The increased prevalence of radiopharmaceuticals has provided the opportunity for patients with prostate cancer to preserve their quality of life. Although not many of these therapies are FDA approved, there is a lot of promise that they will be paradigm-changing in the future, according to Scott T. Tagawa, MD, MS, FACP.
At the 15th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies (NY GU 2022), Tagawa presented a talk on the evolution of therapeutic radiopharmaceuticals in prostate cancer.1 In an interview with Urology Times, he discusses the main points of this presentation as well as other innovations in this space. Tagawa is a professor of medicine and urology and medical director of the Genitourinary Oncology Research Program at Weill Cornell Medicine in New York City. He is also an attending physician on the Cornell campus at New York-Presbyterian Hospital.
At NY GU 2022, I was able to provide a review on therapeutic radiopharmaceuticals, titled, "The Past, the Present, and the Future," [which] really focused on 2 main ones: Radium-223 and PSMA-targeted radionuclides. The background for both is that radiation is one of the cornerstones in the treatment for prostate cancer—most traditionally, either shooting it in with external beam or putting it in with brachytherapy. We use it [to] both cure [patients] as well as [for] palliation, and then more recently, we've had a couple of drugs that have been able to be administered systemically to radiate certain compartments. Radium-223 is a calcium mimetic, meaning that we put into the blood, it circulates around, and lands in bone like calcium and specifically binds to hydroxyapatite. It's an alpha emitter, so a very potent piece of radiation with a very short penetration—just a few cells. [In] the ALSYMPCA trial [NCT00699751], which was in patients with at least 2 bone metastases [who] had symptomatic disease, radium-223 with best supportive care vs best supportive care led to a survival improvement.2
Since that time, we've looked at a number of different [possibilities], such as, should we give more, meaning higher dose or more than 6 cycles? That's a no, answered by my colleague Cora Sternberg[, MD]. Should we combine? There are a couple of ongoing phase 2 and 3 trials. One combination that we know to not give is for patients with non-symptomatic or minimally symptomatic metastatic [castration-resistant prostate cancer (CRPC)]. Starting radium-223 with abiraterone, the ERA 223 trial [NCT02043678] showed us that it did not work, [and this combination] lead to increased toxicity in terms of fractures.3 Bone health agents, which we should be using anyway for patients with metastatic CRPC to bone, decrease that chance of a fracture and other skeletal related events. There are [also] 2 ongoing phase 3 trials assessing radium-223 combinations. So, a similar combination in PEACE III [NCT02194842],4 but rather than in combination with abiraterone [Zytiga], it is with enzalutamide [Xtandi] in men with chemo-naïve mCRPC. The investigators in Europe had the advantage of knowing ERA 223 and were able to institute early bone health agents. We've seen data at ASCO a couple of times, including last year, that shows that with the bone health agents, this looks safe, although we do not yet know efficacy. The DORA study [NCT03574571] is the combination of docetaxel and radium versus docetaxel alone in men with metastatic CRPC including bone metastases based on a positive randomized, phase 2 by Michael Morris[,MD] and colleagues. That is enrolling now for men with metastatic CRPC, and we hope to see a benefit from that combination.
We also learned to target PSMA with radioactive particles. PSMA is a cell-surface antigen expressed on the majority of, but not all, prostate cancers. We know that we can label small molecules or antibodies with either alpha emitters or beta emitters and maybe the future would be auger emitters. But for now, what is furthest along are the small molecules (although 1 antibody is in phase 3) radio-labeled with a beta emitter lutetium-177. In the last year or so, 2 randomized trials have read out. A randomized, phase 2 [trial involving] highly selected patients tested lutetium PSMA 617 vs cabazitaxel [Jevtana] in patients with metastatic CRPC after docetaxel. [A] majority happened to receive an AR pathway inhibitor as well, and there were PSA outcome measures that were improved. And then the VISION trial [NCT03511664] examined lutetium PSMA 617 in combination with best standard of care versus best standard of care alone, which led to an improvement in both overall as well as radiographic progression free survival.5
Overall, this type of therapy is reasonably well tolerated. There are some specific adverse events that we do associate with these drugs, such as myelosuppression (including thrombocytopenia). There is also dry mouth and nausea, likely having to do with the PSMA-positive sites that these small molecules can reach in the salivary gland and small intestine, as well as the possibility of renal toxicity, although we haven't seen that to a significant degree. Despite the increase in some adverse events, there is a prolongation of time to deterioration of quality of life in the VISION trial, likely because of better disease control. So, these are the radionuclides that are either in practice right now, or likely soon to come, and we look forward to the optimization of these drugs.
