EP. 6B: Phenotypic Theranostics in the Future of Precision Medicine – Targeted Oncology

In September 2021, following the publication of results from the phase 3 VISION trial of lutetium (Lu)-177 PSMA-617 (LuPSMA) in select patients with metastatic castration-resistant prostate cancer (mCRPC),1 the United States Food and Drug Administration (FDA) granted priority review to LuPSMA.2

The FDAs decision comes on the heels of the trials positive results, which are explored in How the VISION trial may change prostate cancer therapy, the fourth article in this Targeted Oncology series, entitled New Precision Medicine Approaches in Advanced Prostate Cancer. However, it also comes after recent advances in genetic testing, biomarkers, nuclear imaging, and combination treatments for prostate cancer. These are discussed, respectively, in The role of imaging and genomic testing in prostate cancer therapy, New horizons in nuclear medicine for prostate cancer, and Expert perspective on the changing treatment spectrum for advanced prostate cancer, also in this series.

As the FDA reviews LuPSMA, experts have questions about this novel radiopharmaceutical and how it might be adopted in the US.

Ahead, Oliver Sartor, MD, medical director at Tulane Cancer Center in New Orleans, Louisiana, co-principal investigator of the VISION trial, and lead author of the published results, considers some of the questions about this novel radiopharmaceutical and how it might be adopted in the US. Dr. Sartor also discusses how the VISION trial fits into new prostate-specific membrane antigen (PSMA) research and explores the future of phenotypic theranostics in precision medicine.

TARGETED ONCOLOGY: What are the key takeaways from the VISION trial?

SARTOR: I think there are a couple. No. 1 is [that] we really wanted to design a trial that would result in regulatory approval in multiple countries, so that was the goal starting out. Of course, we wanted to use the PSMA Lu-177 using the PSMA-617 targeting molecule. That was kind of where we started.

I also felt that having prolongation of survival as an end point was key. To meet it, we chose very difficult-to-treat patients. The patients who enrolled in VISION had already gone through chemotherapy and at least 1 taxane. Many of the patientsabout 40%had actually had 2 lines of a taxane chemotherapy prior to enrolling in the trial. Everyone was also required to have use[d] at least 1 novel hormone, but multiple novel hormones were allowed. Abiraterone and enzalutamide, for instance, would have previously been used. A substantial proportion of them had undergone not just 1 but 2 chemotherapies, and all of them had undergone multiple hormonal treatments. These patients were extremely difficult to treat.

We also used the PSMA PET scan to choose and exclude patients. We wanted to choose patients who have PSMA PET metastases greater than just in the liver. This wasn't a stringent criterion, but we wanted to make sure that everybody had PSMA positivity. We also excluded patients who had PSMA negativity, lymph nodes greater than 2.5 cm, or visceral lesions of more than 1 cm.[There] were [also] a variety of other inclusion criteria like adequate performance status, adequate bone marrow, etc.

Included patients were randomized to receive a nonchemotherapeutic standard of care [treatment]. This included additional hormones, radiation therapy, bisphosphonates, maybe steroids plus or minus the PSMA lutetium, etc. There was a 2-to-1 randomization. Overall survival (OS) was an end point. Also, after the trial was already designed, there was a radiographic progression-free survival (rPFS) end point added. Patients were intended to be treated with at least 4 cycles for the PSMA lutetium and could receive up to 6 if there was evidence of clinical benefit. That's the basic framework of the trial.

The bottom line is we hit OS, and we hit rPFS. I think the safety profile was good. We also had health-related quality-of-life improvement for the PSMA lutetium. I believe this trial will result in multiple regulatory approvals, which was the goal that we set out to accomplish.

TARGETED ONCOLOGY: Based on findings from the VISION trial, what might we expect from ongoing clinical trials investigating Lu-PSMA-617 earlier in the natural history of prostate cancer?

SARTOR: Patients in the VISION trial had all failed a novel hormone and a taxane-based chemotherapy, so the VISION trial [included]advanced patient[s] with chemotherapy exposure. However, many patients with prostate cancer never receive chemotherapy, so were now starting a trial for patients with [m]CRPC called PSMAfore (NCT04689828), [which] doesn't require patients prior use of chemotherapy. Here, we're taking patients without chemotherapy exposure, but we're requiring that they have at least abiraterone or enzalutamide as a prior treatment. PSMAfore is moving forward with an rPFS end point with a crossover for those who are on the control arm, [so] they would have the opportunity to also receive PSMA lutetium. That trial is already accruing: I've already personally enrolled patients into the trial.

