OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

Cancer screenings rapidly decreased during the COVID-19 pandemic as health care practices considered not urgent came to a halt. However, as of February 2023, approximately 3 years after the start of the pandemic, cancer screenings still have not reached 100% of expected rates, according to a study published in the Journal of Clinical Oncology. 

As a result of stay-at-home orders, which began to take effect in the United States in late March 2020, cancer screenings declined between 86% and 94% in March 2020 compared with prior years. Between March 15, 2020, and June 16, 2020, there were approximately 285,000 breast, 95,000 colorectal, and 40,000 cervical screenings missed. “Unfortunately, I don’t think we’ve gone back up in terms of where we were before the pandemic [with screening],” study author Electra D. Paskett, PhD, said in an interview with 

®. “The phenomena [of] ‘I missed my mammogram, it’s OK, I feel OK,’ is still continuing. In Ohio, with the state [Comprehensive] Cancer Control Plan, we have a public awareness campaign called Get Back to Basics Ohio, which focuses on encouraging residents of the state to get back to basics in cancer prevention and screening. Every month we vary it by whatever disease month or cancer month it is…we are trying to push people to get back on track.” 

Consequently, as diagnoses were less likely to occur during the pandemic and timing plays a key role in outcomes and survival, the study authors estimated that over the course of the next 10 years, approximately 10,000 excess deaths from breast and colorectal cancer swill be reported throughout the United States.

"There are some factors that are different for each of [the screenings], but it’s time and during the pandemic, people didn’t go out and didn’t go to medical facilities and so they got out of the habit of getting their regular screenings and then everything was okay,” said Paskett, who is director of the Division of Cancer Prevention and Control at The Ohio State University College of Medicine, the Marion N. Rowley Chair in Cancer Research, and founding director of the Center for Cancer Health Equity at The Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus. 

Approximately 3.9 million breast cancer, 3.8 million colorectal cancer, and 1.6 million prostate cancer screenings were missed in the United States because of the pandemic, leading to decreases in diagnoses. As shown in another study by the Massachusetts General Brigham, between March 2020 and June 2020 decreases in diagnoses were 19% to 78%. 

“[Patients may have] said, ‘I don’t need to get my mammogram because I feel OK,’ ” Paskett said. “But the point of a screening test is that you get it when you feel OK because when cancer starts it doesn’t [necessarily] impact how you feel. A lot of times you can’t detect an early breast cancer and that’s the point of mammography; to find an early cancer where it can be treated successfully and with less intense methods than later. It’s the same for the other cancers, too. “It’s important for health care providers to encourage their patients to get back on track and get screened,” Paskett said. “We know that recommendation from a health care provider is the No. 1 reason that patients do anything, whether it’s get a mammogram, stop smoking, getting an human papillomavirus [HPV] vaccination, [etc], so providers need to be cued to do that.”

The study authors were part of a National Cancer Institute consortium tasked with looking at the impact of COVID-19 on cancer screening, which included preventive and screening behaviors. Adult patients from Ohio (95.8%) and Indiana (4.2%) who had agreed to be recontacted from previous studies were included in this study. 

“The [individuals] we reached out to were either part of a prior study that we had conducted or were part of The James Total Cancer Care [Program] and then we invited caregivers of those participants in James Total Cancer Care if they wanted to participate,” Paskett said. “To get a diverse sample, we used community snowballing techniques so that we have community help workers that work in minority underserved communities, and they could go and recruit participants and then snowball from there.” 

The analysis solely included age and sex ranges that were appropriate for each screening: mammogram (women; aged 40-74 years), Papanicolaou test (women; aged 21-65 years), HPV test (women; aged 30-65 years), and colonoscopy/stool blood test (men and women; aged 50-75 years). The average age was 57.3 years, 75% were women, 89.1% were non-Hispanic White, 55.5% had a college or higher degree, 75.2% were married, and one-third of patients lived in rural areas. 

Among 7115 individuals, 60% had a screening planned between March 2020 and December 2020, but 11% to 36% delayed their screenings because of the pandemic. Tests that were planned but later delayed included a mammogram (n = 732 of 2986), Papanicolaou test (n = 448 of 1651), HPV (n = 59 of 220), stool blood test (n = 44 of 388), and a colonoscopy (n = 304 of 840).

When compared with those who did not plan a cancer screening (n = 2849; 40%), participants who did plan a screening (n = 4266; 60%) were younger, female, received higher education, had private insurance, and lived in a rural area (P < .001). They were also more likely to be widowed/separated/divorced and had a higher income. Study authors wrote that “age, race/ ethnicity, education, and health insurance were associated with delays in cancer screenings (all P < .05).” 

Paskett noted the demographics are reflective of populations that would actively pursue routine screening vs those that would not.

When examining mammogram data, older patients were less likely to delay a planned screening (OR, 0.81; 95% CI, 0.72-0.92) and non-Hispanic Black women had lower odds of delaying the test than non-Hispanic White women (OR, 0.60; 95% CI, 0.39-0.94). Women with at most a high school education were less likely to delay a mammogram than those who had received higher education, as follows: women with some college/associate degree (OR, 1.45; 95% CI, 1.07-1.99), college degree (OR, 1.40; 95% CI, 1.03-1.92), or graduate degree (OR, 1.58; 95% CI, 1.16-2.17) were more likely to delay the screening. Data also showed that participants from Indiana had increased odds of delaying a mammogram compared with those who resided in Ohio (OR, 1.72; 95% CI, 1.21-2.45). 

