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Patients with cancer and cancer survivors frequently have difficulty adhering to the rigorous demands of their treatment for a variety of reasons, and a difficult-to-navigate US health care delivery and finance system is troublesome for providers and patients alike. A possible cause of some of the cost-related delays and nonadherence to treatment that patients and survivors experience could be the time and effort they are forced to spend on administrative payment tasks related to their care, according to findings from a study published in 

Cancer Epidemiology, Biomarkers & Prevention

Data from the study showed that patients who reported engaging in more administrative tasks had higher log odds of delaying or forgoing care (

 = 0.18; 95% CI, 0.12-0.24) after study authors accounted for age, race/ethnicity, education, and out-of-pocket costs. Additionally, cost-related delays and nonadherence to care were raised by 32% for each unit of increase in administrative payment burden (

 = 0.32; 95% CI, 0.18-0.46). Overall, investigators determined that administrative patient burden increased the odds of cost-related delays and nonadherence by 49%.

The study was a secondary analysis of cross-sectional survey data collected by Cancer

, a national nonprofit organization that aims to provide psychological support to patients with cancer. “There was a particular [portion of the Cancer

] survey that focused on financial and insurance concerns of people with cancer,” Meredith Doherty, PhD, LCSW, assistant professor in the School of Social Policy & Practice at the University of Pennsylvania in Philadelphia, said in an interview with 

. “There were these questions about administrative burdens and questions about cost-related nonadherence. I thought that these things are probably related given what I know about the concepts of administrative burden, nonadherence, and cost-related nonadherence. This was the impetus to start to explore the data in that way.”

To conduct their study, Doherty and her colleagues analyzed survey item responses from a total of 510 US-based patients with cancer and cancer survivors. To be eligible for the study, participants needed to have a history of any cancer besides nonmelanoma skin cancers, have health insurance coverage, and be 25 years or older. The original Cancer

 survey contained items regarding demographic characteristics, gross household income, cancer type and status, treatments received, health insurance type, and estimated monthly out-of-pocket expenses related to their care.

Investigators identified 10 items of interest to include in their data set: 5 related to administrative tasks and 5 connected to cost-related nonadherence. The items deemed to be related to administrative payment tasks asked patients how often they did the following: received an estimated cost before agreeing to a treatment their doctor recommended, appealed the denial of benefits from their insurance company, found out the out-of-pocket cost before filling a prescription for a treatment drug, asked the insurance company for help in understanding coverage, and/or found out the out-of-pocket cost before getting laboratory tests or scans. The 5 items investigators identified as being pertinent to cost-related delays and nonadherence asked patients how often they did the following to reduce their expenses related to cancer treatment: delayed or skipped appointments, delayed or skipped blood work, delayed or skipped follow-up blood testing, cut pills in half, and/or skipped dosages of prescribed drugs (

Patients’ responses to each of the 10 survey items were assigned values of 0 (never), 1 (rarely), 2 (sometimes), 3 (often), and 4 (always). These findings were compiled into 2 additive scales for each set of questions with scores ranging from 0 to 20, with higher scores representing greater cost-related nonadherence and administrative burden.

Study authors analyzed the data using 2-part modeling to predict cost-related delays and treatment nonadherence. The models first used a logit function to estimate the likelihood of a nonzero outcome, and then generalized linear modeling was used to estimate the relationship between the predictor variables of administrative burden and other covariates and cost-related delays and nonadherence. Investigators also used univariate 2-part models to estimate the correlations between predictor variable and cost-related delays and nonadherence; this information was retained for the multivariate model if the variables displayed a 

Most respondents who completed the survey and were included in the cross-sectional analysis were women (65%), older than 55 years (58%), and White (71%). The most commonly reported household income range was $50,000 to $74,999 (21%), and less than half of the population had attained an education level of a bachelor’s degree or higher (48%). Insurance types consisted of Medicare/Medicaid (55.1%), employer sponsored (36.9%), Medicare plus Medigap (10.5%), marketplace (9.3%), other (5.2%), and Tricare/CHAMPUS (2.7%).

The most common cancer types included in the sample were early-stage breast (22.3%), prostate (10.2%), and colorectal (8%). The sample also included patients with bladder (3.5%), brain (2.2%), metastatic breast (6.5%), gynecologic (6.7%), head and neck (1.8%), kidney (4.9%), leukemia (4.7%), liver (0.4%), lung (5.3%), lymphoma (3.7%), melanoma (2.4%), myeloma (0.8%), pancreatic (2.4%), stomach (0.6%), thyroid (4.9%), and other (8.8%) cancers.

“There’s a huge amount of heterogeneity in the cancer types, the incomes, the regions in which people live, and the states in which people live,” Doherty said. “All those [factors are correlated] to variation in the way that health care is delivered and the quality of care. If we dug deeper and looked at administrative burdens in a very specific population, we might be able to see a lot more. In some cases, heterogeneity in your sample gives you a lot of strength. In this case, I’d say we maximized it to understand differences between groups.”

Fifty-five percent of patients answered the survey by indicating that they never or rarely engaged in any of the tasks that were inquired about. Only 9% of respondents said they engaged in at least 4 administrative payment tasks, and the mean total tasks was 1 (SD, 1.43) of a possible 5. At the item level, each of the 5 administrative payment tasks was associated with cost-related delays and/or nonadherence.