PSMAfore examines the castration-resistant space. We're also moving into the castration-sensitive space. In a phase 3 trial, we're going to be examining metastatic castrate-sensitive prostate cancer. Everybody receives androgen-deprivation therapy (ADT) and a novel hormone. The novel hormone can be [the] doctor's choice: abiraterone, enzalutamide, or apalutamide, all of which are FDA approved. This trial [is] plus or minus the PSMA lutetium. Here again, we're using an rPFS end point. This is going to be a big global trial. It, too, is already accruing patients. We've already consented our first patient here in the United States, and it's accruing in multiple countries around the globe.

We're hopeful that these earlier stage trials with PSMA-617 lutetium are going to result in more regulatory approvals for less heavily pretreated patients than were present in VISION.

There's also another phase 3 trial called the SPLASH trial (NCT04647526) using a PSMA-targeted radiopharmaceutical. Again, [it is] Lu-177, but this time instead of PSMA-617, it is 177 Lu-PSMA-I&T.

The[re] are additional phase 3 trials in the mCRPC nonchemotherapy-pretreated space. These trials are not quite underway to the same degree that PSMAfore is. Nevertheless, I think they can add value as we move forward.

TARGETED ONCOLOGY: If approved, how might Lu-PSMA fit within the current treatment landscape for mCRPC? What challenges do you anticipate for the use or acceptance of this agent?

SARTOR: I think the first label will be in accordance with the VISION-selected patients: mCRPC by conventional imaging and prior treatment with both a novel hormone such as abiraterone or enzalutamide and at least 1 taxane. Everybody would need to be PSMA-positive on the PET scan in accordance with the criteria that we established in VISION, I anticipate. That might not be the case, but I suspect it will.

After approval, the barriers are going to be severalfold. No. 1, there are going to be a lot of patients who do not want chemotherapy and are not treated with chemotherapy. They're going to be frustrated that they can't get this agent because the FDA and other regulatory bodies, I think, are going to require the chemotherapy pre-treatment. That's going to be 1 issue, [and] that's going to be addressed with PSMAfore and others.

No. 2, there are already access issues in the United States for PSMA PET. Not all of the insurance companies have approved it. If a PSMA PET [scan] is required, then somehow all these PSMA PET scans are going to have to be performed. That's a potential holdup.

No. 3, I think that the specialties that are qualified to administer the radiopharmaceuticalseither nuclear medicine or radiation oncologymay be overwhelmed with the demand. I'm worried that not enough centers are going to be ready. Ideally, these patients should be under multidisciplinary care. These are individuals who have multiple potential complications. It's not just pushing an isotope and seeing the patient back in 6 weeks. Multidisciplinary care is optimal. However, getting these patients through multi-d[isciplinary] clinics [to be sent] to those who are qualified to administer the therapy and then ensuring that theyve had chemotherapy and getting them [PSMA] PET scans could all be a hindrance.

There are stumbling blocks that could be apparent, and I think we're going to have to watchall of these as we go forward.

TARGETED ONCOLOGY: Looking beyond Lu-PSMA and the VISION trial, what do you think is most important for clinicians to emphasize in future efforts to treat patients with advanced prostate cancer effectively?

SARTOR: No. 1, we really need to start multidisciplinary care as soon as possible. Everybody can add value to the patient. If a patient is seeing a radiation oncologist, involving a urologist may be of benefit. If somebody is seeing a urologist, a medical oncologist could be helpful. As we move forward, particularly in these complex cases of patients with multiple areas of metastatic disease, coming together as teams can play an important role.

No. 2, we need to be aware of genetics. There are genetically targeted therapies now available. Folks are aware of the PARP inhibitors for homologous recombination repair defects, but things like pembrolizumab are also important. I mention pembrolizumab by name as a PD-1 inhibitor because this is approved in the context of mismatch repair or microsatellite instability (MSI)-high alterations, or even high tumor mutational burdens. Genetic testing is something I think we need to keep in mind, because sometimes the patients can have very robust responses to targeted therapies, provided they have the appropriate genetic milieu.

No. 3, as we move forward, we have to be cognizant of supportive aspects of our care, such as bone health. We have realized that a lot of patients can have pathogenic fractures and pathologic fractures. Mitigating that risk with things like denosumab or zoledronic acid is an important role for our clinicians to play in the management of patients.

TARGETED ONCOLOGY: What are the most exciting or important areas for researchers in this field to focus on?

SARTOR: Im excited about several areas. No. 1 is combination therapies. Currently, PSMA [Lu]-177 is being evaluated in combination with things like PSMA actinium-225. It's being looked at in combination with DNA repair inhibitors such as the PARP inhibitor olaparib, it's being looked at in combination with the PD-1 inhibitors like pembrolizumab, [and] its being evaluated in combination with stereotactic body radiotherapy. As we move forward, combination therapies are important.