However, an age stratification demonstrated that the only factors associated with lower odds of mammogram delays for women aged 40 to 49 years were race and ethnicity (with non-Hispanic Black women less likely to delay screening). Factors for women aged 50 to 74 years associated with higher odds of a mammogram delay were a younger age (40 to 49 years), had higher education, and resided in Indiana. No significant mammogram delays were associated with marital status, health insurance status, and rural/metropolitan residence.

Patients of older age were less likely to delay a planned Papanicolaou test (OR, 0.89; 95% CI, 0.79-1.00), and women with private health insurance (OR, 0.37; 95% CI, 0.18-0.74) or combined public and private insurance (OR, 0.44; 95% CI, 0.19-1.00) also had lower odds of delaying the test compared with those without health insurance. 

Marital status and rural/urban residence were not associated with mammogram delays; however, education and race were factors in having higher odds of delaying a test. Compared with non-Hispanic White women, Hispanic participants (OR, 2.46; 95% CI, 1.34-4.55) and those who identified as other races (OR, 2.38; 95% CI, 1.41-4.02) were more likely to delay a Papanicolaou test. When evaluating education, participants with an associate degree or some college had higher odds of delaying the test compared with those with high school or less education (OR, 1.53; 95% CI, 1.02-2.31).

There was no observed correlation with age, sex, race/ethnicity, health insurance, and rural/urban residence in delaying a colonoscopy. No factors were found to be associated with delays in stool blood tests and they were among the lowest of all the screening tests delayed, at 11.3%. 

Individuals with a graduate-level degree had increased odds of delaying planned colonoscopies compared with those with a high school degree or less education (OR, 2.09; 95% CI, 1.23-3.56). There were lower odds for participants who were widowed, separated, or divorced than single individuals in delaying a planned colonoscopy (OR, 0.48; 95% CI, 0.25-0.92). 

“Fecal immunochemical tests [FITs] have been validated and they have been shown to reduce death from colon cancer,” Paskett said. “During the pandemic we pushed the clinics we work with to focus on FIT tests because they could call up a patient, explain it, and then if the patient was willing to get it, they could do it in their home and then mail it back. They didn’t have to leave their home and come to a medical facility. We did find some increased use of FIT testing during the pandemic because of that. That’s very good unless you are very high risk for colon cancer; a FIT test is fine as long as you get it every year.” 

Investigators found that older patients had lower odds of delaying a planned HPV test (OR, 0.65; 95% CI, 0.46-0.93) and those who identified as other race-ethnicity had higher odds of delaying the HPV test compared with non-Hispanic White individuals (OR, 5.37; 95% CI, 1.44-19.97).

Ohio and Indiana are both Medicaid expansion states, and 14.1% of patients had public insurance, 53.7% of patients had private health, and 29.9% had public and private insurance. Patients with public insurance did not experience any differences in screening delays, which may be due to Medicaid expansion. For patients who do not live in states with Medicaid expansion, there are other options that may encourage screening. 

“The Breast and Cervical Cancer Early Detection Program is operational in all states and if women qualified by income they can go there and get breast and cervical screening as well as HPV vaccination, and then if [they receive a] diagnosis [of] an abnormality, they can get a diagnostic work-up,” Paskett explained. “Those plans vary a little state by state, but most of the states have those funding and that’s where I would suggest [visiting] other than going to a free clinic.” 

Limitations of the study were that it was not nationally representative, and the investigators did not have access to medical records. “We had a biased sample, in terms of who responded to our request,” Paskett said. “It was a cross-sectional design, so we didn’t follow [individuals] longitudinally. It was also self-reported data, which could have some recall bias; [participants] sometimes think that they had their test more recent than they did.”

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Oncology Live®

Cancer screenings rapidly decreased during the COVID-19 pandemic as health care practices considered not urgent came to a halt.

Delays in Cancer Screenings Due to COVID-19  May Result in Trend Toward Excess Deaths

Chimeric antigen receptors (CAR) T cells represent a practice-changing therapy for patients with multiple myeloma who have triple-class refractory (immunomodulatory drug, proteasome, and anti-CD38) disease. When conventional therapy is used for patients with this condition, response rates are approximately 30% and survival is relatively short at only 1 year.

 In contrast, the first CAR T product to reach the market for myeloma, idecabtagene vicleucel (Abecma; ide-cel), manufactured by Bristol Myers Squibb (BMS), resulted in an 80% response rate at the approved cell dose with overall survival of 19 months.

 The second CAR T product, ciltacabtagene autoleucel (Carvykti; cilta-cel), manufactured by Janssen, showed a 98% response rate with approximately 60% of patients free of disease progression at 2 years.

What makes these statistics even more remarkable is that despite being heavily pretreated with a median of 6 lines of prior therapy, patients treated with cilta-cel achieved a higher complete response rate than those who just received a diagnosis and were treated sequentially with a 4-drug induction therapy, autologous transplant, and consolidation,

 clearly establishing cilta-cel as the single most effective treatment for patients with multiple myeloma.

Significantly, the one-and-done schedule of CAR T products also gives patients an extended drug holiday. This break is the first for many since initially receiving a cancer diagnosis.

Although the first FDA approval for CAR T-cell therapy in multiple myeloma was 2 years ago, unfortunately, the treatment remains out of reach for too many patients. In one study, the cumulative incidence of receiving ide-cel was 18% at 6 months, and only 40% of patients received the therapy at 12 months compared with 1 in 4 patients dying while waiting for CAR T.

 In a second study, 17 high-volume centers in the United States experienced challenges with patient selection criteria, allocation of CAR T products, and wait times. At the time of this survey, a median of 1 slot per month was allocated per center, the average waiting list was 20 patients per month, and patients had to wait approximately 6 months before cell collection. The percentage of patients that received CAR T-cell therapy was similar (25%) to the number of patients who died waiting for treatment.