Notably, additional findings from the study showed 2 groups of older patients, defined as those aged 55 to 64 years (

 = –1.26; 95% CI, –2.21 to –0.31) and those aged 65 to 74 years (

 = –1.77; 95% CI, –2.75 to –0.80), both experienced lessened log odds of engaging in cost-related nonadherence to care compared with younger patients aged 25 to 34 years. Moreover, findings from an adjusted generalized linear model revealed that patients aged 55 to 64 years displayed an association with reduced cost-related nonadherence (

There were also disparities reported in terms of cost-related nonadherence among other patient subgroups. Black patients displayed increased log odds of reporting cost-related nonadherence (

 = 1.10; 95% CI, 0.33-1.87) compared with White patients; however, it was not significantly associated with cost-related nonadherence according to findings from the generalized linear model. Patients who said that their monthly out-of-pocket medical costs exceeded $500 had greater log odds of reporting cost-related nonadherence compared with those who reported monthly costs of less than $100 (

 = 1.17; 95% CI, 0.40-1.95). This finding was again observed when investigators used the generalized linear model (

“All the labor and effort that it takes to resolve payment issues to make sure that you’re adequately informed in order to make decisions about payment or dispute payment issues [is something that] many of us are unfortunately familiar with,” Doherty said. “We’ve all tried to seek clarification on a bill related to health care; [things like] that were correlated with this nonadherence. The implications and what we can hypothesize about, what the mechanisms are underlying that, are interesting to think about.”

Regarding these potential mechanisms causing the relationship between payment administrative tasks and care nonadherence and cost-related treatment delays, Doherty explained that it’s hard to pin down a specific cause because of the multifactional nature of the issue, both in patient subgroups and in general. Based on her knowledge of literature in the area, she hypothesized that structural vulnerabilities often divided along race and class lines, such as level of access to health care, lack of knowledge regarding how to deal with the health care system, and lack of access to personalized resources to understand their disease, could all potentially play a role in the disparities between patient subgroups that were observed.

In terms of study limitations, Doherty noted that the study was exploratory in nature with the effect of simply establishing that there is a relationship between administrative burden and cost-related treatment delays and nonadherence. The data provide a correlational but not a causal link between the 2 variables. She also explained that the survey was administered online, and some patients/survivors received a diagnosis of cancer more than 4 years ago. However, Doherty said that study authors measured for recall bias and found that time since cancer diagnosis and treatment did not have a significant effect on the findings.

Doherty M, Thom B, Gardner DS. Administrative burden associated with cost-related delays in care in U.S. cancer patients. 

. Published online August 30, 2023. doi:10.1158/1055-9965.EPI-23-0119

Articles

A possible cause of some of the cost-related delays and nonadherence to treatment that patients with cancer and cancer survivors experience could be the time and effort they are forced to spend on administrative payment tasks related to their care. 

Administrative Payment Tasks Could Be Causing Detrimental Effect of Treatment Delays and Nonadherence for Patients With Cancer

Newer treatment for patients with cancer such as monoclonal antibodies, immunotherapies, antibody–drug conjugates, growth factor receptors, checkpoint inhibitors, and targeted therapies have been shown to improve prognosis. Yet in the real-world setting, cases of 

ocular adverse effects have emerged with greater frequency both in new and established therapies than has been previously observed in many clinical trials.

Investigators at Cleveland Clinic Taussig Cancer Center recently published a clinical review that compiles ocular toxicities of several anticancer drugs in an attempt to predict who will be impacted by these AEs and what treatments and interventions can mitigate these risks. The researchers analyzed patient cases as well as prior medical literature to
better understand ocular complications that have occurred in patients taking antineoplastic agents.

“As clinicians, we need to look at not just the efficacy of a treatment but what toxicities are occurring to vital organs like the eyes and the impact this has on that patient’s quality of life,” Shahzad Raza, MD, a physician in the Department of Hematology and Medical Oncology at Cleveland Clinic Taussig Cancer Center in Ohio, and senior author of the study, said in an article.

“Patients struggle because they don’t know how to navigate the situation, and physicians are often unsure what steps to take to alleviate ocular toxicities. Ophthalmologists should be involved much earlier [on] in treatment decision-making and the potential risks to the eyes.”

Many unknowns remain about how to manage these issues, including when to pause treatment and when to reintroduce
it. The study authors combined in-depth clinical data regarding how ocular toxicities occur with data from published literature to develop a reference tool for providers to help guide them on what steps to take to mitigate these toxicities.

Commonly used chemotherapy agents such as alkylating agents, antimetabolites, microtubule inhibitors, and new targeted therapies can cause eye complications. These include corneal ulcers, keratoconjunctivitis, inflammation of eyelids, uveitis, macular edema, and loss of vision.

In the phase 1 DREAMM-1 trial (NCT02064387), patients treated with belantamab mafodotin-blmf (Blenrep; n = 35) experienced keratopathy at a rate of 53%.

In another study, patients treated with high-dose carmustine (n = 110) experienced retinal hemorrhaging at a rate of 24%.

Several eye toxicities require frequent communication
between oncologists and ophthalmologists. Similarly, it is important to have open communication between oncologists and patients, especially in cases of very advanced cancers with limited prognosis where such treatments may not add much to the quantity or quality of life.

Although eye toxicities are not the norm, they do occur more frequently than is typically observed in clinical trials, and in some cases rapidly. Depending on the therapy, a temporary cessation of treatment or lowering of dose can help reverse more severe toxicities. Based on these findings, the study authors recommend the following if a patient is
receiving a therapy with which there is a risk of ocular AEs:

Administer a baseline ophthalmic exam prior to initiating cancer treatment and perform periodic exams throughout treatment to detect ocular toxicities earlier on.

Discuss the risks of ocular toxicities with patients so that if they experience early symptoms they can notify their care team immediately.

Ensure the patient already has an ophthalmologist so that if a problem arises, they can get an appointment quickly.

“In some cases, eye issues occur gradually but in some instances such as retinal detachment, they can happen right away and become an emergency,” Raza said. “If a patient is just starting to reach out to an ophthalmologist when these toxicities occur, often the damage has already been done, and by the time their oncologist is holding the drug, the cancer [has] progress[ed]. The moment an issue emerges,
there should be a lifeline to an ophthalmologist.”

