Prostate Cancer Theranostics: Concurrent Approvals by the Food and Drug Administration of the First Diagnostic Imaging Drug Indicated to Select Patients for a Paired Radioligand Therapeutic Drug ================================================================================================================================================================================================== * A. Alex Hofling * Anthony F. Fotenos * Gang Niu * Jaleh Fallah * Sundeep Agrawal * Sue-Jane Wang * Libero Marzella The expanding field of theranostics combines the use of both diagnostic and therapeutic drugs that target shared molecular markers of disease. The diagnostic component of a theranostic drug pair is similar to a companion diagnostic in that it provides essential information for the safe and effective use of a corresponding therapeutic product (1). However, whereas companion diagnostics are regulated as medical devices and typically consist of in vitro assays, the theranostic paradigm relies on diagnostic drugs that act in vivo, usually for purposes of medical imaging. On March 23, 2022, the Food and Drug Administration (FDA) approved the first pair of prostate cancer theranostic drugs: Pluvicto (177Lu-vipivotide tetraxetan; Advanced Accelerator Applications) and Locametz (kit for the preparation of 68Ga-gozetotide injection, also known as 68Ga-prostate-specific membrane antigen [PSMA]-11; Advanced Accelerator Applications). These intravenously administered drugs contain different chelated radioisotopes, but both target PSMA, a transmembrane peptidase that is overexpressed by most prostate adenocarcinomas (2). As the therapeutic component of the theranostic drug pair, Pluvicto contains 177Lu, which emits β− radiation to treat PSMA-positive tumor lesions in which the drug localizes. Pluvicto is specifically indicated for therapy of men with PSMA-positive metastatic castration-resistant prostate cancer who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy (3). Locametz, the diagnostic component of the theranostic drug pair, is radiolabeled with 68Ga to enable its approved indication of patient selection for Pluvicto therapy through assessment of PSMA positivity on PET (4). Evidence of effectiveness for the patient selection indication of Locametz and the therapeutic indication of Pluvicto was derived primarily from the multicenter VISION trial ([NCT03511664](http://jnm.snmjournals.org/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03511664&atom=%2Fjnumed%2F63%2F11%2F1642.atom)), in which patients who met 68Ga-gozetotide PET criteria as well as clinical eligibility criteria were randomized 2:1 to either Pluvicto plus best standard-of-care treatment (*n* = 551) or best standard-of-care treatment alone (*n* = 280). 68Ga-gozetotide PET criteria for Pluvicto eligibility in this trial consisted of the presence of at least one tumor lesion with uptake greater than in normal liver and the absence of bulky tumor lesions with uptake equal to or less than in normal liver. Bulky tumor lesions were defined on anatomic imaging as having short-axis measurements of at least 2.5 cm for lymph nodes, at least 1 cm for organ lesions, and at least 1 cm for the soft-tissue components of bone lesions. Statistically significant improvement in the primary endpoints of overall survival and radiographic progression-free survival was demonstrated by adding Pluvicto to best standard-of-care treatment in the VISION trial. Median overall survival was 15.3 mo (95% CI, 14.2–16.9 mo) in the treatment arm receiving Pluvicto plus the best standard of care and 11.3 mo (95% CI, 9.8–13.5 mo) in the treatment arm receiving the best standard of care alone. Safety evaluation supported a favorable benefit–risk balance for both the therapeutic indication of Pluvicto and the patient selection indication of Locametz. In addition to the primary analyses of the VISION trial, the patient selection indication of Locametz was further supported by imaging substudies that leveraged data from the VISION trial (5). One such VISION substudy demonstrated reasonable levels of agreement among masked readers in assessment of the above-described imaging criteria for Pluvicto eligibility on 68Ga-gozetotide PET. The “Warnings and Precautions” section of the Locametz prescribing information cites the risk of misinterpretation of 68Ga-gozetotide PET for determining Pluvicto eligibility and proposes certain risk mitigation strategies (4). Another imaging substudy from the VISION trial that supported the patient selection indication of Locametz consisted of exploratory analyses of collected quantitative PET data (6). In patients who received Pluvicto, higher quantitative measurements