Radiopharmaceuticals are clearly effective. We have 2 drugs that have proven overall survival advantages, [but] we have no head-to-head trials. So, we cannot say that one is better than another. These drugs are complementary. We have an alpha that targets bone. The advantage of an alpha is that it's very potent, with very short penetration and bone is a great target for prostate cancer because many men with advanced prostate cancer have bone metastasis. That is an advantage, as there's not a lot of other toxicity. The disadvantage is it goes to only bone and patients without bone metastasis we don't think will benefit, as well as patients with bone metastasis and other sites of extra-osseous metastasis are less likely to benefit in these sites of metastases. PSMA-targeted radionuclide therapy goes to all sites of PSMA positivity. Most of the drugs—in fact, all of the drugs in phase 3—are labeled with lutetium-177, which is a beta emitter. The advantage of a beta emitter is it has a longer path length, so it can go many, many cells. But the disadvantage is a longer path length and a weaker energy level, so there can be the potential for additional toxicity.
[Overall,] there's no known advantage or disadvantage in a head-to-head trial of either one of these, but I do think they're complementary. A relatively common question that I'll hear is, “Can we use both?” We do not know about the combination together, meaning concurrently. We do have some prospective data about sequential use. Most of the data have to do with radium-223 first, followed by one of the lutetium agents. That is 20% or so of many of the prospective trials. There are also data for patients that got radium-223 after these lutetium PSMA agents in some of the prospective, randomized trials, including VISION.
With the existing drugs, we are looking to make them better. One way, which we've done with many different drugs, whether you're talking about docetaxel, abiraterone, enzalutamide, etc, [is] we made them better by treating a more optimal patient population, and that is early. We think that, particularly for the PSMA-targeted radionuclides, that is going to lead to more major improvements. So, hopefully [that means] translating a median of months to a median of years with a larger hazard ratio. We hope that we can better identify in whatever subset of patient population better patient selection. Imaging appears to be one way that we're able to do that. Hopefully, we'll be able to look at additional factors as well as potential from things like genomics. We're now looking at combinations. An obvious combination to me is in combination with [androgen receptor (AR)] or hormonal therapy, where we might be able to modulate both PSMA expression as well as radio sensitivity. There are a number of other combinations that are ongoing, not limited to but including PARP inhibitors as well as immune checkpoint inhibitors.
What I'm quite hopeful for are PSMA-targeted alpha emitters. We know that alpha emitters work in terms of radium-223, but that's bone-targeted rather than tumor-targeted. So, with these very potent radionuclides, we've seen anecdotes of some very impressive responses with now at least 3 prospective trials that are ongoing. One that is read out with an antibody called J591 radio-labeled actinium-225. There is another antibody radio-labeled with thorium-227 that is also ongoing that I expect to read out later this year. And then, even though the first one published anecdotally was PSMA 617, radio-labeled with actinium-225 because that was retrospective with the first prospective trial being initially last year. So, I think that there is a lot of hope that if we're able to safely administer these targeted alphas, that there is hopefully going to be an even bigger bang for our buck.
With the approved agent radium-223, as well as and probably even more importantly, with what we expect to be the soon-to-be-approved agent lutetium PSMA 617, besides the adverse events that may happen to the patient, we should be aware that there is some exposure to the public. The patient's immediate family and caregivers are likely to be the most effected. Lutetium has a low gamma emission rate, but when we give it at a therapeutic dose, there is a reasonably significant gamma emission where people can be exposed. For the most part, short exposures, especially being feet away from the patient, is not that big of a deal. But, particularly in the first couple of days after a therapeutic dose, we need to be mindful of other living beings. I suppose that could include pets, we generally think about family, so partners, kids, grandkids, etc. [It is] okay to interact, but in the first couple of days, not many, many hours of very close contact.
1. Tagawa ST. Therapeutic radiopharmaceuticals: Past, present, and future. Presented at: 15th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies; New York City, New York. March 11-12
2. Hoskin P, Sartor O, O’Sullivan JM, et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014;15(12):1397-1406. doi:10.1016/S1470-2045(14)70474-7
3. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 March;20(3):408-419. doi: 10.1016/S1470-2045(18)30860-X. Epub 2019 Feb 6
4. Phase III radium 223 mCRPC-PEACE III (PEACE III). ClinicalTrials.gov. Updated July 31, 2020. Accessed March 22, 2022. https://clinicaltrials.gov/ct2/show/NCT02194842
5. Sartor O, de Bono J, B CH, 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