Both studies likely underestimate the number of individuals who could have benefited from treatment. In part, this is because many patients in the United States do not have access to a treatment center where they could be placed on a waiting list. And, as has been seen with so many other medical-related issues, groups that have been economically and socially marginalized continue to be disproportionately affected.

For example, a recent study showed that only 36% of Black patients live in a county with an open CAR T clinical trial.

 Further, in Mississippi and Louisiana, 2 states with the highest population of Black individuals—a group that is twice as likely to die from multiple myeloma compared with White patients—there are no centers that administer ide-cel or cilta-cel. For a patient living in New Orleans, Louisiana, the closest designated CAR T-cell center is more than 300 miles away.

There are multiple factors contributing to the inability to deliver CAR T-cell therapy (

). Chief among them are issues with supply of the viral vector required to produce CAR T cells. The stringent quality control required for commercial products is also a major challenge. Unfortunately, neither barrier to care is likely to improve in the short term.

BMS announced that it does not plan to add any more sites to deliver ide-cel in 2023. Similarly, fourth-quarter sales of cilta-cel did not increase in 2022, suggesting that Janssen may be unable to scale up to meet high demand.

 Based on recent studies showing the superiority of CAR T vs standard therapy after 1 to 3 lines of treatment, one of which has been published,

 both BMS and Janssen seem poised to apply for FDA approval for CAR T therapy for patients after 1 to 3 lines of therapy, a much greater population of patients with multiple myeloma. As both companies have recently increased slot allocation without increasing treatment centers, access will remain challenging for underserved communities.

It remains unexplained why the vector/manufacturing issue has been so difficult for the B-cell maturation antigen (BCMA) CAR T treatments compared with the CAR T products used in lymphoma and B-cell lymphoblastic leukemia where patients’ blood can be collected and harvested for T cells within a week of referral to a cancer center. The ability to promptly deliver CAR T for lymphoma and acute lymphoblastic leukemia proves that individualized patient manufacturing is not an insurmountable barrier.

Can Bispecific Antibodies Remedy Issues With BCMA CAR T Therapy? 

Teclistamab (Tecvayli) is one of several bispecific BCMA-directed CD3 T-cell engagers, and has recently been approved by the FDA based on the results of the phase 1 MajesTEC-1 (NCT04557098) study that showed an overall response rate of 63%, with nearly all of the responding patients achieving a very good partial response or better.

 Responses were rapid, and as a result, a patient’s disease response trajectory was apparent in 2 months or less. In addition, for patients who responded to therapy, the duration of response (18.4 months) exceeded that reported for ide-cel.

As teclistamab and other bispecific antibodies are available off the shelf (and therefore on demand) and are associated with much less severe cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome than the CAR T products, these products can be incorporated more easily in community settings and may well replace CAR T because of lack of access for the latter.

Although there is research that has found patients who progress on 1 T-cell redirecting therapy can respond to a second T-cell redirecting therapy against a different target antigen,

 preliminary evidence suggests that response rates and duration are decreased in patients treated with BCMA CAR T after prior antiBCMA treatment.

From a theoretical point of view, and analogous to B-cell lymphoma, it would be preferable to sequence a bispecific antibody with a different target than the CAR T and there are several bispecific antibodies against non-BCMA targets moving toward approval.

At present, patients with rapid disease progression are likely to receive a BCMA bispecific antibody rather than CAR T, possibly jeopardizing their ability to respond to later CAR T treatment.

Strategies to Facilitate Equitable Distribution of CAR T

As in solid organ transplant, where organ allocation is based on need, a similar strategy could be used for distributing CAR T-cell therapy for patients with multiple myeloma. At present, there are more than 200 Foundation for the Accreditation of Cellular Therapy (FACT)approved centers in the United States capable of administering CAR T cells. The restriction of CAR T-cell therapy to select, high-profile centers, some within miles of each other, when other states do not have any is indefensible.

FACT-approved centers should be geographically organized to cover a maximum number of patients with monthly virtual meetings. This way, CAR T products can become available to individuals most in need and who likely have fewer treatment options. Tumor board type allocation of treatment nearer to the patient’s home would certainly be more equitable than awarding treatment slots based on the number of patients entered onto the manufacturer’s protocol, a strategy that lacks transparency and accountability.

In this regard, perhaps the greatest value of high-volume myeloma centers is to offer treatments in clinical trials that cannot be offered in the community, such as non-BCMA bispecific antibodies, non-BCMA CAR T-cell therapies, next-generation cereblon E3 ligase modulators,

 and other new exciting agents such as modakafusp alfa, a fusion protein that targets interferon, the proinflammatory hormone used to treat viral infections and other cancers to cells that have the surface marker, CD38.

 Such strategies could at least temporize worsening disease without jeopardizing the subsequent response to CAR T therapy.

CAR T-cell therapy is a hugely important therapeutic option for patients with multiple myeloma, but if this treatment is not accessible, it may as well not exist.

We need to mitigate deadly disparities in cancer care and start by rethinking how designated centers are assigned CAR T products. By establishing a comprehensive and equitable way to obtain and administer CAR T, we can start eliminating pervasive inequities. Without establishing accountability for the pharmaceutical industry and others, access to lifesaving treatments will become even harder. Access to a lifesaving treatment cannot just be a matter of being in the right place at the right time.

Mendel Goldfinger, MD, is a medical oncologist at Montefiore Einstein Cancer Center and assistant professor of medicine at Albert Einstein College of Medicine in the Bronx, New York.

Nishi Shah, MD, is an attending physician at Montefiore Einstein Cancer Center and an assistant professor at Albert Einstein College of Medicine.

