EP. 4B: How the VISION Trial May Change Prostate Cancer Therapy

In March 2021, Novartis announced that the VISION trial (NCT03511664), which tested the efficacy and safety of lutetium (Lu)-177 PSMA-617 (LuPSMA) in treating men with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC), had met both of its primary end points. In June, at ASCO 2021, Novartis elaborated that the addition of LuPSMA, a theranostic, significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) compared with best standard of care alone. Moreover, the treatment had no unexpected or concerning safety signals. The full results, published in a recent issue of The New England Journal of Medicine,¹ build upon advances in genetic testing, biomarkers, nuclear imaging, and combination treatments for prostate cancer (PC). These advances are explored 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,” the first 3 articles of the New Precision Medicine Approaches in Prostate Cancer series of Targeted Oncology™.

VISION’s results also demonstrated the high prevalence of PSMA in those men who were assessed for VISION and underwent PSMA PET (positron emission tomography) imaging. This suggests that many patients with mCRPC might benefit from LuPSMA therapy if the FDA approves this agent. However, the complexity of getting a PSMA PET scan in the United States at this time may hinder the rapid adoption of LuPSMA. Moreover, should the United States Food and Drug Administration (FDA) approve LuPSMA—and as investigators examine the use of LuPSMA earlier in the natural history of PC—the potential long-term adverse effects of this agent will need to be considered and investigated.

Ahead, Jorge A. Garcia, MD, FACP, a genitourinary oncologist and the current chief of the Solid Tumor Oncology Division at University Hospitals Seidman Cancer Center/Case Comprehensive Cancer Center in Cleveland, Ohio, discusses the VISION trial, how LuPSMA fits within the current mCRPC treatment landscape, and implications of VISION’s findings for prostate cancer therapy.

TARGETED ONCOLOGY™: The VISION trial tested the efficacy of LuPSMA in men with mCRPC. Why is there excitement about this agent and these results?

GARCIA: Lutetium PSMA [has become]…one of the most attractive novel therapeutics in the field for men with castration-resistant prostate cancer.

Many of us recognize the lack of biomarkers for prostate cancer….[C]ertainly PSA, prostate specific antigen, is a decent biomarker, but it becomes very imperfect when you develop castration-resistant disease. In early disease state settings—including in biochemical recurrence—and in the metastatic castration-sensitive space, PSA is an important prognostic tool. However, once you become castration-resistant, PSA becomes less helpful, especially as many of the existing life-prolonging agents used in the mCRPC space do not necessarily target the androgen receptor, which remains the biggest culprit this late in the disease.

So…PSMA becomes an important target for us because PSMA is [a] transmembrane carboxypeptidase [that] is highly expressed in prostate cancer cells, including in metastatic lesions….[It] is a very specific…target [that]…has a really restricted [relative] expression—or what I would call [a] normal or minimal expression—mainly [in] salivary and lacrimal glands. Therefore, [LuPSMA has a] low likelihood of causing…major systemic side effects….In addition to that, I think that PSMA is an excellent target for PET imaging. Hence, PSMA has become important for diagnostic purposes.

You can also label PSMA with radioactive lutetium 177. Once injected into the patient, lutetium PSMA will go directly to where there is PSMA-avid disease. The expectation then is to see clinical benefit in those with PSMA-avid disease.

TARGETED ONCOLOGY™: Could you describe the mCRPC disease state in which LuPSMA was tested in VISION?

GARCIA: The natural history of prostate cancer is pretty straightforward. Most men can get cured when they present with localized disease—even localized disease with high-risk features. The standard of care for those patients is surgery, radiation therapy, or the combination of both, given in a sequential manner. Contemporary data now clearly demonstrate the importance of treatment intensification with suppression of testosterone and maybe even the addition of adrenal biosynthesis inhibitors for patients with very high-risk localized prostate cancer who are at a significant risk for recurrence.

Unfortunately, 30% to 40% of men are not able to be cured and develop biochemical recurrence or rising PSA syndrome. This is a state of rising PSA in the absence of objective evidence of clinical or radiographic disease. These patients are healthy, they're feeling well, they may not have quality-of-life issues, and there’s no evidence of progression in the scans.

