Though the radioligand therapy lutetium Lu 177 vipivotide tetraxetan was approved in 2022 for PSMA-avid patients, several practical considerations have limited its use among patients with prostate cancer.
Patients with metastatic castration-resistant prostate cancer (mCRPC) have limited options after progression on docetaxel and an androgen receptor (AR)-targeted therapy. One target for these patients is prostate-specific membrane antigen (PSMA). The radioligand therapy lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617; Pluvicto) was approved in 2022 for PSMA-avid patients, but several practical considerations have limited its use.1
To use this agent, patients must have PSMA-avid status on a PSMA PET scan. This scan is gradually becoming more widely used in patients with prostate cancer, but some providers still face availability issues.
Supply issues in 2022 and 2023 prevented many patients from receiving 177Lu-PSMA-617. Even with the shortages resolved, multiple factors contribute to delays in getting patients access to treatment. The time from ordering a PSMA PET scan to accessing 177Lu-PSMA-617 is too long for some patients with aggressive disease, considering that patients in the arm of the pivotal VISION study (NCT03511664) who did not receive the radioligand treatment had a median progression-free survival of only 3.4 months.2 Insurance approvals can also slow the process, and the expense of this medication is an additional barrier.
During the Targeted Oncology™ Case-Based Roundtable Meetings on mCRPC, academic and community oncologists have discussed their perspectives on the use of PSMA PET scans and 177Lu-PSMA-617. Many physicians described their challenges in accessing the agent to treat these patients.
“Due to supply shortages, we can’t even start patients on the drug. But when we could, they still had a delay in start-up,” Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, told participants at a live, virtual Targeted Oncology event he moderated in March 2023 for physicians based in southwestern states. “It’s going to be 6 to 8 weeks at least before they can start on [the] drug and there are patients who are going to decline in that window. This potentially impacts the decision of whether or not to use cabazitaxel [Jevtana] because that is immediately available.”
Physicians discussed the struggles they have had with shortages and the approaches they have taken, such as getting PSMA PET scans earlier and considering other treatment options for this patient population.
177Lu-PSMA-617 has a shelf life of 5 days from the date and time of calibration,3 complicating the availability compared with other agents. In May 2022, there was a temporary suspension of production of 177Lu-PSMA-617by Novartis due to a potential quality issue in its facilities in Ivrea, Italy, and Millburn, New Jersey, leading to shortages not long after its March 2022 FDA approval.4 A report from the Dana-Farber Cancer Institute in Boston, Massachusetts, concerning 146 patients referred between May and October 2022 measured a delay of approximately 8 weeks before starting 177Lu-PSMA-617 therapy, with 6 out of 127 approved patients (5%) dying during this wait.5
Another delay in production was reported in March 2023; the manufacturer reported on April 21, 2023, that production was expected to begin at the facility in Millburn in coming weeks; and another facility in Indianapolis, Indiana, is expected to open as soon as the end of 2023.6
“Until a couple of months ago, we did not have the availability of this. Only 2 centers were doing it. PSMA scan was available but [177Lu-PSMA-617] was not available,” Rao Mushtaq, MD, assistant professor at National Jewish Health Northern Hematology-Oncology in Denver, Colorado, said as a participant in the event moderated by Bryce. “Billing was an issue. Availability is one important factor and the cost is another. Logistics is another thing because I’m in a Denver suburb and the patients I see—for them to go to a center where they can get this treatment would be easily 25 to 30 more miles. This treatment is given every 6 weeks, so that’s another burden on the patient.”
Another virtual event in December 2022 featured oncologists in Pennsylvania and was moderated by Daniel M. Geynisman, MD, chief of the Division of Genitourinary Medical Oncology and associate professor, Department of Hematology/Oncology, at Fox Chase Cancer Center in Philadelphia. Physicians in this event also discussed cost and logistics as barriers to use. Some participants expressed that although they wanted to use the radioligand therapy, it was not cost-effective to provide in their practice or was not available yet.
John A. Kosteva, MD, of Penn Medicine, told others that he was not able to prescribe the therapy at the time of the event but was in the process of getting access. “We tend to refer out to other centers,” he said. “We do have access to PSMA [PET] scanning, although it’s a little more limited. It’s only at our main campus and not the satellite offices out in the suburbs.”
Due to the extended process of accessing 177Lu-PSMA-617, physicians have become concerned with the impact of delays on patient care. The Dana-Farber Cancer Institute study identified a time span of 11 days (IQR, 6-20 days) between PSMA PET/CT scan and tumor board review as an additional source of delays.5 The time between tumor board review and cycle 1 of 177Lu-PSMA-617 was 59 days (range, 32-129 days), with the median delay increasing from 41 days in May 2022 to 96 days in October 2022 as the institution was affected by supply issues.
These delays may lead physicians to use other agents; during this period at Dana-Farber, 45 patients (35%) continued an existing therapy or started a different one instead of waiting.
