Advancements in Prostate Cancer Diagnosis and Treatment

Prostate cancer is the most common cancer among men and ranks second in cancer-related deaths after lung cancer. Patient symptoms and monitoring PSA levels are essential in prostate cancer diagnosis. While multiparametric MRI has achieved a new role in early diagnosis, the role of PSMA PET/MRI in assessing primary lesions more precisely during the initial diagnosis is being discussed. As extensive research has demonstrated that many tumor lesions in the prostate are multifocal, uncertainties around a Gleason score of 7 and the follow-up of these patients, point to an increased profile for the usefulness of PSMA PET.

Ga-68 PSMA (and, although not available in our country, F-18 PSMA and F-18 DCFPyL) is used for targeted diagnosis and follow-up in prostate cancer imaging. Approximately 15% of prostate cancer patients do not exhibit PSMA protein, and this rate increases in the advanced stages of metastatic castration-resistant disease. In high-risk patients with low or absent PSMA activity, F-18 FDG imaging is performed (1). While their PSMA activity is low, strong FDG activity indicates poor prognosis or malignant transformation. Patients with high PSMA uptake benefit from PSMA-labeled radioligand therapy, whereas those with high FDG activity show a lower response to such therapy. FDG PET is not performed on all prostate cancer patients; however, studies indicate that high-risk aggressive primary tumors with a Gleason score above 7 tend to show high FDG uptake (2). FAPI PET positivity has been observed in some cases that cannot be detected by either method, potentially enabling these patients to receive FAPI-labeled radioligand therapy (1). Various radiopharmaceuticals, such as 111-In capromab pendetide (ProstaScint), Tc-99m-HYNIC-Glu-Urea-A, 11C-Choline, and 18F-Choline, have been used for diagnosing prostate cancer and determining its spread (3). In conclusion, prostate cancer is highly heterogeneous, composed of subgroups with varying prognoses, necessitating diverse molecular markers for diagnosis and a multidisciplinary, often combinational, treatment approach.

In a general review by Finn Edler von Eyben, Irene Virgolini, and Richard Baum in July 2024, combination therapies were reported to be superior to monotherapies. Additionally, in PSMA-positive patients, adding Lutetium-PSMA treatment to combination therapies significantly improves treatment outcomes compared to other chemotherapy or hormone therapies (4).

The effectiveness of Lu-177 PSMA as a third-line treatment in metastatic castration-resistant prostate cancer (mCRPC) patients has been proven in VISION and TheraP studies. Its effectiveness in earlier stages is also being evaluated. In the ENZA-p study, a combination of Enzalutamide (ENZA) with Lu-177 PSMA was found to be superior to ENZA monotherapy for first-line treatment in mCRPC. While combination therapy has a 93% rate of lowering PSA levels by at least 50%, monotherapy with ENZA has resulted in a 78% rate (p< 0.001) (4-5).

 In a meta-analysis by Satapathy S. et al., the effects of previous use of taxane-based chemotherapy after hormonotherapy on Lu-177 PSMA treatment were studied.   Studies suggest that administering Lu-177 PSMA before taxane-based chemotherapy as a second-line treatment may be beneficial. The use of taxane previously is found to have a negative effect on Lu-177 PSMA treatment (4, 6). In conclusion, mCRPC patients are recommended to be treated with Lu-177 PSMA therapy as a second-line treatment as opposed to third-line treatment following a taxane therapy. The significance of this finding becomes clear when considering the effects of chemotherapy.

In the PSMAfore study, the effect of Lu-177 PSMA as a second-line treatment was investigated in the taxane-naive mCRPC patient group. Taxane-naive patients who had received an androgen receptor pathway inhibitor (ARPI) and had shown progression once were randomly divided (1:1) into two groups:  ARPI change (to oral abiraterone or enzalutamide) versus Lu-177 PSMA-617 treatment (every 6 weeks for six cycles). Patients treated with Lu-177 PSMA-617 showed more effective PSA reduction and improved quality of life. Lu-177 PSMA-617 treatment doubled radiographic progression-free survival compared to ARPI switch (12 months vs. 5,6 months) and was shown to be safe in terms of side effects. The radiographic complete response rate was also significantly better in the lutetium group (21% vs. 2.6%) (7).

In a study by Barber et al., Lu-177 PSMA was found to be effective in treating mCRPC patients in terms of treatment efficacy and minimal toxicity in both taxane-naïve and heavily pretreated taxane-administered patient groups (early and late-stage prostate cancer groups, second and third line). Progression-free survival and total survival time were found to be better in the group not given taxane (total survival time was found to be 10.7 months in patients given taxane and received intensive treatment, and 27.1 months in taxane-naïve patients). The adverse effect profile was reported to be minimal in both groups (8). All these studies indicate that there is no scientific justification for mandating the use of taxane-based chemotherapy before administering Lu-177 PSMA therapy.