Dennis L. Cooper, MD, is chief of Bone Marrow Transplantation at Montefiore Einstein Cancer Center and professor of medicine at Albert Einstein College of Medicine.

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Kourelis T, Bansal R, Berdeja J, et al. Ethical challenges with multiple myeloma BCMA chimeric antigen receptor T cell slot allocation: a multi-institution experience. 

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Alqazaqi R, Schinke C, Thanendrarajan S, et al. Geographic and racial disparities in access to chimeric antigen receptor-T cells and bispecific antibodies trials for multiple myeloma. 

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Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. 

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Mouhieddine TH, Van Oekelen O, Melnekoff DT, et al. Sequencing T-cell redirection therapies leads to deep and durable responses in relapsed/refractory myeloma patients. 

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Watson ER, Novick S, Matyskiela ME, et al. Molecular glue CELMoD compounds are regulators of cereblon conformation. 

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Vogl DT, Atrash S, Holstein SA, et al. Final results from the first-in-human phase 1/2 study of modakafusp alfa, an immune-targeting attenuated cytokine, in patients (pts) with relapsed/refractory multiple myeloma (RRMM). 

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Although the first FDA approval for CAR T-cell therapy in multiple myeloma was 2 years ago, unfortunately, the treatment remains out of reach for too many patients.

CAR T-Cell Therapy for Multiple Myeloma: Eliminating Disparities Through Accountability

Tumors exhibiting homologous recombination deficiency (HRD) have traditionally been treated with targeted therapies against 

; however, roadblocks such as PARP inhibitor resistance have resulted in an unmet need and uncertain optimal identification concerning patients who would elicit the most benefit from HRD-directed therapies. Data on emerging therapies and early investigative efforts to uncover the root of resistance were presented during the 2022 San Antonio Breast Cancer Symposium (SABCS). Findings from these studies showed that a deeper understanding of genetics and a sharper focus on PARP1 signal actionable paths forward, but further work remains to more effectively target genes involved with HRD.

HRD is defined as the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Deficiencies in the HRR pathway have been identified in multiple tumor types, including breast, ovarian, and prostate cancers. Affected HRR genes associated with the HRD phenotype include 

 have been strongly linked with HRD, and the development of HRD can contribute to the growth of breast cancer. However, there are patients with 

 wild-type breast cancer that also displays HRD. Chemotherapy-based therapeutic strategies and PARP inhibitors have shown some efficacy in targeting the HRD, with the latter gaining significant popularity in the space because of the lack of toxicity that typically accompanies treatment with chemotherapy.

Two PARP inhibitors are approved by the FDA for patients with breast cancer: talazoparib (Talzenna) and olaparib (Lynparza). On October 16, 2018, the FDA approved talazoparib for patients with deleterious or suspected deleterious germline 

-mutated, HER2-negative locally advanced or metastatic breast cancer. On March 11, 2022, the agency approved olaparib for the adjuvant treatment of adult patients with deleterious or suspected deleterious germline 

-mutated, HER2-negative, high-risk earlystage breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy.

Several mechanisms of resistance to PARP inhibition can develop, such as the restoration of homologous recombination proficiency, the transition to alternate DNA repair mechanisms, decreased PARP expression and binding, and secondary mutations in homologous recombination–related genes. All these mechanisms can greatly reduce or even eliminate the therapeutic impact of PARP inhibitors.

Identifying and Overcoming the Mechanisms of PARP Inhibitor Resistance

The homologous recombination and nonhomologous end joining (NHEJ) DNA repair pathways are 2 areas in which double strand breaks can be addressed; the former is associated with PARP inhibition.1 Repairing double-strand breaks is largely based on the functionality of the DNA repair proteins BRCA1 and 53BP1.

 If the doublestrand break is not resected, 53BP1 is functional and is repaired by NHEJ. If BRCA1 is functional, the double-strand break is resected, which has been identified as a prelude to homologous recombination.

However, cells may also use another pathway, θ-mediated end joining, also known as microhomology-mediated end joining.

 During the 2022 SABCS, Chris Lord, MD, director of the Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research in London, England, cited how identifying resistance mechanisms, such as the loss of 53BP1, is the first step to developing ways to target the restoration of homologous recombination. He noted that polymerase theta (Polθ) represents one such route, using the agents ART558 and novobiocin, which are inhibitors of the polymerase activity not the ATP activity of Polθ.

The agent elicited synthetic lethality of BRCA1 activity and synergized with PARP inhibitors, Lord explained.

 Additionally, it allowed for the targeting of 

-mutant PARP inhibitor–resistant tumor cells that lost 53BP1 or the Shieldin complex (SHD3, SHD2, SHD1). Importantly, Lord noted, from a clinical perspective, this does not work in the setting of a reversion mutation if there is a preexisting reversion mutation as the mutation; this is because the mutation, in addition to causing resistance to a PARP inhibitor, also causes resistance to a Polθ inhibitor.

Overexpression of Polθ in some types of breast and ovarian cancers also displaying HRD makes it an intriguing treatment target as inhibition. ART558 is a potent and specific small molecule inhibitor of Polθ that has displayed synthetic lethality and a combinatorial effect with olaparib in isogenic models of 

 deficiency and in tumor cell lines with endogenous pathogenic 

Another Polθ inhibitor, the first-in-class antibiotic novobiocin, has shown selective killing of HRD tumor cells both in vitro and in vivo. The agent directly binds to the Polθ ATPase domain, inhibiting its ATPase activity, and ultimately phenocopies Polθ depletion.