Additional isotopes, combinations of isotopes, bispecific antibodies, and novel hormonal targeting agents that are being developed are also exciting, so there's a lot for us to keep aware of as this field marches forward.

TARGETED ONCOLOGY: PSMA-based radiotracers are the latest in a line of biomarkers used in prostate cancer imaging. Do you foresee other biomarkers becoming relevant? What role might PSMA have alongside them?

SARTOR: Combinations of PET imaging may yield very interesting results. For instance, we're having trouble treating emerging neuroendocrine prostate cancer. Often, after previous treatment with agents like abiraterone and enzalutamide, these neuroendocrine phenotypes emerge. The cell surface markers for neuroendocrine phenotypes may be very interesting. I'll mention the bombesin receptor as one. It turns out that these neuroendocrine tumors express receptors beyond just PSMA.

I think PSMA is a fabulous target, by the way, [but] different ways to image PSMA may also be important. There [are] also image-based biomarkers related to the use of immunotherapy. Being able to image things like PD-L1 [may] also [be] quite important.

As we go forward, Im seeing a whole series of newer PET [bio]markers being evaluated, and utility [may be] growing out of even combinations. The Australians today use 18 F-FDG PET in combination with PSMA PET, and by the way, I think that could potentially add value, but it needs to be properly evaluated in the context of prospective trials.

TARGETED ONCOLOGY: What is on the short-term horizon for research in prostate cancer treatment?

SARTOR: I think the short-term horizon in prostate cancer is going to revolve [around] moving these novel radiopharmaceuticals closer to the front of therapy. I've mentioned several trials, including the SPLASH trial, the PSMAfore trial, and the PSMA addition trial, which is for castration-sensitive [prostate cancer], upfront. All of these are going to be actively accruing subjects. I don't think we'll have results in the next 12 to 18 months, but nevertheless, that's going to be the next chain. In addition, we're going to see the rise of these combination therapies initially in phase 1 moving on to phase 2. And then I think we're going to evolve a whole series of novel biomarkers, and these are going to require additional testing, of course, but the field of biomarkers is alive and well. [It is] evolving so, so rapidly right now.

TARGETED ONCOLOGY: As phenotypic theranostics advance, what might be the role of genotypic precision medicine in prostate cancer? Do you think that these 2 areas will grow alongside one another?

SARTOR: I do. When we talk about precision medicine, I think most [but not all] of what weve become accustomed to is related to the genomic alterations that occur in the context of cancer, but phenotypic alterations such as PSMA expression [are] not going to be something you can detect with a gene rearrangement. Its really about protein expression. I think this area also has a bright future. I mentioned very particularly the expression of neuroendocrine markers. I mentioned the bombesin receptor, which is a gastrin-releasing peptide (GRP) receptor. Maybe somatostatin receptors could be important. Maybe other alterations such as DLL3 could be important. These would be called phenotypic biomarkers as opposed to genotypic biomarkers, which would be things like BRCA2 mutations, mismatch repair, rearrangements, etc.

Precision medicine is going to evolve, I think, on multiple fronts. The beauty of a targeted radiopharmaceutical is that almost anything that you can bind to on the cell surface potentially becomes a target. That means were going to have a vastly expanded series, in my opinion, over the next several decades of targets on cell surfacesnot just for prostate cancer, but for a whole series of different cancers. Right now, we have neuroendocrine cancers of the midgut, the so-called carcinoids, and those neuroendocrine-type cancers that are targeted, but I envision many, many more theranostics going forward, and [LuPSMA] is just a first step.

References

1. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer.N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322

2. FDA grants priority review for investigational targeted radioligand therapy 177Lu-PSMA-617 for patients with metastatic castration-resistant prostate cancer (mCRPC). News release. Novartis. September 28, 2021. Accessed December 9, 2021. https://www.novartis.com/news/fda-grants-priority-review-investigational-targeted-radioligand-therapy-177lu-psma-617-patients-metastatic-castration-resistant-prostate-cancer-mcrpc

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EP. 6B: Phenotypic Theranostics in the Future of Precision Medicine - Targeted Oncology

MODY: A Rare but Increasingly Common Form of Diabetes – Healthline

It wasnt until a quarter century after being diagnosed with type 1 diabetes (T1D) that Lori Salsbury in Arkansas realized the condition shed been living with since she was 15 years old might not be what she thought it was.

Though her mom and sister were both initially misdiagnosed with type 2 diabetes (T2D) and later correctly dubbed T1Ds, Lori didnt have a reason at first to be suspicious of her own T1D diagnosis. Not until 2015, when she began seeing more people with diabetes sharing their stories online and realized something was off for her.

