Even as cultural attitudes shift, LGBTQ+ individuals still face discrimination in health care settings. These communities tend to have higher incidence rates for certain cancers, and on top of these concerns, older individuals must also navigate issues related to aging and the ongoing pandemic, compounding the complexity of their concerns.

Research by the National LGBT Cancer Network has long demonstrated that the risks of being diagnosed with certain cancers are disproportionately higher in LGBTQ+ communities in comparison to their heterosexual counterparts. This research also shows that health outcomes for certain cancers are poorer in LGBTQ+ communities.

The reasons for LGBTQ+ health care disparities are complex but unequivocal, founded in many socio-economic and cultural factors. These include higher rates of smoking and vaping; more obesity in the lesbian and female bisexual communities; broader acceptance and use of illegal substances and alcohol, especially coupled with sexual activity, in the gay male community; and greater numbers of people living with chronic HIV/AIDS.

Poorer health outcomes can be attributed to a lack of training focused on the specific health care needs of LGBTQ+ communities, who may also be affected by homophobic and trans-phobic discriminatory language and attitudes, whether from a health care professional or as part of a health care system’s policies. Some patients may also be harassed, neglected, or denied treatment outright based on providers’ cultural or religious beliefs.

Non-disclosure of sexual orientation is especially prevalent in the older and senior LGBTQ+ communities, and can be compounded by minimal or complete absence of familial support. They may also lack culturally competent home care, rehabilitation, or nursing home services. According to recent independent surveys by the Human Rights Commission (HRC), the Centers for Disease Control (CDC) and Advocacy and Services for LGBT Elders (SAGE), there is consensus that LGBTQ+ persons affected by cancer have an increased risk of severe illness or death if diagnosed with COVID-19. 

For older and senior LGBTQ+ communities affected by cancer and the coronavirus, these disparities are magnified, resulting in greater experiences of fragility, distress, and hopelessness.

According to a report from the Centers for Disease Control and Prevention (CDC) released in February 2021, gay, lesbian, and bisexual people in the United States have higher rates of self-reported conditions associated with severe COVID-19 complications than heterosexual people. These include asthma, heart disease, obesity, kidney disease, stroke, and cancer. Within these populations, Black and Hispanic individuals are particularly vulnerable.

Older persons affected by cancer are less likely to have long-term and stable partnerships than their heterosexual counterparts. They are more likely to have reduced or absent familial interactions, a smaller social support network and a greater need for professional home care, versus unpaid care from a friend or family member. They also often have already experienced significant loss of peer relationships as a result of HIV/AIDS, which diminishes the possibility of creating future community. Those who do have strong relationships face issues associated with aging, including the death of partners and friends.

Finally, many older LGBTQ+ persons with cancer grew up with covert and overt messages that their lifestyles and/or bodies were wrong, unhealthy, and diseased. Having survived stigma and the HIV/AIDS epidemic, coping with another public health crisis has brought up feelings of disorientation and displacement. As stated by a participant of a support group for gay men with cancer at Cancer

, “I was rejected by my family. I have already survived one pandemic where I lost all those closest to me. [I] have been, for years, trying to live with cancer and now am facing another pandemic. I give up.”

As the world shifted, ever so suddenly, in March of 2020 as a result of COVID-19, mandates for sheltering in place, quarantining and social distancing left older LGBTQ+ persons in even greater isolation than before, with few outlets for support and assistance.

In the words of Movement Advancement Project (MAP), “As social isolation reaches crisis levels, financial resources dry-up, and the safety net is stretched thin, many … LGBT older persons remain estranged from family and religiously affiliated institutions on which they [relied] before and during crises. Consequently, we are witnessing an exponential increase in LGBT older people relying on LGBT aging organizations and others whom they trust to deliver life-saving help. And, as a result, the COVID-19 pandemic is uniquely impacting not only LGBT older people, but also the organizations that serve them.”

In a recent article on these aging populations and COVID-19, the Association of Health Care Journalists suggests ways to achieve better outcomes. These include education and outreach to address specific needs, working to make policies inclusive to chosen families rather than just biological ones, using correct gender and pronoun language, and understanding that medical inclusion. They call particular attention to the mental health of these individuals, who may be impacted by feelings of isolation and trauma during the pandemic.

Whether during the coronavirus pandemic or after, providers who wish to better serve older individuals in LGBTQ+ communities must first meet patients where they are. This means recognizing that care for an LGBTQ+ individual is not “one size fits all.” As with any underserved population, it is critical to welcome voices from LGBTQ+ communities to improve access to care, as well as to improve the quality of that care. There is no doubt that eliminating health care disparities is a worthwhile goal—and the journey to achieving it begins with openness and with humility today.

