To date, I've been more than a bit underwhelmed by the results of PSMA theranostics. When I first learned of the concept, it seemed, at least in theory, to be a potential PCa "silver bullet", esp. when targeting patients still hormone sensitive and PSA avid. Here is a MedPage Today article that summarizes the results of the recent AU trial for mHSPCa, UpFrontPSMA. It compares several SOC treatment regimes for metastatic hormone-sensitive PCa patients with and without the addition of 177Lu-PSMA-617 (Pluvicto). It is another trial run by the experts in PSMA at PeterMac in AU.
And for anyone who does not fully understand the medical principles in PSMA theranostics, I strongly recommend they watch this excellent video presentation by Dr. Thomas Hopes from back in 2022 (4). It describes the results of the VISION Trail. In particular, it reveals that patient selection and treatment response is widely individualized and, as yet, the response is not easily determined before treatment. To date, it seems that PSMA therapy, when effective, offers similar response as chemotherapy with less SE and, thus, improved QOL. (Of course, remember before you watch this video, that according to "expert" patient advocates, no useful information can be gleaned from YouTube videos . . . even tho' his mentor now seems to be spitting them out daily. BTW, one of Patrick's "LOL"s should be inserted here)
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Radioligand Shows Promise in Metastatic Hormone-Sensitive Prostate Cancer — Odds of undetectable PSA at 48 weeks doubled with addition of Pluvicto, by Charles Bankhead, Senior Editor, MedPage Today, October 16, 2024
In metastatic hormone-sensitive prostate cancer (mHSPC), adding the radioligand 177Lu-PSMA-617 (Pluvicto) to androgen deprivation therapy (ADT) and chemotherapy more than doubled biochemical recurrence-free survival (BRFS), the randomized UpFrontPSMA trial showed.
BRFS at 48 weeks, defined as a prostate-specific antigen (PSA) value ≤0.2 ng/mL, increased from 16% with ADT and docetaxel to 41% with the addition of 177Lu-PSMA-617 (OR 3.88, 95% CI 1.61-9.38).
Additionally, the median duration of freedom from castration resistance (a secondary endpoint) was 20 months with 177Lu-PSMA-617 versus 16 months without it (HR 0.60, 95% CI 0.38-0.96, P=0.033).
The findings add to existing evidence of the radioligand's antitumor activity in metastatic castration-resistant prostate cancer (mCRPC), reported Arun Azad, MD, of Peter MacCallum Cancer Center in Melbourne, Australia, and coauthors in Lancet Oncology.
"To our knowledge, UpFrontPSMA is the first randomized study in patients with high-volume metastatic hormone-sensitive prostate cancer to show benefit from the addition of 177Lu-PSMA-617 to standard-of-care treatment," they noted. "These data suggest that 177Lu-PSMA-617 could potentially have a role in the therapeutic management of metastatic hormone-sensitive prostate cancer."
"The activity of 177Lu-PSMA-617 in the study population is particularly notable given the addition of only two cycles of radioligand therapy and the poor prognosis of patients with de novo high-volume metastatic hormone-sensitive prostate cancer, who have a median overall survival of 4 years and 5-year survival of just 23% when treated with docetaxel plus androgen deprivation therapy," the authors noted in their discussion.
The emergence of radioligands has contributed to a rapidly evolving therapeutic framework that has led to improved survival for metastatic prostate cancer, Azad and coauthors added. To date, 177Lu-PSMA-617 had shown efficacy in mCRPC, but its efficacy in mHSPC remained unclear, providing a rationale for UpFrontPSMA, a phase II study.
Adverse events did not increase appreciably with the three-drug combination in the trial, which had a median 2.5 years of follow-up.
"Importantly, the activity of 177Lu-PSMA-617 in this population was not associated with an overall increase in toxic effects compared with docetaxel alone, with a similar incidence of grade 3 or 4 adverse events [AEs] in both study groups," Azad's group wrote.
The trial showed improvement in intermediate clinical endpoints -- objective response, progression-free survival (PFS), freedom from CRPC, and radiographic PFS -- that have yet to demonstrate strong correlations with overall survival (OS) in mHSPC, noted Angela Jia, MD, and Daniel Spratt, MD, of UH Seidman Cancer Center and Case Western Reserve University in Cleveland.
However, the totality of improvement in intermediate endpoints might be considered as clinical benefit, they suggested in an accompanying commentary. (1)
Additionally, the results should be interpreted within the context of evolving treatment standards for high-volume disease.