Raza and a team of computational mathematicians are using data mining to evaluate overall toxicity trends of oncology agents. By mining national patient databases of thousands of patients, they hope to discover what role factors such as race, ethnicity, drug dosing, and gene modification play in drug toxicities. “What we don’t yet understand is why one patient
has an AE and another does not,” Raza explained. “What factors are involved? [It] may be inherent genetics but we feel there are particular pharmacokinetic and pharmacogenomic signals involved that may amplify certain toxicities.”

Ultimately, the goal is to bring pharmacovigilance and genomics together to better predict when toxicities will occur so that clinicians can tailor treatment accordingly. 

Eye toxicities more prevalent side effect of cancer treatment than previously understood. Cleveland Clinic. September 7, 2023. Accessed October 10, 2023. https:// consultqd.clevelandclinic.org/eye-toxicities-more-prevalent-side-effect-of-cancer-treatment-than-previously-understood/

Bader A, Begemann M, Al-Obaidi A, Habib MH, Anwer F, Raza S. Ocular complications of antineoplastic therapies. Future Sci OA. 2023;9(7):FSO871. doi:10.2144/fsoa-2022-0081

In the real-world setting, cases of ocular adverse effects have emerged with greater frequency both in new and established therapies than has been previously observed in many clinical trials.

Prevalence of Eye Toxicities in Patients With Cancer Is Much Higher Than Previously Known

The six transmembrane epithelial antigen of the prostate 1 (STEAP1) has gained traction as a potential therapeutic target in recent years in multiple cancer types due to its overexpression in certain malignant tissues and low levels of expression in normal tissues. Because STEAP1 is often overexpressed in prostate cancer, a disease that still largely lacks safe and effective treatment options, investigators are using it as the basis for developing novel therapies.

“STEAP1 is overexpressed in a lot of prostate cancer tissues compared with normal tissues in the body; it has a good therapeutic index to be able to safely target,” Rahul Aggarwal, MD, a medical oncologist in the Division of Hematology/Oncology, coleader of the Genitourinary Medical Oncology program, and the associate director for clinical sciences at the University of California, San Francisco, said in an interview with OncologyLive. “[This is one of] a number of exciting cell surface targets. This is an area [in] general in prostate cancer drug development where you’re seeing a lot of excitement, enthusiasm, clinical trials, and
clinical development.”

STEAP1 is a cell surface protein that is thought to be an ion channel or transporter protein at the cell-to-cell junctions, potentially playing a part
in cell-to-cell communication. Study results have shown that the protein, when overexpressed, can inhibit apoptosis, leading to enhanced cell proliferation and invasion. At the same time, inducing higher than normal levels of STEAP1 can cause epithelial to mesenchymal transition, subsequently leading to heightened tumor progression and disease aggressiveness.

Outside of prostate cancer, STEAP1 also isoverexpressed in other solid tumors, including those of the bladder and colon, as well as Ewing
sarcoma. Although the exact role of STEAP1 in cancer development is not fully understood, there is mounting evidence that overexpression of
STEAP1 could be a biomarker of worsened prognosis in prostate cancer.

STEAP1 is expressed on the surface of approximately 89% of metastatic castration-resistant prostate cancer (mCRPC) lesions, as well as 84% of mCRPC bone metastases, and it displays low or absent expression in normal tissues.

Although patients with mCRPC have gained multiple new treatment options in recent years, the long-term benefit of these agents is inconsistent and often accompanied by significant toxicities, underscoring the need for targeted treatments. Investigators have developed or are planning to evaluate drugs of different agent classes that target STEAP1 for the treatment of patients with mCRPC.

“First-generation [STEAP1-directed] antibody drug conjugates [ADCs] have shown some promising results,” Aggarwal noted. “There’s
also enthusiasm to use some of the newer modalities of therapy, including bispecific antibodies, to see if they may show even more promising results than [what has already been seen].”

An example of a STEAP1 ADC that has been examined in mCRPC is
DSTP3086S. The agent consists of a humanized immunoglobulin 1 anti-STEAP1 monoclonal antibody, MSTP2109A, that is linked to the potent antimitotic agent monomethyl auristatin E (MMAE). After the agent binds to STEAP1 on cancer cells, MMAE is released into the cell, inhibiting cell division and ultimately leading to cell death.

Following encouraging preclinical findings, investigators evaluated DSTP3086S in mCRPC in a phase 1 trial (NCT01283373). The multicenter study enrolled a total of 84 patients: 77 who received treatment once every 3 weeks and 7 patients on a weekly dosing schedule. Patients treated once every 3 weeks experienced dose delays, reductions, and/or discontinuation of DSTP3086S due to adverse effects (AEs) at rates of 38%, 16%, and 22%, respectively. In the weekly dosing cohort, 1 patient had a dose reduction, 3 had a dose delay, and 1 discontinued treatment because of AEs.

Preliminary efficacy was measured by prostate specific antigen (PSA) changes illustrated by waterfall plots, disease progression, and radiographic response. Findings from the study demonstrated that 14% (95% CI, 7%-24%) of patients overall met the criteria of a confirmed
PSA reduction of at least 50%. Among patients who received more than 2 doses of DSTP3086S, (n = 62), PSA responses were observed in 14%
(95% CI, 0%-58%) of patients treated with the 2.25-mg/kg dose (n = 7), 13% (95% CI, 4%-27%) of patients treated with the 2.4-mg/kg dose
(n = 39), and 31% (95% CI, 11%-59%) of patients treated with the 2.8-mg/kg dose (n = 16).

Among 46 patients with RECIST-evaluable disease at baseline, 2 achieved a partial response (PR) and 24 experienced stable disease as their best radiographic response. Fourteen patients were able to continue treatment with DSTP3086S for at least 6 months, including both patients with PRs. However, both patients eventually had to discontinue DSTP3086S due to disease progression.