Human Rights Campaign. Research on LGBTQ People and the COVID-19 Pandemic. 2021. 

https://www.hrc.org/resources/research-on-lgbtq-people-and-the-covid19-pandemic

Schmidt, S. LGBTQ people face higher COVID-19 risks, but no one knows the true toll on the community. Feb. 17, 2021

https://www.washingtonpost.com/dc-md-va/2021/02/17/lgbtq-covid-cdc/

SAGE. SAGE’s COVID-19 Response. December 7, 2020. 

https://www.sageusa.org/sages-covid-19-response/

MAP, SAGE, and Center for Americna Progress. LGBT Older People, and COVID-19.May 2020. 

https://www.lgbtmap.org/file/2020%20LGBTQ%20Older%20Adults%20COVID.pdf

Seegert L. COVID-19 is hitting older LGBTQ adults especially hard. April 22, 2020. 

https://healthjournalism.org/blog/2020/04/covid-19-is-hitting-older-lgbtq-adults-especially-hard/

Articles

The reasons for LGBTQ+ health care disparities are complex but unequivocal, founded in many socio-economic and cultural factors. T

Cancer, COVID-19, and Aging in LGBTQ+ Communities

Whole-genome sequencing in patients with precursor multiple myeloma conditions such as smoldering myeloma or monoclonal gammopathy of uncertain significance (MGUS) may help predict which patients will go on to develop the disease, according to study authors Ola Landgren, MD, PhD, and Francesco Maura, MD.

“In the past 2 or 3 years, we have shown that whole-genome sequencing has the potential to [identify] most myeloma-defining genomic events,” Maura, an assistant professor and principal investigator of the myeloma genomic lab at Sylvester Comprehensive Cancer Center, told 

. “If you [can] define events, you can see which patients with precursor disease have these events, and which do not. You can see that the presence of these events is associated with different clinical outcomes.”

, Landgren, Maura, and colleagues, explored the utility of whole-genome sequencing in patients with MGUS and smoldering myeloma to see whether they could identify genomic signatures that could predict progression to multiple myeloma. Results indicated that clinically stable cases of these 2 precursor conditions are characterized by different genomic landscapes and by variations in the temporal acquisition of myeloma-defining genomic events vs progressive entities.

One genomic signature of interest in the study was APOBEC, which has previously been observed in patients with relapsed multiple myeloma, according to Maura. Investigators noted that the patients who eventually progressed on the study already had this signature when they had MGUS, while those who did not progress did not have this signature.

“All of a sudden, we were able to lift off the lid on the Pandora's box of MGUS and see [those who will progress to] myeloma vs [those who will] not,” Landgren, the inaugural leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, told 

. “Many questions still need to be addressed. For example, [we know that] if a patient has [a specific] signature, that is a bad thing. However, if they do not have it, could they still develop it later? What is the rate of conversion? We do not know.” A large follow-up study is planned to examine this further, Landgren added.

, Landgren and Maura highlighted the evolution of genomic testing in multiple myeloma, further discussed their research with whole-genome sequencing in patients with precursor conditions, and spotlighted next steps for research.

What inspired this research to further examine myeloma precursor conditions?

: For a very long time, it has been recognized that some individuals who have proteins in the blood that are monoclonal do not have multiple myeloma. Others have multiple myeloma, [which] is the second most common blood cancer in adults. [This disease presents] in 35,000 people every year in the United States, and over 130,000 people are living with this disease without a cure. Years back, in the 1960s, there was a debate [regarding these] proteins; 1 group thought that there was no association between these proteins and the cancer, while others felt that maybe there was. In the 1970s, the consensus was that [the question remained open and up for debate].

That takes you into [the realm of] MGUS, which basically means we do not know. In reality, people show up with these proteins for various reasons. Doctors can order blood tests, and all of a sudden, you see these proteins. The patient wonders, ‘What is going to happen with me? Will I develop myeloma or not?’ People are living with this uncertainty. In the 1980s, [investigators were starting to realize that] some people have more protein than others; as such, they didn't fit with this terminology [of MGUS, so investigators] came up with the idea that they could call that smoldering myeloma. However, MGUS and smoldering myeloma are sort of the same thing; smoldering myeloma just has a little bit more of these proteins. For 40 years, blood tests [have been performed] every 3, 6, or 12 months and some people still develop myeloma, [while others] have [these proteins] and never progress. For many years, we have studied blood-based markers and other types of markers to determine whether we could identify those who are going to develop myeloma early on.

