GU Oncologists Anticipate Earlier Role of Lutetium-177 PSMA-617 in Prostate Cancer

When the FDA approved lutetium-177 (¹⁷⁷Lu) vipivotide tetraxetan (¹⁷⁷Lu PSMA-617; Pluvicto), the agent became the first radioligand therapy authorized for use in patients with metastatic castration-resistant prostate cancer (mCRPC).¹ Targeting the prostate-specific membrane antigen (PSMA) protein provides a novel mechanism of action for patients who would otherwise receive chemotherapy.

In the wake of the approval, improved availability of the drug and the PSMA-PET scan have led to its widespread use. Now oncologists are further adapting to the regular use of the radioligand therapy in clinical practice and discovering which patients can benefit most.

As oncologists are seeing the impact of ¹⁷⁷Lu-PSMA-617 in the mCRPC setting, new research data are showing promise for using this drug in other settings. This would meet the need for tolerable therapy earlier in the disease course but could raise questions on the approach to patient selection.

When looking forward to a potential approval of radioligand therapy in the prechemotherapy setting, “we need to do a better job educating our providers on which patient needs a PARP inhibitor [or] chemotherapy, and which is a good candidate to go on [¹⁷⁷Lu-PSMA-617]…,” said Benjamin Garmezy, MD, associate director of genitourinary research for Sarah Cannon Research Institute in Nashville, Tennessee, in an interview with Peers & Perspectives in Oncology.

Using ¹⁷⁷Lu-PSMA-617 before chemotherapy has demonstrated a clinical benefit in radiographical progression-free survival (rPFS) to patients and spares them from challenging adverse events (AEs) and more onerous schedules involved with other therapeutic modalities, such as traditional chemotherapy. As such, genitourinary oncologists are eager to see the outcomes of current trials that may lead to new indications, which will bring new challenges in getting it to the patients who need it most.

“The earlier that you place a given therapy, historically, the greater the benefit that’s seen to the patient,” said Michael J. Morris, MD, Prostate Cancer Section head at Memorial Sloan Kettering Cancer Center in New York, New York, in an interview. “Generally, earlier patients have a lesser disease burden than the later patients; they themselves are in better shape and are in a position to enjoy the benefits of that therapy more so than later patients, and there are fewer resistance mechanisms in place in earlier disease than in more heavily pretreated patients.”

Lutetium-177 Moves Into Practice

Data from the phase 3 VISION trial (NCT03511664) led to the approval of ¹⁷⁷Lu-PSMA-617 in 2022 for patients who have received prior androgen receptor pathway inhibitor (ARPI) therapy and taxane-based chemotherapy, demonstrating benefit in rPFS, overall survival (OS), improved pain control, and improved quality of life (QOL).

Garmezy said that in his experience, the first patients treated in real-world practice were essentially deciding between ¹⁷⁷Lu-PSMA-617 and hospice, and this was not the ideal patient population to gauge the drug’s performance. “When [¹⁷⁷Lu-PSMA-617] first got approved, there was a rush of patients who needed to get it because they were out of all other FDA-approved options for their cancer,” he explained. “They had seen docetaxel, cabazitaxel [Jevtana], the hormonal therapies, [and] some of them had seen radium 223 [Xofigo] or sipuleucel-T [Provenge], and they were coming to get this drug as a last option.”

After this initial period, physicians started giving it more broadly to patients who had relapsed after androgen deprivation therapy (ADT) and ARPI followed by docetaxel, he said. According to Garmezy, ¹⁷⁷Lu-PSMA-617 has shown strong responses in the real-world population, though it comes with toxicities such as cytopenias including anemia and thrombocytopenia, mild fatigue, gastrointestinal AEs, and xerostomia.

He said the therapy’s 6-week dosing schedule is appealing to patients and physicians compared with every-3-week chemotherapy, and patients also avoid the toxicity of chemotherapy. Although patients in the VISION trial received 4 cycles followed by a PET scan before the final 2 cycles, Garmezy said that based on results from other trials, he prefers assessing patients for efficacy and toxicity every 2 cycles, starting at 12 weeks, to potentially modify treatment earlier and improve QOL for patients. However, he is conscious that even patients with prolonged PFS will ultimately experience progression and require additional therapy.

One notable challenge is that only a radiation oncologist or nuclear medicine radiologist can dispense this therapy. Garmezy said this creates a barrier for community oncology practices, who may have to work with a radiation oncologist outside their practice, whereas academic practices can work more closely to assess safety and toxicity risks.