Study authors concluded that DSTP3086S displayed evidence of antitumor activity with an acceptable safety profile. They noted that further optimization of the agent would be needed for further clinical study. However, they said that their findings could help to inform the development of future STEAP1-directed novel ADCs, chimeric antigen receptor T-cell therapies, and bispecific antibodies.


Investigators have been particularly interested in developing immunotherapy approaches based on T cells to target STEAP1 in mCRPC. One such agent is the novel bispecific antibody AMG 509, which has shown high avidity binding to STEAP1 in preclinical study. Once bound to STEAP1, the agent links T cells with cancer cells and mediates the lysis of the cancer cells.

“[AMG 509] is a T-cell engager that is a 2-headed antibody, with one head that binds to STEAP1 on the cancer cell surface and the other
that binds to T cells,” Aggarwal explained. “It tries to bring those tumor cells into close proximity with the T cells and elicit an antitumor
immune response. It also has additional technology to extend the half-life of the agent. [The structure of AMG 509] may permit weekly or
maybe even biweekly dosing schedules.”

Investigators are evaluating the safety and preliminary efficacy of AMG 509 in patients with mCRPC in an ongoing phase 1 trial (NCT04221542). The study opened in January 2020 and is recruiting patients whose
progressive disease is refractory to antiandrogen
therapy.

The trial is divided into 4 parts. In part 1, patients will receive intravenous (IV) AMG 509 monotherapy during dose exploration and again
during dose expansion after the determination of the maximum-tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Patients in
parts 2 and 3 will be treated with subcutaneous AMG 509 and IV AMG 509 in earlier lines of treatment, respectively. AMG 509 will be given in combination with abiraterone acetate (Zytiga) in part 4A and with enzalutamide (Xtandi) in part 4B.


As of June 2022, the study had enrolled 65 of 110 patients for treatment in part 1 and enrollment for parts 2 and 4 had commenced. Part 3 will begin enrollment after the determination of the MTD and the RP2D. Investigators may also choose to add more parts as data emerge. The
coprimary end points are dose-limiting toxicities and safety. Secondary end points include pharmacokinetics, duration of response, progression-
free survival, and overall survival (OS).

Potential Role for STEAP1 in Prostate Cancer 

In addition to being used as a treatment target in the development of novel therapeutics, STEAP1 also has shown potential in prostate cancer as a component in diagnostic imaging techniques. Specifically, investigators developed 

Zr-DFO-MSTP2109A, which consists of the same IgG1 STEAP1-directed monoclonal antibody, MSTP2109, as DSTP3086S but is radiolabeled with the positron emitter 

Zr-DFOMSTP2109A could be used to detect mCRPC lesions because of MSTP2109A’s ability to
bind to STEAP1.

Zr-DFO-MSTP2109A was subsequently evaluated in a prospective phase 1/2 imaging study (NCT01774071) that enrolled patients with
mCRPC. This trial ran parallel to the phase 1 trial of DSTP3086S. The imaging study enrolled 19 patients, 15 of whom were later enrolled in
the therapeutic study of DSTP3086S.

Findings from the study showed that the mean radiosynthesis yield was 81% (range, 64%-92%) and the product radiochemical purity by radio–
thin-layer chromatography was 99.8% (range, 98.7%-100%). Additionally, the median immunoreactivity fraction was 96% (range, 91%-99%).

Zr-DFO-MSTP2109A displayed exceptional uptake in both patients with bone (n = 18) and soft tissue lesions (n = 9), reaching a median maximized standardized uptake value (SUVmax) of 20.6 (range, 4.4-59.3) and 16.8 (range, 9.0-24.0), respectively. Most lesions (n = 16/17)
that were biopsied were positive on imaging with 

Zr-DFO-MSTP2109A, and all sites were histologically positive. Investigators estimated by Bayesian analysis that 86% (95% CI, 75%-100%) of histologically positive lesions were true-positive based on imaging. No correlation was observed between SUVmax tumor uptake and STEAP1
immunohistochemistry or change in PSA level.

In terms of safety, 4 patients had AEs. Two patients experienced grade 1 chills that were thought to be related to infusion, and 1 patient each had back pain and vomiting, which were not attributed to 

Zr-DFO-MSTP2109A. Two patients had serious AEs.

Zr-DFOMSTP2109A was well tolerated and displayed good localization in mCRPC sites in both
bone and soft tissue. They wrote that the reagent warranted further investigation as a companion diagnostic for STEAP1-targeted therapy in mCRPC


Outside of prostate cancer, investigators have begun development of STEAP1 T cell–engaging bispecific antibodies for the treatment of patients with Ewing sarcoma. There remains an unmet need for effective treatment options with fewer toxicities than intensive chemotherapy; Ewing sarcoma is the second most common bone tumor in pediatric and young adult patients, and the OS rate among patients with metastatic or relapsed disease ranges from 20% to 30%. To date, other antigen-targeted immunotherapies have fallen short of producing an effective T-cell receptor-mediated response, but T cell–engaging bispecific antibodies have not been thoroughly evaluated in this disease setting.

In response to this unmet need, investigators used a rehumanized STEAP1 IgG to create the novel T cell–engaging bispecific antibody BC261. BC261 possesses a design similar to that of AMG
509. It carries the anti-CD3 humanized antibody OKT3 single-chain variable fragments as the agent’s second specificity, making it bispecific
for both STEAP1 and CD3.

In preclinical study, BC261 maintained high purity through prolonged heat stress and consistently displayed the greatest mean fluorescence
intensity among the 4 novel STEAP1 bispecific antibodies being examined, all of which were built using the same platform but used differing variable heavy chain and variable light chain components. BC261 was found to expand to the highest number of Ewing sarcoma cell lines and to bind to prostate cancer and canine osteosarcoma
cell lines.

