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

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 FDA’s decision comes on the heels of the trial’s 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 patients—about 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 we’re 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 radiopharmaceuticals—either nuclear medicine or radiation oncology—may 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 they’ve 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 watch…all 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: I’m 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] it’s 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, I’m 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 we’ve 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. It’s 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 we’re going to have a vastly expanded series, in my opinion, over the next several decades of targets on cell surfaces—not 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