After identifying novobiocin as a Polθ inhibitor via a small molecule screen, investigators evaluated its specificity and found that novobiocin-conjugated beads pulled down the purified ATPase domain of POLθ, without affecting purified SMARCAL1, CHD1, BLM, or RAD51. Additionally, they found that in a genetically engineered mouse model of triple-negative breast cancer (TNBC), novobiocin-treated tumors were significantly smaller than vehicle-treated tumors following a week of treatment. Novobiocin was shown to prolong the median overall survival of the tumor-bearing mice vs vehicle at 29 days vs 10 days, respectively. The safety of the agent had already been validated in previous anticancer clinical trials.

Study authors also noted that novobiocin showed synergy with PARP inhibitors. Notably, in mouse models with HRD DF83 ovarian cancer that received novobiocin in combination with olaparib, complete tumor regression was reported with few tumor cells remaining detectable with bioluminescence imaging. Additionally, in a PARP inhibitor-resistant mouse model, treatment with novobiocin monotherapy substantially reduced tumor growth, with no response being observed with olaparib monotherapy. The combination of the 2 agents was even more effective with tumor regression being reported in the first 2 weeks.

Investigators concluded that Polθ expression is a predictive biomarker for novobiocin sensitivity and that many tumors that have developed resistance to PARP inhibition are likely to remain sensitive to novobiocin, depending on their mechanism of resistance.

In addition to overcoming PARP resistance, novel therapies are being developed and that have shown promise in the treatment of patients with HRD breast cancer. In another presentation at the 2022 SABCS, Andrew Tutt, MB ChB, PhD, MRCP, FRCR, also of the Institute of Cancer Research, reviewed data for ATR inhibitors and PARP inhibitors that are selective for PARP1.

Following preclinical study showing that ATR inhibition enhanced efficacy in models with HRD and/or PARP-inhibitor resistance, investigators initiated the phase 2 VIOLETTE study (NCT03330847). VIOLETTE enrolled patients with TNBC and randomly assigned them 1:1:1 to receive either olaparib 300 mg twice daily for a 28-day cycle (n = 150); olaparib 300 mg twice daily for a 28-day cycle plus the ATR inhibitor ceralasertib at a dose of 160 mg daily on days 1 through 7 (n = 150); or olaparib 200 mg daily via a continuous 21-day cycle in combination with the WEE1 inhibitor adavosertib. Patients needed to have previously undergone 1 or 2 lines of metastatic breast cancerdirected chemotherapy to be eligible for the study.

The primary end point was progression-free survival (PFS). Key secondary end points included objective response rate (ORR), duration of response (DOR), change in target lesion size, safety, and tolerability.

Findings from the trial showed that the median PFS was 5.3 months (90% CI, 3.7-5.5) in the ceralasertib arm vs 3.6 months (90% CI, 2.9-5.4) in the monotherapy arm (HR, 0.79; 90% CI, 0.59-1.04; 

 = .1822). The ORR was 28.6% vs 21.1%, respectively (OR, 1.50; 90% CI, 0.90-2.51; 

However, patients with non–HRR-mutant disease who received monotherapy (n = 51) experienced an ORR of only 3.9% compared with 15.4% among 52 patients in this subgroup who received the ceralasertib combination (OR, 4.45; 1.30-21.20; 

 = .0425). Median DOR was also significantly improved in this subgroup, at 11.4 months (90% CI, 7.1-15.7) vs 24.1 months (90% CI, 15.1-24.1), respectively. Tutt mentioned that these findings point to patients with non–HRR-mutant disease as a possible signal subgroup for this treatment regimen.

Tutt noted that early stoppage of the trial limited interpretation of the results. Additionally, the dose of ceralasertib used in the study was lower than that being examined in monotherapy studies. He also emphasized that VIOLETTE was primarily focused on PARP inhibitor–naïve patients to test ATR dependence and the efficacy of ceralasertib. Study authors also noted that further investigation was warranted for ceralasertib plus olaparib among patients who relapse after or while receiving PARP inhibitors.

PARP1 inhibition is another novel treatment approach that is piquing the interest of clinicians who are treating patients with HRD-positive tumors. Approved PARP inhibitors trap both PARP1 and PARP2. However, PARP2 has been shown to be more important for bone marrow function than PARP1. The next generation of PARP1 inhibitors must be able to reduce some of the toxicities of standard-of-care PARP inhibitor monotherapies without significantly reducing efficacy and enable tolerable combination regimen options with chemotherapy or ATR inhibitors.

In the ongoing phase 1/2a PETRA trial (NCT04644068) trial, investigators are examining the safety and preliminary efficacy of AZD5305 in patients with advanced breast, ovarian, prostate, or pancreatic cancer harboring 

 mutations. AZD5305 is a potent, highly selective PARP1 inhibitor that is 500-fold more selective for PARP1 than PARP2 and is also very selective for HRD.

 The agent exhibited superior preclinical tolerability, target engagement, and efficacy compared with traditional first-generation PARP inhibitors that target both PARP1 and PARP2.

Prior treatment with a PARP inhibitor and/or chemotherapy was permitted as part of the trial. The primary end point was safety. Secondary end points included pharmacokinetics, pharmacodynamics, and ORR.

At the November 17, 2021, data cutoff patients were treated with AZD5305 at a dose ranging from 10 to 90 mg daily (n = 46). Responses were observed starting at the lowest dose levels; efficacy-evaluable patients (n = 25) experienced an ORR of 28%, including responses in patients who were PARP inhibitor or platinum resistant. Thirteen of 22 RECIST-measurable patients had stable disease or a partial response up to 51 weeks. The agent was also found to be well tolerated across dose levels and no dose-limiting toxicities were reported.