At some point, men with rising PSA will go on to develop metastatic disease. Other men unfortunately walk into your office with de-novo metastatic disease. The standard of care for men with metastatic prostate cancer in the castration-sensitive or naive space [has] historically…been androgen deprivation therapy (ADT), which is simply defined as medical or surgical deprivation of testosterone. In North America, medical testosterone suppression—so called “castration”—is most common and can be done via GnRH (gonadotrophin-releasing hormone) agonists or antagonists.

The challenge is [that] the longer those men live suppressed from testosterone, the more likely [it is] for them to become castration-resistant. And “castration-resistant” [has] a very simple definition; it requires for you to have a castrated testosterone level (traditionally less than 50 ng/mL) coupled with a rising PSA and/or evidence of clinical or objective progression, meaning symptoms and/or areas of radiographic progression. Importantly, ADT alone is no longer the standard of care for men with metastatic castration-sensitive disease. Treatment intensification with novel androgen receptor inhibitors (ARIs), docetaxel-based chemotherapy, or even adrenal biosynthesis inhibitors has become the standard of care.

TARGETED ONCOLOGY™: What therapy options currently exist for men with mCRPC?

GARCIA: The standard of care for those men [with mCRPC] is quite large today in North America. We have over 7 lines of therapy that are…life-prolonging agents for these patients. They include oral androgen receptor inhibitors: in the M0 (nonmetastatic) space, we have enzalutamide, darolutamide, and apalutamide; for the M1 (metastatic) space, only enzalutamide and abiraterone acetate are approved. Agents such as sipuleucel-T, which is an autologous cell product, is also FDA labelled in that space. It has demonstrated survival improvement but has no impact on PSA decline or radiographic/clinical improvement. You also have radionuclide-based therapies such as radium-223, again approved based upon survival benefit. And you also have 2 chemotherapies; first, docetaxel, and, the second-line of choice, cabazitaxel. Both chemotherapy regimens showed OS benefit and are FDA labelled in that setting.

So what I think is important to understand is when you look at this, there are many lines of therapy that our patients can receive, yet the sequence of such agents is not well understood; we don't understand [the] mechanisms of resistance. Hence, the sequence remains controversial. Further complicating this is that most of these agents—especially the oral agents—are now used earlier in the natural history of the disease. If, for instance, you use an oral androgen receptor inhibitor upfront, you may need chemotherapy in the second line.

Genomics have also increased therapy options for this population. Now, patients with castration-resistant disease who harbor DNA-repair deficiencies or have microsatellite unstable disease can receive oral PARP inhibitors or immune checkpoint inhibitors such as nivolumab and pembrolizumab, respectively.

VISION examined OS and rPFS in mCRPC. VISION’s success with the selected end points could potentially lead the FDA to approve LuPSMA for this indication. Simultaneously, many of us are trying to push this class of agents earlier in the natural history of prostate cancer—to even before patients become castration-resistant—to see whether these agents demonstrate the same efficacy and benefit in earlier disease states.

TARGETED ONCOLOGY™: How significant are VISION’s findings for the treatment of mCRPC?

GARCIA: VISION was a very specific trial. The patients were not clinically unique: They may have seen 1 prior ARI and up to 2 prior taxane-based regimens—which more than likely would have included docetaxel and/or cabazitaxel—which we frequently see in the clinic. However, VISION’s patients were…required to have a PSMA-positive PET.

[M]ost of us in the field realize that whole body bone scans using technetium-99 and CT (computed tomography) scans of the chest, abdomen, and pelvic region…have become obsolete, for the most part….With the approval of PSMA PET in North America this year, I think the field will move quite rapidly into that sophisticated imaging space. PSMA PET imaging is now part of the NCCN (National Comprehensive Cancer Network) guidelines. And I think that…[in] the next year to 5 years, we're going to be…using PSMA PETs right and left to…define how we…treat our patients.

The PET PSMA used in VISION was gallium 68 PSMA-11. All patients were required to have that PSMA PET imaging and to have a positive PSMA PET before they were entered into the trial.