Moreover, findings from an in vivo antitumor study showed the agent achieved complete tumor regression, even in established tumors sized
approximately 2000 mm3.

“STEAP1 is an appealing target for T-cell immunotherapy, and the STEAP1 T-cell bispecific antibody BC261 offers a novel solution to engage T cells to traffic into immunologically ‘cold’ STEAP1-positive malignancies. BC261 induced robust antitumor responses without long-term toxicities for stand-alone bispecific antibodies or bispecific antibody–armed T cells, warranting clinical development for human solid tumors with major unmet need,” the study authors concluded.

Because STEAP1 is often overexpressed in prostate cancer, a disease that still largely lacks safe and effective treatment options, investigators are using it as the basis for developing novel therapies.

STEAP1 Offers Potential Multifunctional Target in Prostate Cancer

Despite advanced ovarian and endometrial cancer still being accompanied by a poor prognosis and remaining largely difficult-to-treat diseases, optimism among clinicians has steadily ramped up in recent years with the development of multiple new promising agents and treatment regimens.

“We can be excited that our patients are living longer, but we’re really not curing that many more patients,” Matthew A. Powell, MD, said during a recent OncLive Peer Exchange. “The more we can do up front to get patients to that cure word—which we’re hesitant to use in oncology—is vital as we look at new agents being added to up-front therapy.”

“The biggest unmet need [in ovarian cancer] is improving outcomes in the homologous recombination–proficient [HRP] patient population,” Bhavana Pothuri, MD, said. “In addition to that, we need more therapeutic opportunities in platinum-resistant ovarian cancer.” 

Ovarian cancer is the deadliest cancer that occurs in women and is the fourth-deadliest disease for women overall; patients with epithelial ovarian cancer have a 5-year overall survival (OS) rate of just 45.6%. Treatment strategies in ovarian cancer are largely dependent on the type and pathological stage of the disease, but chemotherapy remains the most important component. Other treatment approaches include surgery and radiation therapy, as well as targeted therapeutics and immunotherapy for patients with advanced disease.

Endometrial cancer is the most common gynecologic cancer in the United States. In 2018, it was the fourth most common cancer in women and the fifth most common cause of cancer death in the country; there were an estimated 63,230 new cases and 11,350 deaths attributed to uterine cancer during that year alone. The disease is often treated with surgery; other options include radiation therapy, chemotherapy, immunotherapy, and targeted therapies.

In the OncLive Peer Exchange, expert clinicians provided data updates from clinical trials evaluating agents for the treatment of patients with endometrial and ovarian cancer, with a focus on developments in studies and trial analyses evaluating PARP inhibitors in ovarian cancer and immune checkpoint inhibitors in endometrial cancer. Investigators also highlighted ongoing studies examining novel agents and combinations in both disease settings.

The findings referenced were presented during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

Ursula A. Matulonis, MD, started the conversation by giving an overview on the standard-of-care first-line maintenance options for patients with ovarian cancer. She noted that there have been 3 critical phase 3 clinical trials in recent years that have led to FDA approvals in this setting: SOLO-1 (NCT01844986), PRIMA (NCT02655016), and PAOLA-1 (NCT02477644).

Findings from SOLO-1 supported the December 2018 FDA approval of the PARP inhibitor olaparib (Lynparza) for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic 

-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete response (CR) or partial response (PR) following frontline platinum-based chemotherapy. Treatment with the PARP inhibitor led to a significant improvement in investigator assessed median progression-free survival (PFS) compared with placebo (HR, 0.30; 95% CI, 0.23-0.41; P < .0001).

In April 2020, the FDA granted approval to another PARP inhibitor, niraparib (Zejula), for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR or PR after first-line platinum-based chemotherapy. Findings from PRIMA showed that niraparib provided a PFS benefit compared with placebo in both the overall population (HR, 0.62; 95% CI, 0.50-0.76; P < .0001) and in patients with homologous recombination deficient (HRD) disease (HR, 0.43; 95% CI, 0.31-0.59; P < .0001).

Shortly after the approval of niraparib, in May 2020, the FDA expanded the indication of bevacizumab (Avastin) for first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR or PR to first-line platinum-based chemotherapy and whose disease is positive for HRD. Results from PAOLA-1 supported the regulatory decision, showing a pronounced benefit with the combination over bevacizumab monotherapy among patients with HRD-positive tumors (HR, 0.33; 95%

“One of the first decisions is whether you’re using bevacizumab,” Shannon N. Westin, MD, MPH, FACOG, said regarding how she selects an FDA-approved first-line maintenance treatment. “If you’re using bevacizumab, then the place that we have that FDA approval is with olaparib. For a patient population that has not started bevacizumab, you’re going to talk through [factors such as] once-a-day treatment, how long you’re going to do treatment, and toxicities, understanding that certain PARP inhibitors are going to have more gastrointestinal adverse effects and others are going to have more of an effect on platelets.”

The panelists then transitioned into highlighting exciting new data from clinical trials evaluating PARP inhibitors presented during ASCO 2023. “All these up-front phase 3 trials take so much work, effort, and time. We need to see a succession of results. The other issue is that when trials are developed, standard-of-care [treatment] changes when that trial is being executed, launched, and run,” Matulonis said.

The phase 3 DUO-O trial (NCT03737643) evaluated the safety and efficacy of first-line chemotherapy plus durvalumab (Imfinzi) and bevacizumab followed by maintenance therapy with durvalumab and bevacizumab with (arm 3; n = 378) or without olaparib (arm 2; n = 374). The comparator arm received frontline chemotherapy plus bevacizumab with maintenance bevacizumab (arm 1; n = 378). The trial enrolled patients with newly diagnosed stage III or IV high-grade epithelial ovarian cancer who were PARP inhibitor naïve.

