A whole new form of treatment for metastatic castrate-resistant prostate cancer (mCRPC) is here: PSMA-targeting therapy. The first PSMA-targeting therapy approved in the U.S. – with more being tested now in clinical trials – is LuPSMA (177Lu-PSMA-617; Pluvicto®), previously discussed here.
We asked medical oncologist and PCF-funded scientist Michael J. Morris, M.D., of Memorial Sloan Kettering Cancer Center, for a guide to the specifics of getting LuPSMA:
Who’s eligible for this treatment? To qualify, men must have metastatic CRPC that has progressed despite androgen deprivation therapy (ADT), an androgen receptor (AR)-blocking drug such as abiraterone, enzalutamide, apalutamide, or darolutamide and prior treatment with chemotherapy, in addition to having a positive PSMA-PET scan.
What are the benefits? “If you look at the overall study results,” says Morris, “about half the patients had major responses to LuPSMA, and 10 percent of those men had complete responses” – meaning they had no evidence of disease by standard imaging. In the men who had major responses, PSA levels plummeted, spots of metastasis shrank or disappeared, the men felt better, had less pain, more energy, and an improvement in quality of life.
There are some side effects, including a risk of anemia, and “during the period of infusion, about 40 percent have some upset stomach,” which was helped by anti-nausea medication. “Overall, it’s a pretty manageable therapy.” For many men, LuPSMA is better tolerated than chemotherapy, and produces a better response. “This population of patients has very advanced disease and few treatment options,” says Morris. “This is a really promising and helpful therapy to help these men not just live longer, but better, as well.”
LuPSMA is not a cure. But these are early days yet, and LuPSMA promises to open other treatment possibilities. “Perhaps if we move the treatment up earlier in the disease, the benefits for patients will be even more amplified. We have seen this with several drugs in prostate cancer: if you give it when the disease is less advanced, the more benefit you see.” This idea is being explored in other trials, including the PSMAfore trial, which has just completed patient recruitment. “This is an international study testing LuPSMA in men who have not received chemotherapy who have metastatic castrate-resistant prostate cancer (CRPC), and who have progressed through one AR pathway inhibitor, so it’s one step earlier” than what the FDA currently approves.”
A second trial, one step earlier still, is called PSMAddition. “This is for men who do not yet have CRPC, who still respond to hormonal therapy.” Participants in this trial are randomly assigned to receive either ADT plus an AR inhibitor and LuPSMA, or just the hormonal therapy alone.
Still other trials under way are investigating radioligand therapy using many different tactics. Generally, Morris continues, “in advanced disease, if you put someone on a drug that inhibits AR signaling, PSMA expression goes up. When PSMA goes up, the effectiveness of radioligand therapy likely goes up: the more drug that adheres to the prostate cancer cells because there are more PSMA molecules, the more radiation you’re able to get to the tumor.” In laboratory studies, scientists are also working on laying the groundwork for success: exploring ways to turn up PSMA expression to maximize the radioligand’s effectiveness – like preparing a field before the crop is planted.
Another mechanism that might make LuPSMA and other radioligands more effective is to double down on the mechanism of action. “When you deliver radiation to prostate cancer cells, you’re damaging the DNA,” Morris says. “We have agents that inhibit DNA repair in the form of PARP inhibitors (such as olaparib), already approved for prostate cancer patients with DNA repair defects (who have tumor mutations in genes such as BRCA 1/2). We could potentially give a PARP inhibitor with a DNA-damaging agent like LuPSMA, and get a more durable response that way.” Or, it may be that patients with a mutated DNA damage repair gene turn out to be “particularly sensitive to radioligand therapy. There are many different strategies we’re looking at to enhance the effect of LuPSMA, or have radioligand therapy enhance other drugs. All these questions are wide open.”
Yet another way to go might be to use radioligand therapy in combination with immunotherapy. “DNA damage also increases the immune response,” says Morris. “A lot of new immune therapies are being tested right now. Perhaps radioligand therapy can improve the immune response to prostate cancer, and immunotherapy can also improve the response to the radioligand.”
Then there’s the LuPSMA treatment regimen itself. Can it be improved? “Currently, we give it in four cycles, one every six weeks, with the option of two additional cycles if it looks like the person has tolerated treatment well,” says Morris, “so a total of six cycles every six weeks.” There is anecdotal experience from countries that have been using radioligand therapy longer than the U.S., of giving more cycles. “I think we need to do those studies in a formal way, to generate the data as to how many cycles is safe and tolerable, when do you stop, and when do you keep going. There’s nothing magic about six cycles. There’s also nothing to say that’s the optimal way of giving it; perhaps some patients would benefit from fewer treatments, with more prolonged breaks in between if they have a good response. Maybe we could stretch it out.
“There are so many questions about optimization,” he continues. “Certainly, the VISION trial answered some questions: does it prolong life? Yes. Can we identify patients who will benefit from it? Yes. But different sets of questions have now opened up: Which patients will benefit the most? Which patients are less likely to be helped, and should instead try a different treatment?”
Although “we usually give it a cycle or two before we assess whether a patient is responding or not, some patients do really have significant and quick responses” to LuPSMA. “There are some extraordinary responders, and then some patients who don’t respond at all. We really want to understand how to distinguish between the two.”
As a field, radioligand therapy is still very new. “This is that first entrée into it for prostate cancer. The first step of a long road.” And yet, because the results have been so promising, Morris is seeing patients who want to undergo radioligand therapy very early on – “instead of up-front ADT or even before surgery or radiation! We don’t have the data to say we should be using it outside of a clinical trial.”
But LuPSMA has already done something very important in the field of prostate cancer: It has offered new hope, Morris says. “It’s good for everybody.” For patients and their families, it brings results that improve quality of life: “PSA drops, metastatic lesions shrink, patients feel better, have more energy and feel more like their old selves.” It makes doctors feel happy and encouraged, too: “Doctors lose sleep over our patients. We worry about them. We get very attached to them. We want them to live, and live well, and live the best lives they can. Having a therapy that allows them to do well is important to them, and to us.”