177Lutetium-PSMA-617, the Newest Life-Prolonging Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer

Prostate-specific membrane antigen (PSMA) is highly expressed by poorly differentiated, metastatic, and castration-resistant prostate cancer cells,1 creating a good imaging and therapeutic target.  177Lutetium (Lu) is a beta-emitting radionuclide that induces DNA strand breaks and cellular lethality.In the situation of 177Lu-PSMA-617, 177Lu is linked to a 617, which is a small molecule targeting vector that binds to PSMA.  Once bound to the receptor on the target cell membrane, in this case, prostate cancer cell, the complex is internalized.3  Hence, the lethal radiopeptide is delivered internally to induce DNA breaks and eventual apoptosis.


In October 2018, I wrote a UroToday Clinical Trials Portal article summarizing the ongoing therapeutic trials using various PSMA-targeted radioligand therapy.Then in January 2020, I wrote another article that focused on ongoing clinical trials with 177Lu-PSMA-617, including novel combination therapy.5  Since those articles, Lu-PSMA-617, have generated much more data that is highly promising for regulatory approval in the near future.  All the clinical trials previously highlighted in that January 2020 article have fully enrolled and much of the data has been reported.  Many additional clinical trials have been launched and are worth highlighting for our patients, many of whom are currently seeking mechanisms to access 177Lu-PSMA-617 in the United States.

The randomized phase 2, TheraP trial, was recently published.6  This trial enrolled 200 patients with progressive PSMA PET-positive metastatic castration-resistant prostate cancer who had received prior docetaxel in the metastatic castration-resistant prostate cancer setting.  One interesting note is that patients with any PSMA negative sites of disease and with FDG PET positivity were excluded, likely in attempts to exclude patients with neuroendocrine transformation or prostate cancer variant histology.  Eligible patients were randomized to 177Lu-PSMA-617 for up to 6 cycles vs. cabazitaxel 20 mg/m2 IV every 3 weeks for up to 10 cycles.  The primary endpoint was PSA decline of 50% or greater and that was achieved by 66% (95% CI, 56-75%) in patients who received 177Lu-PSMA-617 vs. 37% (95% CI, 27-46%) in patients who received cabazitaxel (p<0.0001).  Although median progression-free survival was 5.1 months in both arms, the Kaplan-Meier curves favored 177Lu-PSMA-617 both prior to and after the median, resulting in a hazard ratio of 0.63 (95% CI 0.46-0.86, p=0.0028).

The phase 3, VISION trial, randomized n=831 PSMA PET-positive metastatic castration-resistant prostate cancer patients, who also lacked any large PSMA PET negative metastatic lesions, and who also received 1-2 lines of taxane chemotherapy and at least 1 novel hormonal therapy (e.g. abiraterone acetate or enzalutamide), in a 2:1 ratio to 177Lu-PSMA-617 for 4-6 cycles in combination with the best standard of care vs. best standard of care alone.7  Alternative primary endpoints of overall survival (Median 15.3 vs. 11.3 months, HR 0.62, 95% CI 0.52, 0.74; p<0.001) or radiographic progression-free survival (Median 8.7 vs. 3.4 months, HR 0.40, 99.2% CI 0.29, 0.57; p<0.001) were both positive in favor of 177Lu-PSMA-617 with standard of care over standard of care alone, respectively.  Other secondary endpoints, like RECIST 1.1 objective response rate and confirmed PSA decline rates were all in favor of the 177Lu-PSMA-617 treatment arm.  Safety data was as expected with high-grade bone marrow suppression in 23.4% and all grade xerostomia in 39.3%, nausea/vomiting in 39.3%, and renal effects in 8.7%.

The outstanding efficacy and safety data from both the VISION and the TheraP trial support the incorporation of 177Lu-PSMA-617 in the metastatic castration-resistant prostate cancer treatment paradigm.  Although the data from these trials support the use of 177Lu-PSMA-617 in the metastatic castration-resistant prostate cancer post-docetaxel chemotherapy disease state, ongoing trials may change future treatment use patterns.  With the use of novel hormonal therapy agents like abiraterone acetate, enzalutamide, and apalutamide for metastatic castration-sensitive prostate cancer and enzalutamide, apalutamide, and darolutamide for M0 castration-resistant prostate cancer, a major unmet need will be first-line metastatic castration-resistant prostate cancer.  In this situation, patients may be progressing on treatment intensified androgen deprivation therapy with a rising PSA but no cancer-associated symptomatology.  Patients may not desire using docetaxel when they are feeling well, and lower toxicity, highly efficacious treatment option may be desired.  As a result, 177Lu-PSMA-617 may be well suited for use prior to chemotherapy, and ongoing clinical trials will help determine efficacy in this situation.