Findings from the study showed that the median PFS in arms 1, 2, and 3 was 19.3 months, 20.6 months, and 24.2 months, respectively. Patients in both experimental arms achieved a benefit in terms of PFS vs the comparator arm, with the benefit being more pronounced with the addition of olaparib (HR, 0.63; 95% CI, 0.52-0.76; P < .0001) compared with that of arm 2 (HR, 0.87; 95% CI, 0.73-1.04; P = .1312). Additionally, arm 3 offered a pronounced PFS benefit over arm 1 in patients who were HRD positive (HR, 0.51; 95% CI, 0.36-0.72) and HRD negative (HR, 0.68; 95% CI, 0.54-0.86).

“Olaparib plus bevacizumab is now a standard of care for patients who receive bevacizumab in the HRD setting and in the 

-mutated
setting,” Matulonis said of DUO-O. “That arm does not exist in this trial. It’s not an omission, but it’s an important deficiency of this study. There [are] also no [OS] data, which are critical for PARP inhibitor trials now.”

In a post hoc exploratory analysis of PAOLA-1, study authors aimed to define the efficacy of subsequent chemotherapy among patients who experienced disease progression after maintenance therapy with olaparib plus bevacizumab. In the olaparib arm, 192 patients experienced
disease progression during olaparib treatment and 145 did so after receiving the agent. In the bevacizumab monotherapy arm, 206 patients
experienced disease progression.

Findings from the analysis showed that patients treated with subsequent chemotherapy who progressed during olaparib treatment experienced a median time from first subsequent therapy to second subsequent therapy of 6.1 months (95% CI, 4.9-7.3). Comparatively, patients who progressed after olaparib treatment and those who progressed in the control arm experienced median times from first subsequent
therapy to second subsequent therapy of 11.4 months (95% CI, 10.2-13.2) and 11.9 months (95% CI, 10.8-12.9). 

“This kind of confirmed what we’ve all had a sense of, which is that patients [who] have progression on a PARP inhibitor are very different
from patients [who] have progression after they complete PARP inhibitor treatment,” Westin said. “That makes biologic sense. Those patients [who] had progression on a PARP inhibitor had lower response to subsequent chemotherapy. That gets at the idea that there are overlapping resistance mechanisms. We know platinum sensitivity predicts PARP response. Conversely, PARP sensitivity [potentially] should predict platinum response.”

Finally, the panelists reviewed findings from an analysis of PRIMA that identified predictors of long-term PFS (defined as 2 years or more) in patients who received niraparib. Study authors identified

mutation and HRD status, International Federation of Gynecology and Obstetrics stage at diagnosis, primary tumor location, and absence of baseline nontarget lesions as being associated with extended PFS. Patients with 

-mutant/HRD disease were much more likely to remain progression free for at least 2 years compared with those who were


 wild-type plus HRP or had undetermined homologous recombination status (odds ratio [OR], 10.75; 95% CI, 5.16-22.41; 

< .0001), as were those with 0 baseline nontarget lesions vs those with 2 or more (OR, 4.67; 95% CI, 2.08-10.49; P = .0002).

The panelists finished up their discussion on ovarian cancer by mentioning an upcoming European phase 2 clinical trial (NCT04742075)
enrolling patients with relapsed ovarian cancer who are in a CR or PR following completion of their last chemotherapy course. Notably, the study will enroll only patients with 

wild-type. Patients will be stratified by HRD status (positive vs negative/unknown) and previous PARP inhibitor exposure (yes vs no).

The study is evaluating the safety and efficacy of the addition of the cancer vaccine UV1 to olaparib plus durvalumab as maintenance therapy
compared with olaparib plus durvalumab as well as olaparib monotherapy. The primary end point is PFS, and secondary end points
include OS, overall response rate (ORR), and disease control rate.

Immune Checkpoint Inhibitors in Endometrial Cancer 

Shifting focus to the treatment of patients with endometrial cancer, the panel moderator underscored the continued difficulties in
treating patients with the disease. “Just like ovarian cancer, we’ve seen some really exciting developments in endometrial cancer,” Ritu Salani, MD, said. “[However], one of the frustrating things about endometrial cancer is that it’s one of the few cancers where we’ve seen a rising incidence and a rising mortality. [We have seen] some exciting updates [although] we were kind of complacent with [endometrial
cancer]. And I don’t mean we weren’t studying it; we just hadn’t made any progress on it.”

A major breakthrough in the endometrial cancer treatment paradigm came in the form of results from the phase 3 RUBY trial (NCT03981796), which evaluated the PD-1 inhibitor dostarlimab-gxly (Jemperli) for the treatment of patients with primary advanced stage III or IV or first recurrent endometrial cancer, including those with mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) disease.10
dMMR/MSI tumors represent 25% to 30% of all endometrial cancers. These types of endometrial cancers display increased expression of PD-L1/2, making them a potentially good target for anti–PD-1 therapy. 

Findings from RUBY, which were published in the New England Journal of Medicine, demonstrated that treatment with dostarlimab led to a benefit in terms of 24-month PFS rate in the overall population compared with placebo (HR, 0.64; 95% CI, 0.51-0.80; P < .001); there was also a numerical OS benefit observed with dostarlimab (HR, 0.64; 95% CI, 0.46-0.87; P = .0021). Notably, among patients with dMMR/MSI-H disease, the 24-month PFS benefit with dostarlimab vs placebo was even more pronounced (HR, 0.28; 95% CI, 0.16-0.50; P < .001).

“Patient-reported outcomes [presented at ASCO 2023] showed that the addition of dostarlimab was not a detriment to patients’ quality of life,” Powell said. “Some of those data are still maturing, but we are quite excited to see that the safety profile held up for the study and quality of life was maintained.”