In 2009, I was the lead investigator on a study that definitively showed that any person who developed myeloma had these proteins in their blood years [in advance]. We had a collection of almost 100,000 blood samples that were drawn every year for many people. We identified all people who had myeloma, and then we went backward year by year and found [those proteins] in every person. That definitively showed that you need to have the protein to develop the cancer. However, the question that still puzzled us for more than 10 years was: Is there a better way to identify those who will [go on to] develop [the disease] vs those who will [not]?

To answer that question, we needed to first ask ourselves whether they were linked; the answer was, yes. There are [challenges to] doing these types of studies, because you need to have a lot of DNA if you are studying whole-genome sequencing. You need to have so many cells for the technology to work. You basically have people who already [are] halfway [to having] the disease. The real question is in those who have a very low level of disease, could you still address this question? Until now, that was not possible. This study takes advantage of a brand-new technology [that requires] low-input DNA. We were able to crack the code.

: This study aimed to answer 1 of the most important questions for the myeloma community. Some scientists [have] recently published very important studies showing that certain genomic drivers are associated with patients who progress. However, the limitation [in those] studies is that most of them are focused on smoldering myeloma because of the [number] of cells [they are able to collect]. [Others used] technologies that are focused on a small fraction of the genomes, so they are able to capture just a small fraction of events.

In the past 2 or 3 years, whole-genome sequencing has emerged and has shown the potential to reveal important myeloma-defining genomic events. [Whole-genome sequencing] is comprehensive and provides most of the answers that we were looking for, answers that the other previous studies could not; this is all possible with this technology.

Could you expand on the goals of this study and its key findings? What did the patient population look like?

: The study particularly focused on people with very low levels of disease; this is [those with] MGUS, which makes this study very unique. As you can imagine, if you study people with smoldering myeloma, they already have so many cells. If you have 1000 people, many will develop myeloma. However, if you have 1000 people with a MGUS, the proportion is going to be lower. For those individuals who are going to progress, [examining this is] equally important. This study, for the first time, focused on whole-genome sequencing, with a particular interest in people with very low disease burden.

What we showed was that we have an activation of certain genomic signatures. For example, a signature called APOBEC is known to be associated with aggressive, solid, and metastatic cancer. We have seen [this signature] in relapsed myeloma. However, when we look at these early disease cases, the patients who eventually progress already [had APOBEC] when they had the MGUS. The [patients] who did not progress, did not have [APOBEC]. That is a huge observation; that [shows us that we] can [predict] myeloma [before it occurs with these signatures]. Other single-variant hotspots, or templated insertions, [were also observed]. For example, chromothripsis also distinguishes these cases from each other.

The question now is [whether a person who does not have these genomic signatures now] can develop them later. [We need to know the rate of conversion.] To this end, we are already planning to open a large follow-up study, here, in Miami, where patients with MGUS and smoldering myeloma will be welcome to come for this test. [The study] will also allow them to come back on an annual basis if they have the low-risk signatures [so that they can] be tested longitudinally to] definitively answer this question. We are also working to develop early intervention studies to treat [patients] based on these signatures.

: Where we are now in the field is that the prediction of the risk of whether patients will progress is based on indirect measurement of disease burden. We have a different prognostic score that was developed by Mayo Clinic and the Spanish group, that is effective in identifying patients [who are] very high risk. We consider these patients to probably already have multiple myeloma; it is just a matter of time [for the disease] to expand and [cause] symptoms. In just a few months, less than 2 years, most of these patients will progress. These scores are less [effective in] predicting [those with] intermediate and low risk. That is [why] our study is important. All our patients enrolled, [those with] MGUS and smoldering multiple myeloma, were all intermediate and low risk. We did not have any high-risk [patients]. The [patients] who progressed were those who did so from an intermediate or low risk to multiple myeloma. That is another important consideration.

Despite the limited cohort, because we're talking about less than 50 patients, the data were clean; the cohort was not contaminated by high-risk patients or by [those with] multiple myeloma that was not yet diagnosed. It is important because this population of myeloma without symptoms is a big problem when you try to extrapolate or understand a large population, particularly [through] retrospective studies. That is another advantage. APOBEC, chromothripsis, templated insertions—all these events can only be detected in an accurate way using whole-genome sequencing. That is why whole-genome sequencing is important. You can detect APOBEC with exome data, but it is less accurate, and you [are left with] a lot of uncertainty.