Other trials have been launched that are moving 177Lu-PSMA-617 to even earlier disease states, for instance for metastatic castration-sensitive prostate cancer.  Finally, rational combinations with other proven efficacious therapies or agents that warrant biologically intelligent combination therapy with 177Lu-PSMA-617 and have promise for synergistic or additive effect, are ongoing.  Many of these ongoing clinical trial options are highlighted below.

Clinical Trials with Radioligand therapy targeting PSMA

  • PSMAfore – randomized phase 3 trial of 177Lu-PSMA-617 vs. androgen receptor-directed therapy in patients with metastatic castration-resistant prostate cancer who have received one approved androgen receptor-directed therapy but are taxane chemotherapy naïve (NCT04689828)
  • EnzaP – randomized phase 2 trial of enzalutamide with 177Lu-PSMA-617 vs. enzalutamide alone in patients with metastatic castration-resistant prostate cancer (NCT04419402)
  • Randomized phase 2 trial of 177Lu-PSMA-617 vs. docetaxel for PSMA PET-positive metastatic castration-resistant prostate cancer (NCT04663997)
  • PSMAddition – randomized phase 3 trial of 177Lu-PSMA-617 + standard of care vs. standard of care alone for metastatic castration-sensitive prostate cancer (NCT04720157)
  • Phase 1 dose-escalation of fractionated 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (NCT03042468)
  • UpFrontPSMA – randomized phase 2 trial of 177Lu-PSMA-617 followed by docetaxel vs. docetaxel alone for newly diagnosed high volume metastatic castration-sensitive prostate cancer (NCT04343885)
  • LuTectomy – Phase 1/2 trial of 177Lu-PSMA-617 prior to prostatectomy (NCT04430192)
  • LuPARP – Phase 1 trial of 177Lu-PSMA-617 with Olaparib for metastatic castration-resistant prostate cancer (NCT03874884)
  • Phase 1 trial of 177Lu-PSMA-617 with pembrolizumab for metastatic castration-resistant prostate cancer (NCT03805594)

Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington


References:

  1. Hupe MC, Philippi C, Rothet D, et al. Expression of Prostate-Specific Membrane Antigen (PSMA) on Biopsies Is an Independent Risk Stratifier of Prostate Cancer Patients at Time of Initial Diagnosis. Front Oncol. 2018;8:623.
  2. Fendler WP, Stuparu A D, Evans-Axelsson S, et al. Establishing 177 Lu-PSMA-617 Radioligand Therapy in a Syngeneic Model of Murine Prostate Cancer. J Nucl Med. 2017; 58(11):1786-1792.
  3. Ferdinandus J, Ferdinandus, Violet J, Sandhu S, et al. Prostate-specific membrane antigen theranostics: therapy with lutetium-177. Curr Opin Urol 2018; 28(2):197-204.
  4. Yu EY. Clinical Trials Portal. Prostate-Specific Membrane Antigen (PSMA)-Targeted Radioligand Therapies are Finally Arriving. UroToday On-line: October 1, 2018.
  5. Yu EY. 177Lutetium-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer; Randomized Controlled Phase 3 Trial Data is Pending and Novel Combinations are Being Tested UroToday Clinical Trials Portal. On-line: January 6, 2020.
  6. Hofman MS, Emmett L, Sandhu S, et al. [ 177 Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet 2021; 397:797-804.
  7. Sartor O, de Bono J, Chi K, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2021; epub June 23, 2021.


Related Content:

ASCO 2021: VISION Study Results – Phase III Study of Lutetium-177-PSMA-617 in Patients With Metastatic Castration-Resistant Prostate Cancer
ASCO 2021: VISION Study Results Discussion: Lutetium-177-PSMA-617 in Patients With Metastatic Castration-Resistant Prostate Cancer
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