Morris agreed that collaboration is sometimes an issue and said relationships between medical and radiation oncologists can vary from center to center, both in academic and community practice. “All of the medical stakeholders whose patients are receiving this therapy need to all be communicating together [and] reviewing their patients together. We should be doing that for any patient, but for this therapy specifically, it’s absolutely necessary to have those pipelines of communication open so that everyone can work together as a team to really comprehensively care for the patient, bringing their own expertise to the table.”

Employing PSMA-PET for Patient Selection

Garmezy said that in addition to prioritizing patients with unmet needs, he has put greater attention into patient selection based on other factors such as PSMA-PET scan uptake. Study data have shown that with a higher mean standardized uptake value (SUV) of 10 to 20, the chance of response with relative cut points of 20 or greater, 10 to 20, and less than 10, though patients with a mean SUV under 10 still have a chance of response with ¹⁷⁷Lu-PSMA-617.² He said he is eager for more data on stratifying patients based on PSMA levels to determine if they could receive a better option.

“There’s a misapprehension there that if you don’t have an SUV mean of 10, you’re not going to benefit from lutetium. That’s not true,” Morris noted. “VISION [data] showed that even if you have a lower SUV mean than 10, you may not do as well in terms of responding as those who had a higher SUV. Nonetheless, even those with lower SUV values who received lutetium had superior cancer outcomes relative to those in the control group, who did not.”

The PSMA-PET scan was less commonly available at the time of the FDA approval, but Garmezy said he no longer sees it as a barrier to access. “What you’re seeing is more and more community physicians using PSMA-PET scans in other settings—in the frontline metastatic setting [and] in the high-risk localized disease setting, to see if there are oligometastases that pop up on a PSMA-PET scan that wouldn’t otherwise show up on a CT scan, and in the biochemical recurrence setting.” The information in a PSMA-PET lets physicians know earlier whether patients would be eligible for ¹⁷⁷Lu-PSMA-617. Garmezy said that a PSMA PET needs to be repeated prior to assessing candidacy for ¹⁷⁷Lu-PSMA-617 if it hasn’t been performed recently, because expression can change over time.

Earlier Therapy Shows Efficacy and Tolerability

Positive outcomes from the phase 3 PSMAfore study (NCT04689828), data for which were first presented at the 2023 European Society for Medical Oncology (ESMO) Annual Congress, have led to great interest in using ¹⁷⁷Lu-PSMA-617 before chemotherapy, although still in the mCRPC setting. In this trial, patients who had received 1 prior ARPI (enzalutamide [Xtandi] or abiraterone [Zytiga]) in any setting were randomly assigned 1:1 to receive a different approved ARPI or ¹⁷⁷Lu-PSMA-617.

At the third interim analysis, with a median follow-up of 24.11 months, ¹⁷⁷Lu-PSMA-617 demonstrated a superior rPFS vs ARPI switch with a median of 11.60 months vs 5.59 months (HR, 0.49; 95% CI, 0.39-0.61); P < .0001), the primary end point.³ The agent also showed improvement in overall response rate (41.9% vs 12.6%, respectively) and QOL.⁴ In the third interim analysis, investigators also reported it significantly prolonged time to symptomatic skeletal even vs ARPI change (HR, 0.41; 95% CI, 0.26-0.63).⁵

Because proceeding to docetaxel instead of switching ARPI is another recommended treatment option in this setting, physicians determined that patients in this study were appropriate candidates for an ARPI switch before enrollment in this trial. Patients randomly assigned to the control arm were permitted to cross over and receive ¹⁷⁷Lu-PSMA-617 when they reached the primary end point of radiographic progression. Seventy-eight percent of patients eligible for crossover received ¹⁷⁷Lu-PSMA-617, a possible contributing factor to there being no observed OS difference between the arms reported at the third data cutoff (unadjusted HR, 0.98; 95% CI, 0.75-1.28).⁶

Morris, who was an investigator on the trial, said that the QOL data presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and 2024 ESMO Congress provide strong support for ¹⁷⁷Lu-PSMA-617 in this setting. “If you look at those QOL data, there is a clear advantage in terms of tolerability and preservation of QOL and pain control in favor of [¹⁷⁷Lu-PSMA-617].”

At the third interim analysis, Functional Assessment of Cancer Therapy-Prostate total score showing time to deterioration was a median of 7.46 months with ¹⁷⁷Lu-PSMA-617 vs 4.27 months with ARPI (HR, 0.61; 95% CI, 0.50-0.75). Additionally, its subscales of physical, functional, and emotional well-being also favored ¹⁷⁷Lu-PSMA-617, with only social/family well-being not showing a clear difference.⁵ The EQ-5D-5L utility score for health-related QOL also favored ¹⁷⁷Lu-PSMA-617, with a median of 6.28 vs 3.88 (HR, 0.67; 95% CI, 0.54-0.82). The Brief Pain Inventory-Short Form measures showed a reduction in time to worsening in pain intensity (HR, 0.72; 95% CI, 0.59-0.88) and time to worsening in pain interference (HR, 0.67; 95% CI, 0.54-0.83).