Lord C. Mechanisms of sensitivity and resistance to HRD targeting agents in breast cancer – PARPi and beyond. Abstract presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

d’Andrea A. Pol-theta inhibitors in HRD tumors. Abstract presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

Tutt A. ATR inhibitors and PARP1 selective PARP inhibitors. Abstract presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

Stewart MD, Merino Vega D, Arend RC, et al. Homologous recombination deficiency: concepts, definitions, and assays.

. 2022;27(3):167-174. doi:10.1093/oncolo/oyab053

denBrok WD, Schrader KA, Sun S, et al. Homologous recombination deficiency in breast cancer: a clinical review. 

FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. FDA. Updated December 14, 2018. Accessed February 22, 2023. https://wayback.archive-it.org/7993/20201222064856/https:/www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-gbrcam-her2-negative-locally-advanced-or-metastatic-breast-cancer 

FDA approves olaparib for adjuvant treatment of high-risk early breast cancer. FDA. March 11, 2022. Accessed February 22, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-adjuvant-treatment-high-risk-early-breast-cancer 

Mekonnen N, Yang H, Shin YK. Homologous recombination deficiency in ovarian, breast, colorectal, pancreatic, non–small cell lung and prostate cancers, and the mechanisms of resistance to PARP inhibitors. 

. 2022;12:880643. doi:10.3389/fonc.2022.880643

Li H, Liu ZY, Wu N, Chen YC, Cheng Q, Wang J. PARP inhibitor resistance: the underlying mechanisms and clinical implications. 

. 2020;19(1):107. doi:10.1186/s12943-020-01227-0

Zatreanu D, Robinson HMR, Alkhatib O, et al. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. 

. 2021;12(1):3636.doi:10.1038/s41467-021-23463-8

Zhou J, Gelot C, Pantelidou C, et al. A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. 

. 2021;2(6):598-610. doi:10.1038/s43018-021-00203-x

Tutt A, Nowecki Z, Szoszkiewicz R, et al. VIOLETTE: randomisedphase 2 study of olaparib (ola) +ceralasertib (cer) oradavosertib (ada) vs ola alone in patients (pts) with metastatic triple-negative breast cancer (mTNBC). 

. 2022;33(suppl 3):S194-S195. doi:10.1016/j.annonc.2022.03.180

Yap TA, Im SA, Schram AM, et al. PETRA: first in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations. 

. 2022;82(suppl 12):CT007. doi:10.1158/1538-7445.AM2022-CT007

Roadblocks such as PARP inhibitor resistance have resulted in an unmet need and uncertain optimal identification concerning patients who would elicit the most benefit from homologous recombination deficiency–directed therapies. 

HRD-Directed Therapeutics Hold Potential in Breast Cancer, But Challenges Remain

The first-line standard of care for patients with HER2-postive metastatic breast cancer has long been held by the combination of pertuzumab (Perjeta), trastuzumab (Herceptin), and a taxane established with the publication of data from the CLEOPATRA trial (NCT00567190).

“This regimen has really landed very solidly in that space and has yet to be dethroned and for a good worthwhile reason,” Virginia F. Borges, MD, said in a recent 

. Final results from the CLEOPATRA trial demonstrated significant improvement in overall survival (OS), at 56.5 months with the pertuzumab combination compared with 40.8 months in the placebo combination group.

 “Fast forward to 2022, [and] the only thing I’ve incorporated into my practice around those original data is some flexibility on what my choice of taxane might be,” Borges said. Despite the long-held success in the frontline, most patients eventually experience disease progression, and the demand for effective second- and third-line options for patients with HER2-positive, metastatic disease have recently undergone a shake-up. “It’s wonderful how the metastatic setting has become a little bit of an embarrassment of riches in comparison with where we were a decade or 2 ago,” Borges said. 

Joining Borges, a panel of breast cancer experts discussed the recent updates to the second-line setting with the incorporation of fam-trastuzumab deruxtecan-nxki (Enhertu), as well as the successes and challenges seen in the third- and later-line arena for these patients.

In patients who fail to respond to first-line therapy, the preferred second-line treatment for HER2-positive metastatic breast cancer is to use the antibody-drug conjugate (ADC), trastuzumab deruxtecan based on findings from the DESTINYBreast03 trial (NCT03529110).

 “I think most, if not all of us, would agree that trastuzumab deruxtecan is really the current standard of care in that second-line space for these patients,” Maryam Lustberg, MD, MPH, said. 

The phase 3, open-label trial evaluated the safety and efficacy of trastuzumab deruxtecan compared with the reigning standard-of-care ado-trastuzumab emtansine (Kadcyla; T-DM1) in 524 patients who had disease progression following treatment with trastuzumab and/or taxane therapy.

 Updated findings presented at the 2022 San Antonio Breast Cancer Symposium (SABCS) and published in the 

 supported the sustained progression-free survival (PFS) benefit of the regimen from the original publication and demonstrated an OS advantage with trastuzumab deruxtecan.

The primary end point of median PFS was 28.8 months (95% CI, 22.4-37.9) in the trastuzumab deruxtecan arm (n = 261) vs 6.8 months (95% CI, 5.6-8.2) in the T-DM1 arm (n = 263). The HR for disease progression or death was 0.33 (95% CI, 0.26-0.43; 

 < .0010). The 12-month PFS rates were 75.2% (95% CI, 69.3%-80.2%) and 33.9% (95% CI, 27.7%-40.2%), respectively, with 24-month PFS rates of 53.7% (95% CI, 46.8%-60.1%) and 26.4% (95% CI, 20.5%-32.6%), respectively.