Whole-genome sequencing is pretty robust; [either] you have [it] or you don't have [it], and if you don’t have it, then you’re sure you don’t have it. That is another advantage.

Finally, we performed a bit of a complicated analysis using mutations that are constant over time and we showed that the first genomic-defining events that we were able to time are acquired in multiple myeloma around the second decade of life. [Patients with] smoldering myeloma and MGUS who progressed [did so] in a similar time window: the second or third decade of life. What was interesting is that in the [patients with] MGUS or smoldering myeloma who did not progress, [events were acquired] in the fifth and six decades of life. We don't know whether these patients will progress, but we can also [hypothesize] that most of these patients, if they take the same path that multiple myeloma requires, will progress when [they are] more than 100 years [of age].

Oben B, Froyen G, Maclachlan KH, et al. Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities. 

. 2021;12(1):1861. doi:10.1038/s41467-021-22140-0

This article was originally published on OncLive as, "

Whole-Genome Sequencing in Smoldering Myeloma and MGUS Could Predict Outcomes

Whole-genome sequencing may hold the answers for patients with myeloma precursor conditions.

Whole-Genome Sequencing Helps Predict MGUS and Smoldering Myeloma Outcomes

A cancer diagnosis can be nerve-wracking enough, but sitting in the waiting room anticipating chemotherapy treatment can make anxiety even worse.

A nurse-led intervention was recently implemented at the SUNY Upstate Medical University, in Syracuse, NY, to decrease wait times and the length of inpatient stays, as well as lessen the amount of anxiety patients were feeling before getting treatment.

“According to the Centers for Disease Control, 65,000 patients will undergo chemotherapy – some of these patients requiring inpatient treatment,” said Kristin Soper, MS, RN, ANP-BC, AOCNP, while presenting her findings at the 45th Annual ONS Congress. “Patients electively admitted for chemotherapy tend to have long wait times associated with their treatment.”

Soper implemented a complete redesign of the elective chemotherapy program. The following changes were instated:

Patients had to have lab results, treatment plans signed, and all necessary testing and central access obtained before being admitted

Chemotherapy wait times were measured using the electronic medical record (EMR)

Staff were educated on the urgency of chemotherapy, as well as the benefits of reducing treatment-related wait times

The following were measured to determine success of the program: time of admission, RN release of orders, pharmacy verification, and time of infusing chemotherapy.

Ultimately, wait times decreased by 41%, “and in doing so, length of stay was found to be less impacted than expected,” Soper said, explaining that this may be a result of patients being scheduled for treatment late in the day.

“Satisfaction and anxiety were measured quantitatively with results suggesting that decreasing wait times did improve both anxiety and satisfaction,” Soper said. Additionally, qualitative results showed that shorter wait times led patients to feel that their time was more respected, and the process was more efficient and seamless.

Shorter wait and stay times not only improve patient satisfaction but can also result in cost savings for the hospital.

“Nurses could be leaders in this project to help ensure that care provided is patient-centered,” Soper said. “The focus on cost savings could be monumental to guide other nurse-led initiatives.”

Soper K. Workflow redesign of the elective chemotherapy program to reduce wait times associated with chemotherapy. Presented at: 46th Annual ONS Congress. April 20, 22, 27, 29, 2021. Virtual

An intervention to decrease chemotherapy wait times led to better patient satisfaction and reduced anxiety. 

Reduce Chemo Wait Times and Improve Patient Satisfaction

Offering patients with metastatic gastroesophageal tumors a more personalized and adaptable treatment approach using monoclonal antibodies matched to genetic profiles in combination with chemotherapy may result in higher rates of survival compared with historic controls, according to the results from the phase 2 PANGEA study (NCT02213289).

A 1-year overall survival (OS) rate of 66% (95% CI, 54%-76%) was reported in the 68 patients who comprised the intent-to-treat population, meeting the primary efficacy end point of the trial (one-sided, 

 = .0024). The median OS was 15.7 months (95% CI, 13.4-17.7) in these patients; the median time to treatment failure (TTF) was 13.6 months (95% CI, 11.3-15.8). Moreover, the 2-year OS rate in this population was 29%, the 3-year rate was 14%, and the 5-year rate was 11%. The 1-year OS rate in the non-ITT population (n = 12) was 33.3%, with a 2-year rate of 8% and a median OS of 9.0 months (95% CI, 4.6-20.3).

“At first there was only chemotherapy for HER2-negative tumors in the first-line setting, but now other targeted therapies are coming out, including anti–PD-1, anti-FGFR2 and anti-claudin,” Daniel Catenacci, MD, an associate professor of medicine and director of the Gastrointestinal Oncology Program at the University of Chicago, as well as the assistant director of Translational Research in the Comprehensive Cancer Center, stated in a press release.