Sure, there is a mantra in our community that Your Diabetes May Vary. But for Salsbury, the particulars of her T1D just didnt match what she saw others in the D-Community sharing or what doctors and nurses described as the symptoms most newly diagnosed T1D experience.

At the time of her diagnosis, Salsbury was in her mid-20s and seemed quite healthy. She didnt get nauseous or sick, even a full day after missing an insulin dose. Her insulin dosing needs would change frequently, often sending her into super high glucose levels for weeks until adjusting her insulin or carb ratios; the same would happen on the low end of the scale.

One day, Salsbury heard about a rare, inherited form of diabetes called MODY (maturity onset diabetes of the young), that doesnt require as much insulin, at least initially. That piqued her interest.

She did some online research, and then consulted her endocrinologist and received antibody tests that came back negative. He also ran a C-peptide test that came back at T1D levels, but that was most likely due to her 20+ years of using insulin. A referral to a geneticist led to more bloodwork, and in January 2020 the findings came back showing a genetic mutation, which causes one of the several different known types of MODY.

MODY has the potential of changing how you manage your diabetes, depending on the particular form youre diagnosed with. Some changes could include stopping medications completely or changing from insulin to a different injectable or oral medication, while some MODY forms mandate changes in your diet.

In Salsburys case, the MODY diagnosis brought her some clarity, and finally an explanation of why her diabetes experience seemed so different than others in the T1D community. But she continues insulin therapy.

Since I was originally diagnosed T1D, I am still (labeled that) in my charts so that I wont lose coverage for my insulin pump and CGM that I require to live by, Salsbury said. Most often, if asked I just tell people that I was diagnosed with type 1. Its easier than going through the whole What is MODY? spiel.

The easiest way to think about MODY is that its a subset of diabetes caused by a mutation in one of at least 14 genes in a persons DNA. That mutation impacts the insulin-producing beta cells, which in turn impacts insulin production and glucose regulation.

Since just an estimated 1 to 2 percent of those with diabetes have a genetic mutation leading to MODY, there isnt much discussion about it within the patient community, and most medical professionals dont bring it up unless they are questioned. Yet some advocates and researchers believe the various types of MODY are more common than many think, and that view is becoming more accepted as genetic testing becomes more widely available.

The term MODY was first coined in the 1970s by pioneering researchers who identified what appeared to be a mild form of diabetes in children that didnt necessarily require insulin as was needed for those with the more common juvenile diabetes (before it was later renamed type 1). At that time, MODY was defined as fasting hyperglycemia diagnosed under age 25 which could be treated without insulin for more than two years, and it is inherited, as they found.

While most research existing shows its as rare as 1 to 2 percent of all diabetes cases, more current research now indicates that as many as 6.5 percent of children with antibody-negative diabetes may have a form of MODY.

MODY is passed down genetically from parent to child, making that the common thread for this form of diabetes compared to the other types that are autoimmune, partially genetic, or more lifestyle-based. The typical diagnosis comes before age 25, and its rarely diagnosed in those older than 35 or 40. While children have roughly a 50 percent chance of developing MODY if one of their parents has it, that does not mean mutations cant occur at random and appear in those without a family history of gene mutation.

The gene mutations arent the same for everyone, and they affect different organs in the body, meaning its difficult to diagnose without genetic testing, and it can be more challenging to recognize glucose fluctuations commonly found in those who are newly diagnosed.

Significantly, 80 percent of MODY cases are misdiagnosed as T1D or T2D as the signs are pretty much the same extreme thirst, increased urination, and weight loss. But some forms of MODY do not produce any symptoms. The number of misdiagnoses may be even higher at 95 percent in the United States, according to some researchers.

Dr. Miriam Udler at Massachusetts General Hospital is one of the more well-known names in MODY clinical research. She believes more cases are being diagnosed in recent years as genetic testing has become more available, particularly after COVID-19 led to a telehealth explosion and more at-home testing kits for bloodwork and diagnostic tests normally done in a lab.

Dr. Miriam Udler

It used to be rare and expensive, and that was a barrier to testing and diagnosing MODY correctly, she told DiabetesMine. But now, more providers have access to this and can order the tests to their clinics or patients at home, and insurance is increasingly covering MODY genetic testing.

While MODY is still less common and infrequently discussed in clinics, Udler says it comes down to that particular doctor or patient recognizing something might be different about their diabetes.

That matters a lot, and a correct diagnosis can change management, Udler said. In most common MODY forms, it could mean coming off medication.