on pretreatment 68Ga-gozetotide PET, such as the mean SUVs of tumor lesions throughout the body, were associated with greater overall survival. A postmarketing commitment was agreed upon to conduct similar quantitative PET analyses on patients in the VISION trial who did not receive Pluvicto. The results of these analyses may further clarify the potential utility of quantitative measurements on pretreatment 68Ga-gozetotide PET for predicting Pluvicto treatment effect and for providing general prognostic information on disease severity (7). An additional agreed-upon postmarketing commitment will evaluate the safety and efficacy of Pluvicto in patients with advanced or metastatic prostate cancer who have at least one PSMA-positive tumor lesion on 68Ga-gozetotide PET but do not meet the criteria used in the VISION trial related to bulky PSMA-negative lesions. To reflect the use of 68Ga-gozetotide PET for patient selection in the VISION trial, section 2 (“Dosage and Administration”) of the prescribing information for Pluvicto contains instructions to select patients for treatment using Locametz or another approved PSMA-11 imaging agent (3). Additional supporting data might be needed to extend patient selection instructions to drugs that are approved for other prostate cancer imaging indications but are molecularly distinct from gozetotide and might differ in biodistribution, binding characteristics, and other properties. In addition to the patient selection indication, Locametz was also approved for the same disease detection indications as those of previously approved 68Ga-gozetotide PET drugs, namely PET of PSMA-positive lesions in, first, men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy and, second, men with prostate cancer with suspected recurrence based on elevated serum prostate-specific antigen level (4). Through the 505(b)(2) new drug application (NDA) pathway, these Locametz indications were supported by reliance on the FDA’s findings of effectiveness for the listed drug product (68Ga-PSMA-11 injection under NDAs 212642 and 212643). This regulatory approach required establishment of a bridge between Locametz and the listed drug product to demonstrate that such reliance was scientifically justified. Of note, the novel patient selection indication and certain formulation differences relative to previously approved 68Ga-gozetotide drugs precluded approval of Locametz as a generic drug through an abbreviated NDA under the 505(j) pathway. Bridging between 68Ga-gozetotide prepared by Locametz and the listed drug product focused on differences between their formulations, including diastereomer composition, mass dose of gozetotide, and other physiochemical properties. An adequate bridge was established through comparison of biopharmaceutical data and measurements of in vitro cell binding and internalization between 68Ga-gozetotide prepared by Locametz and the listed drug product, as well as comparison of gozetotide mass doses between subsets of patients who either met or did not meet PSMA positivity criteria on Locametz PET in ongoing trials. The resultant approval of disease detection indications for Locametz provided additional support for the patient selection indication. The joint approval of Locametz and Pluvicto represents successful codevelopment of a pair of theranostic drugs in parallel. In addition to the success of a therapeutic trial with patients selected by imaging, multiple imaging substudies that efficiently leveraged the therapeutic trial data provided further support for a patient selection indication (5). The same applicant sponsored a separate NDA for each drug. During the development program, multiple meetings were held between the FDA and the applicant to establish an effective plan for parallel theranostic codevelopment. Both NDAs were concurrently approved under a priority time line after their simultaneous submission. ## DISCLOSURE No potential conflict of interest relevant to this article was reported. ## ACKNOWLEDGMENT This editorial reflects the views of the authors and should not be construed to represent the FDA’s views or policies. ## Footnotes * Published online Jul. 7, 2022. * © 2022 by the Society of Nuclear Medicine and Molecular Imaging. ## REFERENCES 1. 1.List of cleared or approved companion diagnostic devices (in vitro and imaging tools). Food and Drug Administration website. [https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools](https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools). Updated June 30, 2022. Accessed August 4, 2022. 2. 2.Afshar-Oromieh A, Haberkorn U, Eder M, Eisenhut M, Zechmann CM. 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