 “How does a physician decide which treatment to prescribe when a patient might be eligible for multiple options given known overlap in a tumor of the predictive biomarkers for each of these therapies? This study shows that using an algorithm such as ours could help with that prioritization to direct optimal care and may potentially lead to better outcomes for patients.”

Although advances made in genetic testing have created opportunities to better inform treatment strategies, heterogeneity can cause difficulties in identifying the best targeted therapy for each individual patient. To address this unmet need, investigators developed a new treatment strategy for this patient population.

The goal of the study was to optimize survival in patients through the use of sequential doublet chemotherapy in combination with an individually matched monoclonal antibody at baseline diagnosis, then again serially over up to 3 lines of therapy.

To account for the potential of several therapeutic approaches because of concurrent molecular alterations in a given patient’s sample, a predefined prioritized biomarker and treatment assignment algorithm was applied at each line of therapy. Investigators hypothesized that the individualized treatment approach, which comprised 8 biological subsets with 6 matched monoclonal antibodies, could address formidable hurdles presented by molecular heterogeneity, resulted in improved outcomes over historical controls.

From June 2015 through May 2019, investigators enrolled 80 eligible patients. The median age of the study population was 61 years (range 28-81), the majority of whom were male (80%; n = 64). Of the 80 total patients enrolled to the study, 43% (n = 34) had esophageal tumors and 30% (n = 24) and gastroesophageal junction tumors. Seventy-four percent of patients (n = 59) had signet ring cells absent.

In the total patient population, baseline metastases were noted in the lymph nodes (63%; n = 50), peritoneum (38%; n = 30), liver (36%; n = 29), lung (8%; n = 6), bone (5%; n = 4), adrenal gland (4%; n = 3), or another location (1%; n = 1). Additionally, 40 patients (50%) had a performance status of 0, 33 (41%) had a status of 1, and 7 (9%) had a status of 2.

The biomarker prioritization and treatment assignment algorithm utilized by investigators placed patients in 1 or 8 treatment arms based on genetic testing results:

PD-L1 IHC combined positivity score of over 10, who were microsatellite instability–high, had a tumor mutation burden less than 15 mutations/mb, and/or Epstein–Barr virus–positive received anti-PD-1 nivolumab (Opdivo)

-amplified received trastuzumab (Herceptin)

-amplified received anti-MET (no agents available)

In the ITT population, all patients received a first-line therapy, 87% (n = 53/61) went on to receive a second-line therapy, and 42% (n = 60) progressed and received a third-line therapy. Those who progressed on all 3 lines of therapy in the PANGEA study went on to receive a fourth line of therapy (12%; n = 8). No fifth-line or later therapies reported.

During the first cycle of treatment, 41.2% (n = 28) of patients in the ITT population received modified oxaliplatin, levofolinate, 5-fluorouracil (5-FU), and bevacizumab (Avastin; mFOLFOX7) without 5-FU bolus while the remainder were given leucovorin, 5-FU, and oxaliplatin (mFOLFOX6) with 5-FU bolus. Through the duration of their treatment, 20.6% of patients received palliative radiotherapy to the primary tumor, all of which were proximal esophagogastric junction tumors (28%; n = 14/50).

Additional findings indicated that 79% (n = 54) of patients in the ITT population and 83% (n = 10) of those in the non-ITT population had measurable disease. Four patients (7.4%) in the ITT population had a complete response (CR), 36 (66.7%) had a partial response (PR), 13 (24.1%) had stable disease, and 1 (1.9%) had progressive disease. No patients (0%) within the non-ITT population experienced a CR. However, 4 (40%) patients in the non-ITT population achieved a PR, 3 (30%) had stable disease, and 3 (30%) had progressive disease.

No diagnostic or treatment-related deaths were reported on the study, and only 1 patient required overnight monitoring due to abdominal pain following a baseline ultrasound-guided biopsy of a peritoneal nodule. The most frequent grade 3 or higher hematologic treatment-related adverse effects (TRAEs) reported across all lines of therapy included neutropenia (18%; n = 12), anemia (16%; n = 11), and white blood cell decrease (9%; n = 6). Other grade 3 or higher TRAEs included fatigue (13%; n = 9), as well as nausea and vomiting (9%; n = 6).