Interestingly, over 85%—the vast majority—of patients were PSMA PET-positive by the definition used in this trial. This suggests that roughly 8-9 out of 10 of all mCRPC patients will have PSMA-positive PET scans and will be likely candidates for this LuPSMA if the FDA approves it.

The primary end points used [in VISION] were what they call…alternative primary end points. And that simply meant, as Mike Morris presented at ASCO this year, that the study…would have been positive if either or both primary end points were statistically significant. One end point was rPFS under the Prostate Cancer Working Group 3 (PCWG3) criteria: time from random assignment to symptomatic progression, radiographic progression, or death through any cause. The other end point was OS. The key secondary end points were typical for prostate cancer trials in that space: time to symptomatic skeletal-related events, overall response rate, disease control rate, PSAresponse, and safety and tolerability.

Regarding results…the important part…is that [for] the primary end point [of OS], the hazard ratio…in that trial was 0.62, which…means [a] 38% relative risk reduction of dying from prostate cancer if you receive LuPSMA, against the control arm….[T]his translates [to a median OS of 15.3 months and 11.3 months, respectively, with a] difference of around 4 months or so, between the 2 arms.

If you look…at the [other primary end point of] rPFS in the prolonged survival, just for this set of patients who actually had rPFS analysis, that also actually met their primary end point with a hazard ratio 0.6.

The important part is also that the hazard ratio observed in this study is somewhat consistent with other existing hazard ratios seen in that mCRPC setting. Remember, the hazard ratio for survival in most of the CRPC studies has ranged between 0.6 and 0.8, if you will, to 0.79. So [it’s] really consistent with what we have observed for for other drugs developed for this patient population.

Now, we don’t know the risk reduction of LuPSMA, relative to, for instance, multiple lines of chemotherapy. However, for patients who have been treated with a prior ARI and 1 prior chemotherapy—or even 2—there are very few options. Due to this and VISION’s positive results, I think that we in the field will embrace LuPSMA quite rapidly.

The expectation from most of us in the field is that LuPSMA will be labeled. The question is: How will the FDA be labeling this agent? Are they going to go strictly with the data? Are they going to adjust based upon what we feel is clinically relevant for these patients?

If this is labelled based upon PET-PSMA uptake, every patient who's interested and who meets the criteria for LuPSMA will be required to have PSMA PET imaging. The need for imaging could certainly create some delays in the adoption of LuPSMA. Likewise, because LuPSMA requires coordination between radiation oncology, nuclear medicine, and medical oncology, creating a multi-disciplinary approach (MTD) approach will be key to operationalize the use of this important agent.

Getting positive PSMA PET scan results won’t be a big barrier for LuPSMA because, as I said before, over 85% of CRPC patients are PSMA-positive. However, actually getting a PSMA PET scan might be a barrier. Although getting a PSMA PET is part of the NCCN guidelines, the recommendation is restricted to a specific group of patients. As clinicians across the states seek to expand use of PSMA PET and LuPSMA, it’ll be up to payers. Sometimes we struggle to get this imaging approved for our patients.

This said, I'm looking forward to testing our patients and to using LuPSMA for therapeutic purposes.

TARGETED ONCOLOGY™: What else should we keep in mind about the VISION trial?

GARCIA: We're attracted to this kind of new technology. However, there are still a lot of open questions.

For instance, we know that a lot of patients with mCRPC have heavily pretreated disease. Some have their bone marrow compromised by virtue of their bone metastases and previous treatments. Others have had prior radiotherapy for the primary tumor and even palliative radiation for a bone metastasis. Some get chemotherapy—number 1 with docetaxel and chemotherapy—number 2 with cabazitaxel. If you move those patients to LuPSMA, there could be concerns with myelosuppression. The emerging toxicity profile of this new class of agents—of the radioactive material—certainly contains myelosuppression: leukopenia, lymphopenia, anemia, thrombocytopenia. We're not accustomed to seeing that with chemotherapy.