The median OS was not reached in either the trastuzumab deruxtecan arm (95% CI, 40.5-not estimable [NE]) or the T-DM1 arm (95% CI, 34.0NE), with a reported 36% reduction in the risk of death with trastuzumab deruxtecan (HR, 0.64; 95% CI, 0.47-0.87; P = .0037).

 The 12- and 24-month OS rates with trastuzumab deruxtecan were 94.1% (95% CI, 90.4%-96.4%) and 77.4% (95% CI, 71.7%-82.1%), respectively, compared with 86.0% (95% CI, 81.1%-89.8%) and 69.9% (95% CI, 63.7%-75.2%) in the T-DM1 arm.

“We had been concerned that with trastuzumab deruxtecan the responses might be short lived [based on data] from the later-line trials, but these are very durable responses,” Debu Tripathy, MD, said. “Now the concern, of course, is how long patients are going to be on this [agent]. How long are they going to tolerate [it]? Those are things we’re going to need to sort out as time goes on. What is the natural history post trastuzumab deruxtecan? But so far, the most important step is that patients are doing well and going a long time without progression. This is really a tour de force, [and] the big questions are more about understanding why it is effective. Is it the payload? Is it something about the design of the [ADC] in terms of how it’s internalized?” 

Another key concern for Tripathy is staying on top of the associated toxicities, something he affirms has gotten better with awareness. “The key challenge here is to make sure we stay on top of the toxicities, particularly the very concerning risk of interstitial lung disease [ILD], which thankfully we’ve seen that with awareness and monitoring, rates are very low in the more recent trials, but it does still occur.” 

The rate of ILD did see an increase from the original publication to the updated data (10.5% to 15.2%), but investigators noted that this was a result of increased treatment duration and follow-up.

 Moderator Joyce A. O’Shaughnessy, MD, said that most ILD occurs in the first year but some reports came at 2 years. “We have to always be vigilant,” she said. “I’m interested in what my colleagues are doing. One of the things I’ve been hearing is that they’ve been getting CT scans every 6 weeks, or even more likely 9 weeks because we can get those covered. Even if [the patient] doesn’t have lung metastases, they’ve been getting CT scans every 9 weeks.” Borges agreed saying that her decision point is 6 weeks, because “we can’t afford to miss this.” 

O’Shaughnessy added that the way to avoidgrade 4 and grade 5 toxicity is “don’t treat through symptoms. Pay careful attention, but if symptoms [develop], we’ve got to stop and then evaluate [and] treat [them]. And at least based on what we have right now, we don’t have any data that say with symptoms we can go back.” Other key safety data from the study are reflected in the Table.

Treatment guidelines now reflect the use of the HER2CLIMB regimen (NCT02614794) which includes tucatinib (Tukysa), trastuzumab, and capecitabine or T-DM1.1 “What I’m using for third line is usually the HER2CLIMB regimen,” Tripathy said. The final OS analysis of the HER2CLIMB trial showed that at a median follow-up of 29.6 months, the median OS with the addition of tucatinib was 24.7 months vs 19.2 months for trastuzumab and capecitabine alone (HR, 0.73; 95% CI, 0.59-0.90; P = .004).

 The 12-month OS rates were 51% and 40%, respectively. 

The triplet also showed efficacy among patients with active and stable brain metastases. The median OS was 21.6 months (95% CI, 18.1-28.5) vs 12.5 months (95% CI, 11.2-16.9), respectively (HR, 0.60; 95% CI, 0.44-0.81).

 “Over half the patients [who] were enrolled had brain metastases, which was allowed,” Tripathy said. “And half of those patients actually had active brain metastases or untreated brain metastases. This is important because we all know that in later lines of therapy, brain metastases become common and we sometimes find many [tumors] amenable for gamma knife, and we would like to avoid whole brain radiation….that benefit now has been maintained on follow-up analysis, and I see it as an important adjunct, particularly for patients with brain metastases. That’s our preferred go-to regimen after trastuzumab deruxtecan.”

Tripathy noted that he then turns to T-DM1 or other investigational agents. “I’m using [T-DM1] pretty far out. Sometimes I’ll use it in fourth line, [but] I tend to use the tyrosine kinase inhibitors [TKIs], capecitabine, neratinib [Nerlynx], or even margetuximab-cmkb [Margenza]. It’s really hard with all these regimens to know which is the best one to use. Some of my colleagues tend to use TDM-1 more than I do, and I’ve seen responses and maintenance of disease control with it as well.” 

O’Shaughnessy agreed, noting that she uses T-DM1 in the third line almost consistently. “Back in the old days, when patients progressed on first line with trastuzumab/pertuzumab, they’d go onto capecitabine/lapatinib [Tykerb]. That’s what we had,” she said. She also added that after T-DM1 became available, patients proceeded onto T-DM1. “That’s where I saw multiyear benefits. I remember I went back to the charts [to see] what was common about these exceptional responders, and it was interesting. The antecedent therapy to the T-DM1 had been a TKI. And there’s some preclinical evidence that [shows] when you get the TKI and you’re squeezing the tyrosine kinase, HER2 levels can be upregulated by the cell, which is of course when T-DM1 really works. When there’s enough HER2, it can get internalized because after trastuzumab/pertuzumab, you get downregulation. Interestingly, we’re seeing a lot of data now that with trastuzumab deruxtecan, upon progression, you see downregulation. This probably isn’t the best time to come in with T-DM1, we’re speculating, because we don’t have data. [And] you want it to work; it’s such a well-tolerated agent. I’d love to give it after the [HER2CLIMB regimen], but real-world evidence would be awesome in this space.”