"Since the trial's conception, the standard of care for [mHSPC] has shifted from androgen deprivation therapy combined with either an androgen receptor pathway inhibitor [ARPI] or docetaxel (double therapy) to include all three agents (triplet therapy)," explained Jia and Spratt. "More recently, consideration of radiotherapy to the primary tumor has further expanded treatment to a quadruplet therapy approach."
"Notably, the benefit of chemotherapy is unknown in the setting of androgen deprivation therapy plus [ARPI] or androgen deprivation therapy plus 177Lu-PSMA-617," the editorialists cautioned.
Recent trials have shown similar results with treatment regimens that did not include 177Lu-PSMA-617. For example (2), adding an ARPI to chemotherapy and ADT improved PSA undetectability at 52 weeks from 24% to 55% in patients with high-volume disease. Another trial (3) showed that adding an ARPI and prednisone to chemotherapy and ADT improved PSA undetectability at 34 weeks from 25% to 51% in the subgroup with high-volume disease.
Ongoing trials are evaluating 177Lu-PSMA-617 in combination with ADT and ARPIs in patients with low-volume and high-volume mHSPC, as well as 177Lu-PSMA-617 plus radiotherapy in ADT-free treatment strategies.
"We look forward to seeing whether PSMA-RLTs [radioligand therapies] will be used across the prostate cancer disease spectrum," Jia and Pratt concluded.
For the present study, investigators at 11 sites in Australia enrolled patients with de novo high-volume mHSPC, defined as visceral disease or four or more bone metastases with at least one outside the axial skeleton. All patients received ADT and were randomized to docetaxel with or without two cycles of 177Lu-PSMA-617.
Data analysis included 130 randomized patients (median 69 years), including 83% who had been on ADT for 28 days or less at the time of registration and 91% with high-volume disease on imaging.
The primary endpoint was BRFS at 48 weeks. Two patients in each treatment group were not evaluable for the primary endpoint.
Median radiographic PFS was not reached in the 177Lu-PSMA-617 arm versus 22 months in the control group (P=0.067). Median OS had yet to be reached in either arm.
Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients treated with 177Lu-PSMA-617 and 27% of patients in the control group. The most common grade 3/4 TRAEs were febrile neutropenia (11% vs 10%) and diarrhea (6% vs 0%).
No grade 3/4 thrombocytopenia occurred in either group, and grade 3/4 neutropenia occurred in 3% of the 177Lu-PSMA-617 arm and 2% of the control group. Serious AEs occurred in 25% of each treatment arm, none related to 177Lu-PSMA-617. Rates of discontinuation because of AEs were 10% in the 177Lu-PSMA-617 group and 6% in the control group.
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Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007
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Here is the link to the MedPage Today Article:
Radioligand Shows Promise in Metastatic Hormone-Sensitive Prostate Cancer — Odds of undetectable PSA at 48 weeks doubled with addition of Pluvicto, by Charles Bankhead, Senior Editor, MedPage Today, October 16, 2024:
medpagetoday.com/hematology...
And links to the research and commentary mentioned in the MedPage article. Note, however, that the The Lancet commentary (1) is fully behind a paywall and, thus, inaccessible:
(1) A step closer to the use of [177Lu]Lu-PSMA-617 in metastatic hormone-sensitive prostate cancer, The Lancet Oncology, Volume 25, Issue 10, October 2024, Pages 1246-1247
(2) Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer, N Engl J Med 2022;386:1132-11, Published February 17, 2022
nejm.org/doi/10.1056/NEJMoa...
(3) Prostate irradiation in men with de novo, low-volume, metastatic, castration-sensitive prostate cancer (mCSPC): Results of PEACE-1, a phase 3 randomized trial with a 2x2 design, Journal of Clinical Oncology, Meeting Abstract: 2023 ASCO Annual Meeting II, June 07, 2023
ascopubs.org/doi/10.1200/JC...
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Here is the link to the excellent 2022 video by Dr. Thomas Hope on PSMa therapy:
(4) Lu-PSMA Radioligand Therapy, 2022 Prostate Cancer Patient Conference, Dr. Thomas Hopes, University of California Television (UCTV), Recorded on 10/15/2022. [Show ID: 38578]:
youtube.com/watch?v=0AgvaUG...
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In addition to many on-going PSMA therapy trials, there is continuing research searching for more effective radioligands to use for PCa and other cancers.
Stay S&W, Ciao - cujoe
BCR May Not Be a Strong Surrogate End Point for Prostate Cancer Survival
