paris. “Specifically, we didn’t find any increase in [adverse] events (AEs) such as falls, fractures, cognitive disorders, seizures, and hypertension compared [with] placebo.”
Progression-free survival (PFS), which included local relapse, distant metastases, and death, was an exploratory endpoint. Median PFS was 36.8 months in the darolut¬amide arm versus 14.8 months in the placebo arm (HR, 0.38; 95% CI, 0.32-0.45; P <.0001).
Median time to cytotoxic chemotherapy was not reached for the darolutamide group versus 38.2 months for placebo (HR, 0.43; 95% CI, 0.31-0.60; P <.0001), and median time to first symptomatic skeletal event was not reached for either group but also favored darolutamide (HR, 0.43; 95% CI, 0.22-0.84; P = .0113).
Nonmetastatic CRPC is associated with high risk for progression and cancer-specific mortality. In men with high-risk nonmetastatic CRPC, 2 next-generation androgen receptor inhibi¬tors, apalutamide (Erleada) and enzalutamide (Xtandi), have recently been shown to improve MFS,2,3 “although they were associated with increased cognitive impairments, falls, and other [adverse] events,” said Fizazi. Both apalutamide and enzalutamide have received approval from the FDA for the treatment of nonmetastatic CRPC.
Darolutamide is structurally distinct from apalutamide and enzalutamide and is charac¬terized by low blood–brain barrier penetration. Preclinical data show that darolutamide has a high affinity to the androgen receptor and a low potential for drug–drug interactions.
Robust anticancer activity was observed in men with CRPC, including patients who had previ¬ously received a taxane and, to a lesser degree, abiraterone, said Fizazi. No clear drug-related AEs could be detected in these studies.
The multicenter, double-blind phase III ARAMIS trial accrued 1509 patients with nonmet¬astatic CRPC and a prostate-specific antigen (PSA) doubling time <10 months who were being treated with ADT and determined to be at risk for developing metastatic disease. All men had an ECOG performance status of 0 or 1. Patients were randomized 2:1 to darolutamide at 600 mg twice daily while maintaining ADT or matching placebo plus ADT.
At baseline, the median PSA doubling time was 4.4 months and 4.7 months in the darolutamide and placebo groups, respectively. Only 3% and 6%, respectively, were taking a bone-sparing agent. The median duration of treatment was 14.8 months for darolutamide and 11.0 months for placebo. At data cutoff of September 3, 2018, 64% of patients on darolutamide and 36% on placebo were still on treatment.
Grade 3/4 AEs were rarely observed. “The inci¬dence of drug discontinuation due to [adverse] events was remarkably similar in the darolut¬amide and the placebo groups, about 9%,” Fizazi said.
The only AE with an all-grade rate >10% in the darolutamide arm was fatigue (12.1% vs 8.7% in the placebo arm). The difference in the rate of fatigue between groups disappears when adjusting for duration of exposure, Fizazi said. There was no difference in the incidences of falls and fractures between arms (about 4% for each AE in both arms) and no significant difference in the incidence of hypertension (6.6% in darolut¬amide arm vs 5.2% in the placebo arm).
Pain interference and pain severity scores and urinary symptom scores favored darolutamide. “For patients with a PSA doubling time shorter than 6 months, there’s a much greater risk and more rapid progression of developing bone metastases and death compared with patients with doubling times longer than 6 months,” said invited discussant Ian D. Davis, MD, professor of medicine at Monash University and Eastern Health in Melbourne, Australia. ARAMIS there¬fore meets 1 criterion for a practice-changing study because 69% of the patients enrolled had a PSA doubling time ≤6 months, he said.
Although a MFS improvement is accepted by the FDA as a meaningful endpoint for clinical trials in nonmetastatic CRPC, if supported by achievement of secondary endpoints, ARAMIS should not be considered practice changing until data on subsequent treatment efficacy and cost-effectiveness become available, Davis said.
- Fizazi K, Shore ND, Tammela T, et al. ARAMIS: Efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC). Presented at: 2019 Genitourinary Cancers Symposium; February 14-16; San Francisco, Calif. Abstract 140.
- 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 36, 2018 (suppl 6s; abstract 161).
- Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36 (suppl 6S; abstr 3).