For Salsbury, the particular BLK gene mutation she has causes MODY 11, an insulin secretion defect that makes her beta cells less responsive to glucose and leads to less insulin being sent out by the body when its needed. Being overweight is one common feature of this particular gene mutation, according to research.

Once MODY is recognized and diagnosed, it can also be difficult to regulate glucose levels in the same ways that T1D and T2Ds often do, because the symptoms and glucose levels can vary significantly.

As MODY 11 usually presents like T1D and is treated in much the same way, Salsbury has been using insulin since she was diagnosed at age 15 in 1991 and wears an Omnipod tubeless insulin pump and Dexcom CGM, combined into a homemade do-it-yourself (DIY) closed loop system. For her, life with MODY isnt much different from being T1D.

But she knows everyone is not as fortunate on that front and can have many challenges in getting a correct diagnosis and finding a management routine that works for their particular form of MODY.

In New York, Laurie Jones shares her story of being diagnosed at 30 with gestational diabetes late in her first pregnancy through the test often given to pregnant women. She changed her diet and followed it to the letter on exact carb and calorie allowances, and took varying doses of long and short-acting insulins. Though she describes it as intense, all signs of diabetes went away after her first pregnancy.

But within a few years during her second pregnancy, gestational diabetes returned. She began insulin injections right away as well as a strict diet, but Jones found it more difficult than before to regulate high and low blood sugars.

A number of years later, her A1C results were creeping higher and that led to a T2D diagnosis. She took Metformin on the advice of her doctor, but it didnt work to keep her blood sugars in check.

Most adult medicine endos do not push for MODY testing even when the medicine is not working, she explained. Being overweight is usually assumed the reason, therefore even star doctors dont push for MODY testing unless weight is lost.

Her sons diagnosis changed everything. When he was 6 years old, he was diagnosed with eosinophilic esophagitis, and that mandated a diet free of the top allergens. He was about 12 when she took him to an endocrinologist, as he was not growing and low on the weight scale and didnt show any signs of puberty. That endo noticed his blood sugars were elevated and assumed he was in the honeymoon period prior to becoming a fully diagnosed T1D.

Months progressed, and the doctor suggested it was MODY. Genetic testing led to a MODY 2 diagnosis.

We had no idea what that was, and before [the doctor] explained it to us, she noted that most endocrinologists and almost all doctors outside of major medical teaching and research hospitals have not heard of it, the D-Mom said.

After her sons diagnosis, Jones got her own genetic testing and learned she also had MODY 2.

Most controlled by diet, MODY 2 is one of the more common but less intensive forms of MODY that usually doesnt require insulin or other glucose-lowering meds.

That led her to stopping Metformin, and shes been eating healthier and managing her weight for better glucose levels.

MODY 2 is not just about how you produce or use insulin, but mainly when you produce the insulin, she said. We were both told that our pancreas is like a house cooling or heating system that is off-kilter. Basically, our sugar levels have to get much higher than what is considered normal before the pancreas produces insulin. There are also insulin efficiency issues.

Without her sons diagnosis, Jones doesnt think she wouldve ever had the needed genetic testing and would have remained with a T2D diagnosis taking the wrong medications.

Thats likely the story for so many people in our D-Community, she believes.

With a 50 percent chance of being passed on, chances are MODY is not as rare as it is now believed, Salsbury said. If more people knew of it and were tested, we may come to find out that it is the most common or second only to T2D in commonality.

Importantly, a correct MODY diagnosis can highlight other health issues that might potentially arise. For example, a MODY 11 mutation to the BLK gene can increase the chances of developing systemic lupus erethematosus (SLE).

While being correctly diagnosed as MODY may not change your treatment, it can give you other information, Salsbury said. Many forms of MODY also come along with other health issues that the mutation may have caused. Knowing you have MODY can alert your doctors to watch you or check you for other related health conditions.

Researchers note the same, including Dr. Toni Pollin, a genetic researcher and counselor who in 2016 co-founded the Monogenic Diabetes Research and Advocacy Project (MDRAP) at the University of Maryland School of Medicine. The MDRAP effort promotes the correct diagnosis of MODY and also helps raise money for that effort. She co-founded MDRAP with a patient advocate whod been diagnosed with a form of MODY.

While improving MODY diagnosis will certainly improve the clinical care for patients, it will also have broader implications, researchers wrote in this 2015-published Undiagnosed MODY: Time for Action manuscript. Screening and genetic testing for MODY among patients with diabetes will provide a model for identifying and diagnosing highly penetrant forms of other otherwise common complex diseases [through] the power of genetics and genomics for improving patient care and public health.

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MODY: A Rare but Increasingly Common Form of Diabetes - Healthline