Findings from RUBY led to the July 2023 FDA approval of dostarlimab with carboplatin and paclitaxel followed by dostarlimab monotherapy for the treatment of patients with dMMR/MSI-H primary advanced or
recurrent endometrial cancer.

In another phase 3 study (NCT03914612) published in the New
England Journal of Medicine, the PD-1 inhibitor pembrolizumab (Keytruda) in combination with chemotherapy displayed efficacy in patients with stage III or IVA or stage IVB or recurrent endometrial cancer. In the cohort of patients who were dMMR, a 12-month PFS benefit was reported with the combination compared with chemotherapy alone (HR, 0.30; 95% CI, 0.19-0.48; 

< .001). Moreover, a benefit in terms of 12-month PFS rate was also observed among patients who were mismatch repair proficient and received the PD-1 inhibitor vs those treated with chemotherapy alone (HR, 0.54; 95% CI, 0.41-0.71; 

“Much like RUBY, [this study] found an astounding benefit in the dMMR [subgroup],” Pothuri said. “This trial was designed to have 2 separate analytics groups that were powered to detect a difference in each group. The preliminary data were presented [at ASCO 2023] and showed a benefit in both subgroups. This is really practice changing and there was benefit irrespective of biomarker status.”

Outside of the updated findings from phase 3 clinical trials, investigators also presented designs for several upcoming studies in endometrial cancer during ASCO 2023. “It’s a big year for endometrial cancer,” Powell said. “We’ll [likely] see 4 more trials reporting in the next year.
There’s a lot of information we’ll be discussing, and hopefully profound benefits for our patients.”

The phase 3 DOMENICA study (NCT05201547) will examine the benefits of substituting anti–PD-1 maintenance immunotherapy for standard chemotherapy in patients with endometrial cancer. Anti–PD-1 agents have displayed promising results as monotherapy and in combination with chemotherapy in patients with dMMR/MSI-H endometrial cancer. DOMENICA aims to answer whether anti–PD-1 therapy alone possesses superior efficacy vs chemotherapy, in which case firstline patients with advanced/relapsed dMMR/ MSI-H disease could be deescalated to prevent chemotherapy-related toxicities.

The study will enroll patients with advanced/metastatic stage IIIA to IIIC2, stage IV, or relapsed dMMR endometrial cancer. Patients will be randomly assigned 1:1 to receive either dostarlimab monotherapy or chemotherapy. Crossover between the 2 arms is allowed at progression. The primary end point is PFS, with OS representing a key secondary objective.

In the phase 2 GY012 trial (NCT03660826), investigators are attempting to evaluate multiple novel drug combinations. GY012 is the first platform
study in endometrial cancer. Investigators presented the design of the second set of arms during ASCO 2023. Findings from the first set
established improved PFS for the combination of olaparib plus cediranib over cediranib monotherapy; however, they did not meet prespecified
statistical significance.

Patients will be randomly assigned 1:1:1:1 to receive cediranib monotherapy, olaparib plus capivasertib, olaparib plus durvalumab, or an
alternative dosing schedule of cediranib plus durvalumab. Eligible patients must have recurrent, metastatic, or persistent endometrial cancer and have received at least 1 prior line of chemotherapy. The primary end point is PFS, and secondary end points include OS, ORR, and safety.

Finally, another phase 2 trial (NCT03617679) is aiming to replicate the successes observed with PARP inhibitors in 

 mutations are not common in endometrial cancer, but loss of function of the tumor-suppressor gene PTEN has been reported
in more than 80% of patients with endometrial cancer. Preclinical data have shown that endometrial cancer cell lines with PTEN loss
of function are sensitive to PARP inhibition. Moreover, this sensitivity to PARP inhibition in PTEN loss of function is independent of microsatellite
instability status.

Patients with metastatic/recurrent endometrial cancer with a CR or PR following their most recent therapy will be randomly assigned 1:1 to receive the PARP inhibitor rucaparib (Rubraca) or placebo. The primary end point is PFS, with OS, ORR, and safety and tolerability representing
secondary end points. As of June 2023, 79 patients were enrolled in the study.

“All the upcoming ideas and landscape changes are going to be really instrumental,” Salani said. “Even though we started off [this discussion]
talking about the increasing incidence and mortality [of endometrial cancer], we are going to hopefully start seeing a real impact from the therapies and treatments that we’ve discussed today. And we’re not being complacent, we’re continuing to push forward to identify new needs and gaps and address those as quickly and as thoroughly
as possible.”

Recent Developments in Ovarian and Endometrial Cancers Stir Excitement Among Clinicians

It is difficult to contemplate a health care environment in this country with a fundamental approach to the development of new therapeutic strategies that is not firmly based on well-conceived, well-designed, and well-conducted clinical trials with results that are reported in peer-reviewed literature.

Further, it is widely and reasonably acknowledged that the highest level of evidence in the clinical trials arena is provided through outcomes obtained in phase 3 randomized clinical trials. These trials compare an existing standard of care at a given point in time in a specific clinical setting to 1 or more alternatives believed to potentially be superior (based on the objective evaluation of earlier research efforts) to this standard. Historically it has been the outcomes of such trials that formed the foundation of scientifically based modern medicine.

Throughout multiple decades, cancer care has been, and will surely continue to be, the poster child for the success of this clinical investigative paradigm. Older approaches to disease management in particular settings are potentially discarded, modified, or supplemented based on the favorable results of new generations of innovative studies published in high-impact general medical or oncology journals.

Unfortunately, the lofty rhetoric—as truthful as it may be in the aggregate and evaluated over a relatively long period of time—may mask certain realities that challenge the simplicity of the language used to communicate the clinical meaning and declared objectivity of outcomes reported to scientific and clinical colleagues, policy makers, payers, patients, and families.