[So] now we're going to have to start paying more attention to the side effects, as these can be quite cumbersome to manage. Blood product transfusion has stringent requirements, and myelosuppression can have a negative impact on our patients’ quality of life. I'm not too worried about nausea or vomiting, or about dry mouth or dry eye; we have a little bit of PSMA expression in the eye and the oral mucosa. But there are some unique side effects that are important for us to be aware of. They have to be learned—I shouldn't say learned, because medical oncologists do this—but certainly [we need to] be a little bit more in tune with [them], as we're not accustomed to see[ing] them drastically with the standard chemotherapies that we use, or for that matter, with the oral agents that we're using in that space.

Side effects will be particularly important as we move this agent earlier in the natural history of the disease, which is obviously anticipated. In oncology, drug development is based upon time from registration to end point. Testing an agent really late in the natural history of a disease is the best way to get to that end point. That is how we develop these trials to get an agent registered with the FDA. But biologically, it doesn't make any sense to hold that agent until that time. So, we've been moving all the agents—the ARIs, the abiraterone acetates, the chemotherapies—earlier in the natural history of prostate cancer. It is expected that LuPSMA will likely be moved earlier, as well. The big question then becomes: What is the long-term toxicity profile of LuPSMA? The sooner you use this class of agents, the longer it will take for us to truly see outcome improvement. How can you be sure that you’ll actually see those patients, 3, 5 years down the road?

We should also keep in mind that LuPSMA is not the only radioligand out there. There are many early agents out there looking also for a space in mCRPC: actinium-225–labeled PSMA ligands and the like. So this is probably the beginning of a new era of imaging as a biomarker and of treatment options for our patients.

TARGETED ONCOLOGY™: Should it be approved, do you foresee barriers to the adoption of LuPSMA?

GARCIA: The big question is whether a PSMA PET will be required for LuPSMA. Again, the results of the VISION trial suggest that the vast majority of men are PSMA-positive. If a PSMA PET were not required, it would be a pretty straight line: You’d meet the criteria for postchemotherapy and/or post-ARI and go on LuPSMA. However, if imaging with a PSMA PET is required, it’d be a 2-layer process: you’d go through PSMA PET imaging first, and if that were positive, you’d go on to LuPSMA.

There will also be a learning curve regarding who's going to own this patient: Is it medical oncology, nuclear medicine, or radiation oncology? Regardless, multidisciplinary care will be important. Someone will serve as quarterback and will bring the people who are needed to maximize care for that patient.

TARGETED ONCOLOGY™: How might the results of the VISION trial impact prostate cancer therapy in the near future?

GARCIA:I don't think the future could be more exciting for our patients, for all of us who do drug development in prostate cancer. I think we have accomplished quite a bit in the last 7 years [and] have drastically changed how we manage our patients. And I think the future is bright for the field and certainly for our patients, which is the primary reason why we do what we do.

There are 4 areas in which I expect that we're going to see a lot of movement. The first is in immune modulation and immune resistance for prostate cancer.

The second is in novel AR inhibitors—basically, they're not the traditional AR-binding inhibitors, but may be internal domain, or inhibitors of the co-ativator recruitment machinery as part of the biology of the androgen receptor. So AR will remain a player here. The question is, how do we target AR? And we’ve tried to move away from the traditional targets such as ligand-binding domain inhibitors.

The third area is genomics. Genomics will continue to play a major role in this disease. As we move forward with better genomic platforms, I think we're going to start discovering more relevant therapeutic targets.

The fourth area is what we’ve been discussing: imaging and the novel agents that we're developing. LuPSMA is probably the very beginning of these agents. There are a lot of agents out there very early in development that are vying for space in prostate cancer. And as I said before, actinium, the BiTE (bispecific T-cell engager) technology—there's a lot of excitement in those as well.

Our biggest hold is the lack of thorough understanding as to how patients become resistant. Right now we're treating to some extent as though 1 treatment fits all, with exceptions of PARP inhibitors; microsatellite, unstable tumors; maybe agents such as lutetium PSMA that require a PSMA-positive PET. However, the true biology behind 1 person becoming resistant on an ARI and moving to another agent and how they become resistant to a new agent has become quite elusive for us. A lot of people are hoping to develop more personalized therapy following resistance to a particular agent.

Reference

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