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Advances in targeted alpha therapy for prostate cancer.

ABSTRACT: Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (T?T) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of T?T in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that T?T is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of T?T provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine T?Ts with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, T?Ts that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in T?T trial development suggest that T?T occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of T?T in prostate cancer treatment.

SUBMITTER: De Vincentis G

PROVIDER: S-EPMC6927314 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Advances in targeted alpha therapy for prostate cancer.

De Vincentis G G Gerritsen W W Gschwend J E JE Hacker M M Lewington V V O'Sullivan J M JM Oya M M Pacilio M M Parker C C Shore N N Sartor O O

Annals of oncology : official journal of the European Society for Medical Oncology 20191101 11

Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens e ...[more]

PMID: 31418764

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Project description:Rationale: Despite the success of several standards of care treatment options in metastatic castration-resistant prostate cancer (mCRPC), a significant number of patients attain therapeutic resistance and eventually develop disease progression. Managing these patients are currently challenging. Hence, there is an unmet need for further efficient therapeutic options that induce anti-tumor activity and improve survival. The objective of this study was to assess the safety and therapeutic efficacy of 225Ac-PSMA-617 targeted alpha therapy (TAT) in mCRPC patients in real-world conditions. Methods: In this prospective study, we recruited patients with mCRPC who either were refractory to 177Lu-PSMA-617 radioligand therapy (RLT) or did not receive previous 177Lu-PSMA-617 RLT. Patients were treated with 225Ac-PSMA-617 TAT (100 KBq/Kg body weight) at 8-weekly intervals. The primary endpoint included the assessment of biochemical response by measuring the serum prostate-specific antigen (PSA) response rate as per the prostate cancer working group criteria (PCWG3). Secondary endpoints comprised the estimation of overall survival (OS), progression-free survival (PFS), molecular tumor response assessment (PERCIST 1 criteria), disease control rate (DCR), toxicity according to CTCAE v5.0, and clinical response evaluation. Results: A total of 28 patients were recruited for this cohort study among whom 15 (54%) received prior 177Lu-PSMA-617 RLT and the remaining 13 (46%) patients were 177Lu-PSMA-617 RLT naïve. The mean age was 69.7 years (range: 46-87 years). All patients, except one, had extensive skeletal metastases on baseline 68Ga-PSMA-11 PET/CT scan; one patient had lymph node dominant disease and advanced primary prostatic tumor. The mean activity administered was 26.5 ± 12 MBq (range: 9.25 - 62.9 MBq) [715.5 ± 327 µCi, range: 250 - 1700 µCi] with a median of 3 cycles (range: 1 - 7 cycles). At 8th week of post first cycle of 225Ac-PSMA-617 therapy (initial follow-up) and the end of the follow-up, >50% decline in PSA was observed in 25% and 39%, respectively. The median PFS and OS were 12 months (95% CI: 9 - 13 months) and 17 months (95% CI: 16 months - upper limit not reached), respectively. Molecular tumor response by PERCIST 1 criteria could be conducted in 22/28 (78.6%) patients, which revealed complete response in 2/22 (9%), partial response in 10/22 (45.4%) patients, 2/22 (9%) with stable disease, and 8/22 (36%) with progressive diseases. The disease control rate, according to the biochemical and molecular tumor response criteria, was 82% and 63.6%, respectively. Multivariate analysis revealed PSA progression as adverse prognostic indicator of OS, and any PSA decline as a good prognostic indicator of PFS. There was no Grade III/IV toxicity noted in this series. The most common side-effect was transient fatigue (50%) followed by grade I/II xerostomia (29%). Conclusion: 225Ac-PSMA-617 TAT showed promising disease control rate, even when all other therapeutic options were exhausted, with low treatment-related toxicities.

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Advances in targeted alpha therapy for prostate cancer.

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Advances in targeted alpha therapy for prostate cancer.

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