The WARMTH study, which evaluated the efficacy of Ac-225 PSMA, showed that administering radioligand therapy as a second-line treatment, rather than as a third-line treatment, extended survival time among similar patient groups (4,9).

The SPLASH study assesses the efficacy and safety of 177 Lu I&T in mCRPC patients who have progressed after ARPI treatment and have not received taxane in the past year. 177Lu-I&T significantly increases progression-free survival compared to ARPI (9.5 months vs. 6 months) (10).

The PRINCE study, conducted with the hypothesis that Lu-177 PSMA-617 and the monoclonal PD-1 antibody pembrolizumab (an anti-programmed cell death 1 antibody) may have a synergistic effect to enhance and sustain immune response, has shown this combination to be safe and effective (11).

In the UpFrontPSMA study, Docetaxel (DOC) monotherapy was compared with a combination of DOC + Lu-177 PSMA treatment. When compared to DOC alone, Lu-177 PSMA-617 with DOC combination therapy in patients with de novo high-volume metastatic hormone-sensitive prostate cancer (mHSPC) enhanced the antitumor effect without increasing toxic side effects. This study suggests that Lu-177 PSMA therapy may play a potential role in mHSPC patients (12).

The LUNAR study is evaluating the efficacy and safety of either stand-alone stereotactic body radiotherapy (SBRT) or SBRT + Lu-177 PSMA I&T in oligorecurrent mHSPC patients undergoing ablative radiotherapy. The study aims to compare SBRT with the combination therapy of Lu-177 PSMA with SBRT to all metastasis sites (13). This study will also provide insights into the effectiveness of Lu-177 PSMA therapy at the hormone-sensitive stage.

In the LuPARB study, it was shown that the combination of Lu-177 PSMA-617 with Olaparib, a treatment used for BRCA2 mutations, was well tolerated and achieved an objective treatment efficacy of 78% in mCRPC patients (14).

The efficacy of Tb-161 PSMA-I&T was proven in mouse models. The ongoing VIOLET study is evaluating the efficacy of Tb-161 PSMA-I&T in humans (15). The effectiveness of Tb-161 PSMA is being tested in approximately seven centers in Turkey.

Although surgery or radiotherapy are effective treatments for prostate cancer, the rate of local recurrence is high, especially in high-risk disease. Recently, the use of Lu-177 PSMA in neoadjuvant therapy to prevent recurrence has gained notable attention (4). It has been shown that neoadjuvant androgen deprivation therapy (ADT) alone before radiotherapy is ineffective, while ENZA and Darolutamide are more effective. Adding neoadjuvant DOC has been reported to enhance ADT efficacy (4,16,17). Two recent pilot studies demonstrated that administering neoadjuvant Lu-177 PSMA-617 was effective in improving outcomes (18-19). In a study by Golan et al., patients with high-risk localized prostate cancer received two or three doses of Lu-177 PSMA (7.4 GBq) at two-week intervals, followed by robot-assisted radical prostatectomy and lymph node dissection four weeks after the last dose. PSA levels decreased by 17% after two doses of Lu-177 PSMA and by an average of 34% after three doses. In this 14-patient study, it was reported that robotic surgery after neoadjuvant Lu-177 PSMA therapy was safe and the continence recovery was not affected by the Lu-177 PSMA treatment (18).

In the LuThectomy study published this year, 20 patients with high-risk localized disease were enrolled. They were divided into two groups that received one or two cycles of lutetium treatment, followed by robotic surgery six weeks later. This study showed that administering up to two cycles of Lu-177 PSMA-617 before radical prostatectomy is safe and provides effective radiation doses to the tumor. Treatment-related side effects were minimal, and surgical complications were low. PSA reduction was observed to be significant (19). It was reported that neoadjuvant Lu-177 PSMA therapy before radical prostatectomy provided a notably longer survival time compared to second- or third-line lutetium therapies administered in mCRPC cases (4). It has been suggested that a combination with immunotherapies or other therapeutic agents could be more effective.

Currently, Ra-223 and Lu-177 EDTMP therapies are used for bone metastases. In our country, the use of Lu-177 EDTMP is more widespread. Lu-177 EDTMP is used not only for prostate cancer but also for other types of cancer metastases, primarily for pain palliation.

Lu-177 PSMA therapy in prostate cancer makes a difference in all combinations it is added to. Additionally, it provides the best quality of life due to its low side effect profile. Considering the approach in oncology of administering the most effective drugs early on, we can foresee that Lu-177 PSMA will be included in neoadjuvant therapy combinations, especially for high-risk disease. The evidence of its effectiveness at the hormon sensitive and castration resistance stages is also available. In this situation, similar to thyroid cancer, we may expect that prostate cancer patients will be followed more frequently in nuclear medicine clinics for diagnosis and treatment from the outset, within a multidisciplinary approach.