“We have to send them for the PSMA PET [scan], and then we have to send them to another institution for the [177Lu-PSMA-617],” Joshua A. Strauss, MD, of Advanced Care Oncology & Hematology Associates in New Jersey said of his own practice at the event moderated by Geynisman. “By that time, you could get 3 doses of cabazitaxel in. One thought was maybe [using] both…you could use cabazitaxel as a bridge to the [177Lu-PSMA-617] because it takes time. From the moment I conceive of it to the time that it’s actually given, it’s many weeks.”
The chemotherapy cabazitaxel is approved in the same space as 177Lu-PSMA-617, and the TheraP trial (NCT03392428) showed similar outcomes for the 2 agents.7 However, the outcomes of using one therapy before the other have not been studied fully, and it may cause a poorer response or be intolerable.
“The question is how much can the bone marrow take? If you look at the TheraP trial, [patients] did get cabazitaxel after [177Lu-PSMA-617] and vice versa. I think it’s feasible; I think it’s possible. I think there are going to be some patients [for whom] you can’t [do it],” said Geynisman.
In addition to the potential for a patient’s condition to decline due to delays, the Dana-Farber report also noted that a patient’s PSMA status may change if the scan is performed 3 or 4 months prior to use of 177Lu-PSMA-617, especially when other agents are used.5
Bryce observed that physicians may have opportunities to use 177Lu-PSMA-617 earlier, as other trials are finding evidence supporting the use of taxanes and AR-targeted therapy in the hormone-sensitive setting. “If you do triplet therapy for hormone-sensitive disease, a patient is eligible for [177Lu-PSMA-617] as second-line therapy because they’ve already cleared that bar, or [also for] cabazitaxel.”
Waiting for disease progression to get a PSMA PET scan is one source of delays, so ordering the scan earlier is seen as a way to streamline the process of using 177Lu-PSMA-617. Geynisman said it is easier to get the scan first and then be able to send patients to a treatment center at progression.
Because the PSMA PET scan is being used earlier for patients with prostate cancer, this also enables physicians to know in advance whether patients can be considered for 177Lu-PSMA-617.
“A lot of times they’ve been getting it for the high-risk patients with localized disease where you’re worried there may be more than localized [disease]. That’s where the radiation oncologists are getting it. We’ve been getting it for patients with biochemical recurrence, trying to find lesions that potentially we can [use] stereotactic body radiation therapy and avoid systemic therapy for a while,” Geynisman explained.
A retrospective study of patients at Sydney Adventist Hospital in Wahroonga, Australia, found that among 30 patients on active surveillance for low or favorable intermediate prostate cancer, 15 out of 19 who needed treatment had adverse features on a PSMA PET/CT scan.8 Alternately, it can show when patients will not benefit from localized treatment due to unknown metastases.
“Sometimes it really is helpful, I think, especially in situations where maybe someone wants to do surgery and then all of a sudden you get a PSMA [PET scan], and there’s much more than meets the eye. You can spare somebody that unnecessary noncurative surgery,” Geynisman said.
Other physicians at the event moderated by Geynisman agreed that they may use the scan earlier. “Prior, I was doing the fluciclovine [18F] PET scan [Axumin] as my go-to prostate [cancer scan] but I think now I’m replacing it with the PSMA [PET]. A lot of times we already had the results of it before we get to the point of even determining if they’re eligible [for 177Lu-PSMA-617] or not,” said Kosteva.
“If the PSMA PET scan is available, there is no reason to do the regular PET scan,” said Alexander Barsouk, MD, of Allegheny Clinic Medical Oncology in Natrona Heights, Pennsylvania. “You might as well do PSMA [PET] for prostate cancer. I think it has more utility and answers more questions for you,” he added.
A caveat is that the FDA’s approval for 177Lu-PSMA-617requires a gallium Ga 68 gozetotide [gallium Ga 68 PSMA-11; Locametz] PSMA PET scan as opposed to a piflufolastat F 18 (Pylarify) PET scan, so patients who received this scan for other purposes may still require another PSMA PET scan for 177Lu-PSMA-617eligibility.1 The National Comprehensive Cancer Network panel for prostate cancer stated, “The panel believes that both Ga 68 PSMA-11 or F 18 piflufolastat PSMA imaging can be used to determine eligibility,”9 but because of the FDA’s requirement, the Ga 68 scan is generally required for insurance approval of 177Lu-PSMA-617.
Although there are challenges due to availability and logistics, following a referral process that puts patients on the path to treatment as quickly as possible can help avoid these barriers. A tumor board can help identify patients who could benefit more from other therapies.
Additionally, it is crucial to follow upcoming clinical trials as the landscape for patients with prostate cancer is constantly developing. PSMA is playing a greater role as a biomarker in detection and diagnosis of prostate cancer, and early use of the PSMA PET scan can influence later treatment approaches. 177Lu-PSMA-617 is being evaluated in taxane-naïve patients with mCRPC in the PSMAfore trial (NCT04689828) and in combination with AR-directed therapy and androgen deprivation therapy in the hormone-sensitive setting in the PSMAddition trial (NCT04720157). These results could change how and when this agent is employed. As radioligand therapy shows potential to extend survival for patients with few other treatment options, it is vital that oncologists can access and use it effectively for patients in need.