In the first-line setting, the most common high-grade hematologic toxicities included anemia (10%; n = 7), neutropenia (9%; n = 6), and thrombocytopenia (6%; n = 4), with other TRAEs including nausea and vomiting (6%; n = 4) and fatigue (4%; n = 3). Patients in the second-line setting experienced some neutropenia (8%; n = 4), fatigue (6%; n = 3) and diarrhea (6%; n = 3). Lastly, in the third-line setting, the most common TRAE was fatigue (16%; n = 4) with hematologic TRAEs including neutropenia (12%; n = 3), anemia (12%; n = 3), and thrombocytopenia (12%; n = 3).

“During the study, we learned that not only is it common to see genetic heterogeneity between the primary and metastatic tumor — about 40% of the time, the metastatic tumor differed substantially from the primary tumor — but also that about 45 or 50% of the time, patients had their therapies changed as the disease evolved,” Catenacci added. “By going after the metastatic site at the start of treatment, reassessing the tumor if and when there was clinical disease progression, and using the algorithm to prioritize therapy each time, the survival outcome was substantially higher than would be expected using standard therapies.”

Catenacci DVT, Moya S, Lommnicki S, et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): a phase II study evaluating an individualized treatment strategy for metastatic disease. 

. Published online November 20, 2020. doi:10.1158/2159-8290.CD-20-1408

Dynamic, personalized treatment approach may improve outcomes in gastroesophageal cancers. News Release. University of Chicago Medicine. January 21, 2021. Accessed January 22, 2021. 

Personalized, Adaptable Treatment Strategies May Improve Survival in Metastatic Gastroesophageal Cancer

Personalized and adaptable treatment regimens seem to be the way forward in treating gastroesophageal cancer.

Individualized Treatment May Improve Outcomes in Gastroesophageal Cancer

Homologous recombination deficiency (HRD) status, 

 mutational status, and prior bevacizumab (Avastin) treatment should be used to inform which PARP inhibitor—olaparib (Lynparza), rucaparib (Rubraca), or niraparib (Zejula)—a patient with ovarian cancer should receive in the frontline or recurrent maintenance settings, said Bradley J. Monk, MD, FACOG, FACS, who added that, ultimately, the goal is for every eligible patient to receive PARP inhibition in the frontline maintenance setting alone or in combination with bevacizumab.

“The standard treatment for ovarian cancer is global. Whether you are a medical oncologist or a gynecologic oncologist, and whether you are in Phoenix, Arizona or Berlin, Germany, [the standard of care] is the same: chemotherapy, maximum cytoreductive surgical effort, and maintenance, either with a PARP inhibitor alone or in combination [with bevacizumab],” said Monk.

“It is important for us to understand the benefit [of PARP inhibitors in the maintenance setting, even though the period the patient receives maintenance therapy] is supposed to be a [treatment-free] holiday,” Monk added. “If managed correctly, [adding a PARP inhibitor doesn’t] reduce quality of life; the patient can not only remain symptom free from a PARP inhibitor but also progression free from cancer.”

® during an Institutional Perspectives in Cancer webinar on ovarian cancer, Monk, a professor in the Division of Gynecologic Oncology at Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, Creighton University School of Medicine at St. Joseph’s Hospital, medical director of the Gynecologic Program at the US Oncology Research Network, and co-director of GOG Partners, discussed findings from key studies that solidified the role of PARP inhibition as maintenance therapy for patients with ovarian cancer, as well as guidelines for selecting PARP inhibitors alone or in combination with bevacizumab.

®: What about the patient population made the SOLO-1 trial (NCT01844986) unique?

: SOLO-1 was the first randomized, phase 3 trial to show the efficacy of [frontline] PARP maintenance therapy in newly diagnosed advanced ovarian cancer. The unique aspect of SOLO-1 was [that it was] limited to patients who had a 

-associated tumor, either germline or somatic.

Having said that, [the data from SOLO-1] were transformational [when they were] presented during the 2018 ESMO Congress. [Olaparib] was FDA approved [in this indication] in 2019.

[The data from SOLO-1] changed the landscape [of ovarian cancer] by showing that a PARP inhibitor could be given as frontline maintenance [therapy], as well as that biomarkers matter.

What key goals were reached in the PRIMA trial (NCT02655016) with niraparib?

PRIMA had 3 goals. [The first goal was] to go beyond what SOLO-1 showed and show that [frontline] PARP inhibitor maintenance therapy could [extend] beyond 

 to all-comers. [PRIMA] did that. The second goal was to look at the highest-risk patients, such as those with gross residual disease [after] neoadjuvant [therapy] or stage IV cancer and bring relief to those patients suffering the most. [PRIMA] did that. The third goal was to personalize the dose of niraparib [for patients]. Niraparib is the only frontline, once-daily PARP inhibitor [for] all-comers [given in an] individualized dose. All of that is a result of the PRIMA trial.