References:

1.      Laudicella, R. et al. Preliminary Findings of the Role of FAPi in Prostate Cancer Theranostics. Diagnostics 2023, 13, 1175. https:// doi.org/10.3390/diagnostics13061175

2.      Jadvar H. Is There Use for FDG-PET in Prostate Cancer? Semin Nucl Med. 2016 Nov;46(6):502-506. doi: 10.1053/j.semnuclmed.2016.07.004. Epub 2016 Sep 3. PMID: 27825430; PMCID: PMC5119923.

3.      Jetty S. et al. Prostate Cancer-PET Imaging Update. Cancers (Basel). 2023 Jan 28;15(3):796. doi: 10.3390/cancers15030796. PMID: 36765754; PMCID: PMC9913636.

4.      Von Eyben F.E. et al. Review on the Increasing Role for PSMA-Based Radioligand Therapy in Prostate Cancer. Cancers (Basel). 2024 Jul 12;16(14):2520. doi: 10.3390/cancers16142520. PMID: 39061160; PMCID: PMC11274522.

5.      Emmett, L. et al. 177Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.  The Lancet Oncology, 2024, Volume 25, Issue 5, 563 – 571

6.      Satapathy S. et al.  177Lu-PSMA-Radioligand Therapy Efficacy Outcomes in Taxane-Naïve Versus Taxane-Treated Patients with Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Metaanalysis. Journal of Nuclear Medicine Aug 2023, 64 (8) 1266-1271; DOI: 10.2967/jnumed.123.265414

7.      Morris, M.J. 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.  The Lancet, 2024, Volume 404, Issue 10459, 1227 – 1239.

8.      Barber, T. W. et al. Clinical Outcomes of 177Lu-PSMA Radioligand Therapy in Earlier and Later Phases of Metastatic Castration-Resistant Prostate Cancer Grouped by Previous Taxane Chemotherapy. Journal of Nuclear Medicine, 2019, 60 (7) 955-962; DOI: https:// doi.org/10.2967/jnumed.118.216820 

9.      Ahmadzadehfar, H. et al. Prior therapies as prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients treated with 177Lu-PSMA-617. A WARMTH multicenter study (the 617 trial). Eur. J. Nucl. Med. Mol. Imaging 2021, 48, 113–122.

10.    Hansen, A.R. et al. 1400P Efficacy and Safety of 177Lu PNT2002 Prostate-Specific Membrane Antigen (PSMA) Therapy in Metatatic Castration-Resistant Prostate Cancer (mCRPC) Initial Results from SPLASH. Ann. Oncol. 2022, 33, S1185.

11.    Sandhu, S. et al. PRINCE: Phase I trial of 177Lu-PSMA-617 in combination with pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC) J Clin Oncol. 2022; 40, 5017

12.    Azad, A. et al. Sequential 177Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone-sensitive prostate cancer (UpFrontPSMA): a multicentre, open-label, randomised, phase 2 study.  The Lancet Oncology 2024, Volume 25, Issue 10, 1267 – 1276

13.    Ma T.M. et al. LUNAR: a randomized Phase 2 study of 177 Lutetium-PSMANeoadjuvant to Ablative Radiotherapy for Oligorecurrent Prostate Cancer (clinical trial protocol). BJU Int 2023; 132: 65–74 doi:10.1111/bju.15988Original Article

14.    Sandhu S. et al. LuPARP: Phase 1 trial of 177Lu-PSMA-617 and olaparib in patients with metastatic castration resistant prostate cancer (mCRPPC). J. Clin. Oncol. 2023, 41 (Suppl), 5005. DOI:10.1200/JCO.2023.41.16

15.    Buteau J.P. et al., VIOLET: A phase I/II trial evaluation of radioligand treatment in men with metastatic castration-resistant prostate cancer with [161Tb]Tb-PSMA-I&T.. JCO 41, TPS281-TPS281(2023). DOI:10.1200/JCO.2023.41.6_suppl.TPS281

16.    Carles, J. et al. Phase 2 Randomized Study of Radiation Therapy and 3-Year Androgen Deprivation With or Without Concurrent Weekly Docetaxel in High-Risk Localized Prostate Cancer Patients. Int. J. Radiat. Oncol. Biol. Phys. 2019, 103, 344–352.  

17.    Perera, M.B. et al. Neoadjuvant Systemic Therapy Prior to Radical Prostatectomy for Clinically Localized High-Risk Prostate Cancer. Front. Oncol. 2022, 2, 864646. 

18.    Golan, S. et al. Neoadjuvant 177Lu-PSMA-I&T Radionuclide Treatment in Patients with High-risk Prostate Cancer Before Radical Prostatectomy: A Single-arm Phase 1 Trial. Eur. Urol. Oncol. 2023, 6, 151–159. 

19.    Eapen, R.S. et al. Administering 177Lu-PSMA-617 Prior to Radical Prostatectomy in Men with High-risk Localised Prostate Cancer (LuTectomy): A Single-centre, Single-arm, Phase 1/2 Study. Eur. Urol. 2024, 85, 217–226