“Although they may not have a demonstrable improvement in OS, they have delayed cancer deterioration in terms of radiographic progression; they have an improvement in terms of maintenance of their QOL that is superior in favor of lutetium by 2 different QOL tools and an improvement in their pain control as well,” said Morris. “That’s a pretty compelling reason to choose one drug over another. Even if patients haven’t been demonstrated to be living longer by receiving [¹⁷⁷Lu-PSMA-617] instead of an ARPI, they’re living better if they have lutetium as opposed to the ARPI switch.”

In PSMAfore, 15% of patients required a dose reduction of ARPI because of treatment-related AEs vs only 3.5% with ¹⁷⁷Lu-PSMA-617. Morris said this was a surprise because the ARPI switch is considered a “benign” approach in terms of AEs, and he suggested that a lower rate of treatment-emergent AEs with ¹⁷⁷Lu-PSMA-617 could be attributed to its tolerability and superior tumor control.

The rate of any-grade xerostomia in PSMAfore was 57.3%, with only 1.3% of grade 3 or higher.⁶ Although the rate of any-grade anemia was 24.2% with ¹⁷⁷Lu-PSMA-617 vs 16.8% with ARPI switch, the rate of high-grade anemia was similar at 6.2% vs 6.0%, respectively. Any-grade fatigue was comparable at 22.9% vs 25.4%. In the VISION trial, ¹⁷⁷Lu-PSMA-617 plus standard of care was associated with 43.1% any-grade fatigue, 31.8% anemia, and 38.8% xerostomia compared with 22.9%, 13.2%, and 0.5%, respectively, with standard of care alone in the postchemotherapy setting.⁷

“All in all, when you take into account that lutetium-177 looks more tolerable and preserves QOL, and the [AEs] look quite acceptable, it’s the preferred way to go,” said Morris.

Another phase 3 trial of a radioligand therapy, SPLASH (NCT04647526), reported positive outcomes at the 2024 ESMO Congress compared with ARPI switch in mCRPC. The trial met its primary end point of rPFS with a median of 9.5 months for ¹⁷⁷Lu-PNT2002 vs 6.0 for ARPI (HR, 0.71; 95% CI, 0.55-0.92; P = .0088) and demonstrated a favorable safety profile.⁸

Further Research Paths

The current use of ¹⁷⁷Lu-PSMA-617 has left some gaps that researchers are now addressing. Morris noted that many patients don’t respond to it, whereas others will relapse during the course of 6 cycles or afterward. “There is a clear need for better strategies because you want to be able to effectively treat those patients who aren’t responding—and I’m talking about patients who otherwise do have PSMA-avid disease—and you want salvage therapy as well for patients who either respond and then progress while on treatment, or who continue to respond but aren’t eligible to receive any more therapy.”

He said radiopharmaceuticals based on alpha emitters have different properties than beta emitters such as ¹⁷⁷Lu-PSMA-617, and data suggest that patients whose disease responded to ¹⁷⁷Lu-PSMA-617 could continue to respond, and those whose disease did not respond to ¹⁷⁷Lu-PSMA-617 could respond to an alpha emitter such as actinium-225. “The alpha [emitters] are in various stages of clinical development, from phase 1 to more mature studies, to determine…the best way to utilize this class of drug, as well as what the clinical benefits are. We’re pretty excited about this next generation of radiopharmaceuticals,” he said.

There are other targets for radiopharmaceuticals besides PSMA; Morris brought up his recent ASCO presentation of a first-in-human study [NCT04644770] of JNJ-69086420 (JNJ-6420), a first-in-class anti-hK2 antibody-based targeted radiotherapy delivering actinium-225 in patients with mCRPC. This agent showed durable biochemical and radiographic responses targeting this kallikrein encoded by the KLK2 gene, although patients also experienced toxicities, including dose-related thrombocytopenia and interstitial lung disease which can be mitigated by imposing a cumulative dose cap.⁹ Morris also said targeting DLL3 in neuroendocrine prostate cancer and the STEAP gene family are soon to be explored.