Emerging therapies are playing a larger role in HER2-positive disease including novel therapies such as zanidatamab, ARX788, and GLSI-100. 

Zanidatamab is a bispecific antibody that uses biparatopic binding so that each antibody molecule can bind to 2 different HER2 receptors.

 In a single-arm phase 2 trial the agent was assessed among 45 patients in combination with palbociclib plus fulvestrant. The median number of prior HER2 therapies in the metastatic setting was 3 (range, 1-9). Among patients with measurable disease at baseline and postbaseline assessment (n = 36), the confirmed objective response rate was 33% (95% CI, 18.6%51.0%). The confirmed best overall response included a complete response in 1 patient (3%), partial response in 11 patients (33%), and stable disease in 21 patients (58%). The disease control rate was 92% (95% CI, 77.5%-98.2%). The primary end point of PFS at 6 months was NE at the interim analysis.

“Zanidatamab is a very interesting drug. It binds to epitopes and these are involved in not only enhanced binding, but it brings about more clustering and receptor internalization. Which of those phenotypes gave it its activity isn’t clear,” Tripathy said. He added that activity has been seen across tumor types that are HER2 positive. 

Another ADC is ARX788, which is a HER2specific monoclonal antibody that is conjugated with the tubulin inhibitor Amberstatin269.8 Early results from the ongoing phase 2 ACEBreast-03 trial (NCT04829604) in 7 patients with HER2-positive metastatic breast cancer revealed a confirmed ORR of 57.1% 

Lastly, GLSI-100 comprises GP2, an amino acid peptide vaccine of the HER2/ neu protein and granulocyte-macrophage colony-stimulating factor (GM-CSF).

 GLSI100 is under investigation in the ongoing FLAMINGO-01 trial (NCT05232916), which is a double-blind, randomized, phase 3 study that will evaluate the effects of GLSI-100 on survival following 1 year of trastuzumab therapy.

Tripathy highlighted that several peptide vaccines have been evaluated over the past 15 to 20 years but have elicited inadequate immune responses. “The question is: Are these [immune] responses sufficient to bring about a clinical difference? So far, we haven’t seen that…large, well-done randomized trials in the right setting, maybe with minimal residual disease burden, are what’s needed. That’s what we hope to see with some of these trials, including the FLAMINGO-01.”

Future directions for the field will also have a focus on resistance and will pay close attention to biologic changes with the ADCs. “We’re into this realm of [ADCs, and] it brings up a novel set of questions for us to begin wondering about the known [and] unknowns, if you will,” Borges said. “In the setting of sequential chemotherapy, we try to avoid drugs that have similar mechanisms of action for the cross-resistance that has been described for a very long time. In the HER2 space, we know there are mechanisms by which those drugs can be outsmarted by the cancers. Now we’re marrying the 2 situations: we have targeted therapies that need the HER2 to work but then we also have molecules that are linked to these ADCs. Which is more important? The answer might be both: the target vs the companion drug. At least in this case, we can see that going from one HER2targeted ADC to another HER2-targeted ADC, there’s reason to feel very convinced that it’s a great idea as opposed to avoiding that plan. How will that look as we move forward with ADCs that target similar things but have different linkers? It is a whole new field to explore to keep the resistance scientists in business.”

NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 1.2023. Accessed February 1, 2023. https://www.nccn. org/professionals/physician_gls/pdf/breast.pdf 

Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734. doi:10.1056/NEJMoa1413513 

Cortés J, Kim SB, Chung WP, et al; DESTINY-Breast03 Trial Investigators. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):11431154. doi:10.1056/NEJMoa2115022 

Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY- Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023;401(10371):105-117. doi:10.1016/S0140-6736(22)02420-5 

Hurvitz S, Hegg R, Chung Wei-Pang, et al. GS2-02 Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated survival results of the randomized, phase 3 study DESTINY-Breast03. Presented at: San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. 

Curigliano G, Mueller V, Borges V, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022;33(3):321-329. doi:10.1016/j.annonc.2021.12.005 

Escriba-de-Romani S, Alba E, Rodriguez-Lescure A, et al. Treatment of HER2-positive (HER2+) hormone-receptor positive (HR+) metastatic breast cancer (mBC) with the novel combination of zanidatamab, palbociclib, and fulvestrant. Poster presented at: San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

Hurvitz S, Kalinsky K, Gansu V, et al. ACE-Breast-03: efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1. Poster presented at: San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. 

Patel S, Thompson J, Patel M, et al. A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01. J Clin Oncol. 2022;40(suppl16):TPS1110. doi:10.1200/JCO.2022.40.16_suppl.TPS1110 

Phase 3 study to evaluate the efficacy and safety of HER2/Neu peptide GLSI-100 (GP2 + GM-CSF) in HER2/Neu positive subjects (FLAMINGO-01). ClinicalTrials.gov. Updated February 28, 2023. Accessed February 28, 2023. https://www.clinicaltrials.gov/ct2/ show/NCT05232916

The first-line standard of care for patients with HER2-postive metastatic breast cancer has long been held by the combination of pertuzumab, trastuzumab, and a taxane established with the publication of data from the CLEOPATRA trial.

Vol. 24/No. 6 | Oncology Live®

Delays in Cancer Screenings Due to COVID-19 May Result in Trend Toward Excess Deaths

CAR T-Cell Therapy for Multiple Myeloma: Eliminating Disparities Through Accountability

HRD-Directed Therapeutics Hold Potential in Breast Cancer, But Challenges Remain

Integrating New Standards for Metastatic HER2+ Breast Cancer

Coleman Illuminates Opportunities in Gynecologic Malignancies

Diagnostic Cancer Trends Showcase Urgent Need to Increase HPV Vaccination