Frequently employed buzzwords in research manuscripts and high-impact journal commentaries include such terms as 

 Consider, for example, the term overall survival (OS) as used to describe the primary end point of a phase 3 oncology study comparing an established regimen of drug A plus drug B to a novel strategy of drug A plus drug C, an investigative agent not yet approved by the FDA for commercial sale.

There will be no debate that a major—even the main—goal of a therapeutic regimen for patients with advanced cancer would be to meaningfully improve their survival, if not to ultimately achieve the state of cure for the disease. This specific consideration justifies the use of OS as a primary end point within a randomized trial’s statistical design.

But now we turn away from the quite understandable rhetoric and deal with the reality of clinical investigation and mandatory ethical care, at least in the United States.

It would be possible to use a number of known experiences to emphasize the changing nature of OS as a valid study end point, but for this exercise, this commentator has selected his area of clinical and research interest: epithelial ovarian cancer.

In 1996, the gynecologic oncology world was upended following the publication of findings from a landmark study revealing that first-line administration of cisplatin (drug A) plus paclitaxel (the experimental drug C) in advanced disease improved both progression-free survival (PFS; median 18 months vs 13 months; 

< .001) and OS (median 38 months vs 24 months; 

 < .001) compared with cisplatin (drug A) plus cyclophosphamide (drug B), the standard-of-care trial control arm.

Because it was recognized at the time this study was initiated that second-line chemotherapy after the delivery of a platinum agent in advanced ovarian cancer was, at best, of marginal utility, it was not surprising that improved PFS, a so-called surrogate end point, would quite easily translate into improved OS, the declared true measure of clinical benefit.

However, the rarely discussed Gynecologic Oncology Group trial that immediately followed the landmark study—conducted by the same group of clinical investigators in an essentially identical patient population in terms of eligibility and ineligibility criteria comparing initial treatment with single-agent cisplatin (drug A) vs single-agent paclitaxel (drug B) vs the combination of cisplatin plus paclitaxel—unfortunately revealed a strikingly different survival outcome. Although patients randomly assigned to single-agent cisplatin experienced a significantly superior PFS (

 < .001) compared with single-agent paclitaxel, there was no difference in OS between the treatment groups (

Why did this study totally fail to substantiate the utility of PFS as a surrogate for OS? Did the trial’s results indicate there was no survival impact associated with the new drug paclitaxel? Was the prior study simply wrong in its conclusions?

Of course, the answers to these questions are quite clear, and they have nothing to do with the strange labeling of PFS as a surrogate or with any difficulty interpreting outstanding clinical investigation. In this second trial, patients initially receiving paclitaxel who failed to respond or progressed following an initial response were offered the opportunity, assuming medically appropriate to do so, to cross over to receive cisplatin. As a result, patients randomly assigned to what was found to be the inferior treatment regimen were subsequently provided the opportunity, 

, to benefit from the antineoplastic effects of the superior single agent.

The critical point to be made here—and the response to academics and others who continue to focus on OS as an end point—is that the delivery of effective treatment after a patient has been removed from a clinical trial may have a meaningful impact on their ultimate survival outcome. In fact, as observed with the experience above, the failure to see a trial-associated difference in OS was 

 an indication of failure to demonstrate the superiority of one treatment regimen vs another, but rather evidence that all study patient groups ultimately benefited from the multiple therapeutic strategies administered along the continuum of their care journeys.

With increasingly effective second-line or later strategies available in the oncologist’s armamentarium after a patient ends participation in a therapeutic trial, it is reasonable to seriously challenge the concept that OS should continue to be considered the gold standard metric in a randomized trial.

Finally, it is relevant to briefly acknowledge that the vocabulary employed to interpret clinical trial outcomes is frequently linked in academic and policy discussions to the prices set by manufacturers of newly approved patent-protected pharmaceutical agents. Some have vigorously challenged favorable regulatory decisions for increasingly expensive anticancer agents that have been shown in studies to “improve PFS in the absence of statistically significant differences in OS.”

It is surely time for society to directly address the critical nature of our current unsustainable oncology pharmaceutical marketplace, and it is also essential that whatever solutions are proposed and implemented do not incorporate inappropriate labeling of outcomes that negate meaningful measures of clinical benefit.

Maurie Markman, MD, is president of Medicine & Science at City of Hope, Atlanta, Chicago, Phoenix

Gyawali B, Kesselheim AS, Ross JS. The accelerated approval program for cancer drugs — finding the right balance. 

. 2023;389(11):968-971. doi:10.1056/NEJMp2306872

McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. 

. 1996; 334(1):1-6. doi:10.1056/NEJM199601043340101

Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a Gynecologic Oncology Group study. 

. 2000;18(1):106-115. doi:10.1200/JCO.18.1.106

Mathews AW. Employers’ health-plan costs to swell. 

. September 6, 2023. Accessed October 16, 2023. https://www.wsj.com/public/resources/documents/ROT8DV3i7ppUyhF6koI2-WSJNews-Paper-9-8-2023.pdf

It is time for society to address the critical nature of our current unsustainable oncology pharmaceutical marketplace, and it is also essential that whatever solutions are proposed and implemented do not incorporate inappropriate labeling of outcomes that negate meaningful measures of clinical benefit.

Vol. 24/No. 18 | Oncology Live®

Administrative Payment Tasks Could Be Causing Detrimental Effect of Treatment Delays and Nonadherence for Patients With Cancer

Prevalence of Eye Toxicities in Patients With Cancer Is Much Higher Than Previously Known

STEAP1 Offers Potential Multifunctional Target in Prostate Cancer

Recent Developments in Ovarian and Endometrial Cancers Stir Excitement Among Clinicians

Reality Takes a Back Seat to Rhetoric Used in Objective Assessments of Cancer Treatment