Other trials are looking at earlier use of ¹⁷⁷Lu-PSMA-617, such as the randomized phase 2 ENZA-p trial (NCT04419402) from the Australian and New Zealand Urogenital and Prostate Cancer Trials Group, whose data showed the efficacy of using adaptive dosing to combine the drug with enzalutamide as first-line therapy for mCRPC. Investigators reported improved prostate-specific antigen PFS for the combination, with a median of 13 months vs 7.8 months for enzalutamide alone (HR, 0.43; 95% CI, 0.29-0.63; P < .001).¹⁰

Morris is also involved in the ongoing phase 3 PSMAddition study (NCT04720157), which is investigating the combination of 6 cycles of ¹⁷⁷Lu-PSMA-617 with standard-of-care ARPI plus ADT vs standard of care alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC). The primary end point is rPFS, with OS being a key secondary end point. He said the study has fully accrued its target number of approximately 1126 patients to be randomly assigned on a 1:1 basis. Due to the longer rPFS and OS expected of this population, Morris said this trial will take longer to yield results compared with VISION or PSMAfore.

Garmezy noted that data from the ARASENS (NCT02799602) and PEACE1 (NCT01957436) trials of ADT, ARPI, and docetaxel demonstrated the advantage of triplet therapy in the mHSPC setting vs chemotherapy plus ADT. “Because of that story, I am thinking that [¹⁷⁷Lu-PSMA-617] in that setting might do the same thing that chemotherapy is doing, which is debulking the disease, reducing the amount of potential resistant clones that can develop to hormonal therapy, and therefore extending the duration in the hormone-sensitive setting,” he said.

Another ongoing trial, PSMA-DC (NCT05939414), is comparing ¹⁷⁷Lu-PSMA-617 with observation in the oligometastatic setting after radiation to all sites of disease, with the goal of controlling progression and the need for ADT/ castration. “Is there a way that we can use this to help or one day cure a patient with low-volume metastatic disease?” Garmezy asked. “Or is there a way to at least improve the QOL of men and extend their survival, whether it’s delaying castration [or] improving the time with no skeletal events…or bone pain? We are at the beginning of the radioligand chapter in prostate cancer and look forward to more results to improve the lives of men with prostate cancer.”

REFERENCES:

1. Novartis Pluvicto approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA-positive metastatic castration-resistant prostate cancer. News release. Novartis. March 23, 2022. Accessed September 10, 2024. https://tinyurl.com/54h6x47b

2. Kuo P, Hesterman J, Rahbar K, et al. [68Ga]Ga-PSMA-11 PET baseline imaging as a prognostic tool for clinical outcomes to [177Lu]Lu-PSMA-617 in patients with mCRPC: a VISION substudy. J Clin Oncol. 2022;40(suppl 16):5002. doi:10.1200/JCO.2022.40.16_suppl.5002

3. Morris MJ, Castellano D, Herrmann K, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. Published online September 15, 2024. doi:10.1016/S0140-6736(24)01653-2

4. Sartor O, Castellano Gauna DE, Herrmann K, et al. Phase III trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). Ann Oncol. 2023;34(suppl 2):S1324-S1325. doi:10.1016/j.annonc.2023.10.085

5. Fizazi K, Morris MJ, Shore ND, et al. Symptomatic skeletal events, health-related quality of life and pain in a phase 3 study of [177Lu]Lu-PSMA-617 in taxane-naive patients with PSMA-positive metastatic castration-resistant prostate cancer: third interim analysis of PSMAfore. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Poster 1599P.

6. Fizazi K, Morris MJ, Shore ND, et al. Health-related quality of life and pain in a phase 3 study of [177Lu]Lu-PSMA-617 in taxane-naïve patients with metastatic castration-resistant prostate cancer (PSMAfore). J Clin Oncol. 2024;42(suppl_16):5003. doi:10.1200/JCO.2024.42.16_suppl.5003

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

8. Sartor O, Jiang DM, Smoragiewicz M, et al. Efficacy of 177Lu-PNT2002 in PSMA-positive mCRPC following progression on an androgen-receptor pathway inhibitor (ARPI) (SPLASH).Presented at: ESMO Congress 2024. Barcelona, Spain. September 13 – 17, 2024. Abstract LBA65.

9. Morris MJ, Wong JYC, Nordquist L, et al. A phase 1 study of JNJ-69086420 (JNJ-6420), an actinium-225 (225Ac)-labeled antibody targeting human kallikrein 2 (hK2), for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2024;42(suppl 16):5010. doi:10.1200/JCO.2024.42.16_suppl.5010

10. Emmett L, Subramaniam S, Crumbaker M, et al. Enzalutamide and 177Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer (mCRPC): a randomised, phase II trial: ENZA-p (ANZUP 1901). Ann Oncol. 2023;34(suppl 2):S1325. doi:10.1016/j.annonc.2023.10.086