The beauty of [the PRIMA study] is that between the collaboration with ENGOT [The European Network for Gynaecological Oncological Trial groups] and Gynecologic Oncology Group (GOG) Partners, we were able to get [niraparib] FDA approved 37 months from the time that the first patient was enrolled [on the study]. This was a transformational study [with regard to] the agent, the opportunity, the dosing, and the speed [in which it led to an FDA approval].

How had the addition of bevacizumab to PARP inhibitor therapy affected the treatment landscape? Is toxicity a concern with this type of combination?

In 2011, we published GOG-218 [NCT00262847] in the 

, which led to almost immediate global approval [of bevacizumab], except in the United States where it was not FDA approved until June 2018. [The 7-year delay] was because we needed to show the value [of bevacizumab] to the regulatory agency in prolonging progression-free survival [PFS]. Therefore, while the Europeans were utilizing bevacizumab routinely, the United States did not have an FDA approval. The European Network, led by the French group, decided to take what they were already doing with bevacizumab and add olaparib in the [frontline] maintenance phase to create the first randomized trial of a combination with a PARP inhibitor and, in this case, bevacizumab. [The results of that study] were positive, meaning that it met its primary end point of PFS, but the [results] were only impactful in those patients who were homologous recombination deficient.

[Bevacizumab plus olaparib] is a wonderful combination, but giving 2 agents together obviously increases toxicity. It’s not really fair to compare [the combination] with single-agent olaparib from the SOLO-1 trial or single-agent niraparib from the PRIMA study because [the PAOLA-1 trial (NCT02477644)] did not have a PARP inhibitor alone–arm.

Generally, particularly in Europe, if [patients receive] both [bevacizumab and olaparib] in the beginning, there is not reimbursement [by] the time of recurrence. The comparator is not the PAOLA-1 regimen vs the PRIMA or SOLO-1 regimens; rather it is the PAOLA-1 regimen followed by chemotherapy alone vs the SOLO-1 or PRIMA regimens followed by chemotherapy and bevacizumab. [One caveat of the combination regimen is that] when we utilize both opportunities in the frontline setting, we increase toxicity and perhaps eliminate options moving forward.

If [the] PAOLA-1 [regimen] cures more patients, it is definitely the best opportunity, but we don’t know that answer yet. [We don’t know] whether there will be an improvement in overall survival [OS] in PAOLA-1 or, for that matter, in SOLO-1 or PRIMA. There was no survival advantage with bevacizumab alone in GOG-218.

What does treatment selection look like for patients with platinum-sensitive ovarian cancer?

We have 9 FDA approvals for PARP inhibitors [in ovarian cancer]: 3 frontline [indications] and 6 recurrent [indications]. Three of those [approvals] in the recurrent setting are for platinum-sensitive maintenance therapy. That is very unique because in platinum-sensitive maintenance treatment, patients have to respond to platinum[-based therapy] to qualify for the indication because that was the eligibility for the 4 studies: Study 19 [NCT00753545], SOLO-2 [NCT01874353], NOVA [NCT01847274], and ARIEL3 [NCT01968213]. We don’t use HRD or even 

 that much at the time of [recurrent] platinum-sensitive maintenance therapy because the biomarker here is platinum sensitivity. Regardless of the biomarker, if the patient does respond to a platinum doublet, they are very likely to respond to PARP inhibitor maintenance treatment [in the recurrent setting].

The interesting component though is that because [PARP inhibition] is such a no-brainer, all 3 PARP inhibitors are approved in [the recurrent maintenance] setting. It creates a situation where we have identical approvals and we have to make a decision [as to] which of the 3 PARP inhibitors—olaparib, niraparib, or rucaparib—is the best option for a patient. It’s a particularly challenging question and frankly, [requires] a shared and personalized decision with the patient and provider. There is really no right answer.

Should PARP inhibitors be utilized in the frontline maintenance setting for patients with platinum-sensitive ovarian cancer? How does that affect the data from recurrent maintenance trials?

NOVA was the first randomized, phase 3 trial to specifically address the utilization of a PARP inhibitor in platinum-sensitive [disease as] maintenance treatment [for patients with] 

Study 19 and ARIEL3 [evaluated PARP inhibitors in this setting], but Study 19 was a complicated, small study. NOVA [evaluated PARP inhibition] in a systematic way and set the paradigm. [The data were] published in the 

My goal with patients who [are eligible for] platinum-sensitive maintenance therapy is to use it in the first-line setting. Therefore, these platinum-sensitive maintenance trials are almost historical, but there are still patients who didn’t have the opportunity [to receive frontline maintenance therapy] because [olaparib from] PRIMA was FDA approved in April 2020 and [olaparib plus bevacizumab] from PAOLA-1 was FDA approved in May 2020. There are patients who are recurring who didn’t receive a frontline PARP inhibitor.

Over time, my goal is to have every patient, if eligible, have the potential benefit of a PARP inhibitor, ideally in the frontline maintenance setting. If a patient missed [the] opportunity for [frontline] platinum-sensitive maintenance therapy, there are 3 treatment opportunities [in the recurrent maintenance setting] based on 

How have the ASCO guidelines incorporated PARP inhibitors as maintenance therapy?

In October 2020, the ASCO guidelines for PARP inhibition were published in the 

; the first author was [William P. Tew, MD, of Memorial Sloan Kettering Cancer Center]. [This publication] was really transformational because it basically said that every patient should be considered for niraparib and every patient should be considered for olaparib if they have a 

 tumor mutation. The other indications in [the setting of recurrent,] platinum-sensitive maintenance [therapy] are listed as “may,” which is a lower level [of recommendation compared with “should”].

These [guidelines] provide clinical guidance for [what] providers and payers should utilize in [the setting of] frontline maintenance treatment, either niraparib in all-comers or olaparib in molecularly defined subsets.

Do the National Comprehensive Cancer Network (NCCN) guidelines mirror the ASCO guidelines with respect to the incorporation of PARP inhibitors?

As published in February 2021, the NCCN guidelines provide clear direction on the utilization of PARP inhibitors in the frontline maintenance treatment of [patients with] ovarian cancer. In fact, [the NCCN guidelines] closely mirror what John K. Chan, MD, [of the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center] and I published in 

[That publication] basically [stated] that there are 3 key decisions [that need to be made when selecting an up-front treatment for patients with advanced ovarian cancer]. Even before the first decision is made, everyone needs to agree to do germline testing, generally with a panel. If [the patient has] a germline 

 mutation, we’re done [considering options]. If [the patient doesn’t have] a germline 

 mutation, we have to pivot to tumor testing because not only can you identify, the family [members who] need risk-reducing surgery or screening, but also patients who are most likely to benefit from a PARP inhibitor.

How do you go about determining whether a patient should receive a PARP inhibitor alone or in combination with bevacizumab?

If there is no germline mutation, we look for the opportunity to use a PARP inhibitor [via] tumor testing, which is basically an HRD test. There are 2 FDA-approved HRD tests [available] in the clinic.

After we’ve done [HRD testing], we are able to make the first hard decision: Do we give neoadjuvant chemotherapy? Remember, there is no such thing as optimal debulking [surgery] because we can either cut it out or we can’t. If we can cut [the tumor] out [and the patient is R0], it is good. If we can’t, we begin neoadjuvant chemotherapy with interval debulking between the third and fourth cycles.

The second decision is that after [either giving or not giving] neoadjuvant chemotherapy: [Do we give bevacizumab]? The indication for bevacizumab is all-comers with stage III or IV ovarian cancer. I [understand] that a 10-month OS advantage was suggested [with bevacizumab] even in the highest-risk population with stage IV disease. When or if bevacizumab is utilized has a lot of controversy. Personally, having first reported bevacizumab’s activity in ovarian cancer in the current setting, I used to utilize bevacizumab commonly up front.

After we’ve made the first and second decisions, we have to make the third decision, which is what this conversation about PARP inhibitors [comprise]. That [decision] is informed by bevacizumab because if we are [giving] bevacizumab, we are not going to stop it if it is effective and tolerable. However, if the patient has an HRD molecular signature, we are going to add olaparib as per the PAOLA-1 trial. If we are not using bevacizumab, there are 2 buckets: [patients with] 

 [mutations] and [patients with] HRD without 

-mutant cohort not on bevacizumab, the options are olaparib per SOLO-1 or niraparib per PRIMA. That’s a tough decision, but it is most important that patients with 

 mutations get a PARP inhibitor as [frontline] maintenance treatment. If we are not using bevacizumab, the only PARP inhibitor that is utilized in the HRD non–

-mutant cohort is niraparib per PRIMA. If we don’t use bevacizumab in the non-HRD [cohort], we can use niraparib in the HR-proficient group.

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