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The GnRH receptor is expressed in many endocrine cancers, including breast, ovarian, endometrial, and prostate tumors. Its presence provides the means to target oncolytic drugs to these cancer cells to supplement the clinical benefits currently achieved with ADT alone [90,95]. Zoptarelin Doxorubicin (AN-152, AEZS-108, ZoptrexTM) is a peptide-drug conjugate composed of a GnRH analog and doxorubicin through an ester bond with a glutaric acid spacer (Figure 2) [96]. The conjugate proved more effective than doxorubicin in inhibiting cell proliferation in GnRH receptor positive cancer cell lines [96]. It also was more potent than either agent alone in several xenograft mouse tumor models [97]. These results validate the virtue of targeted, complementary GnRH and doxorubicin pharmacology. Phase 1 studies in endometrial, ovarian and prostate cancer established Zoptarelin Doxorubicin’s safety, pharmacokinetics, and maximum tolerated dose [98,99,100]. In several phase 2 studies the drug-conjugate exhibited promising clinical activity with low systemic toxicity in castration and taxane-resistant prostate cancer [101], advanced or recurrent endometrial cancer [102], and platinum refractory ovarian cancer [103]. In a recent large phase 3 registration trial in advanced endometrial cancer Zoptarelin Doxorubicin disappointedly failed to improve median overall survival, or progression-free survival when compared to standard doxorubicin therapy [104]. The basis of the failure is unknown but given that doxorubicin at highest dose did not significantly improve patient survival there is a suspicion that deficiencies specific to doxorubicin might be the primary cause, as opposed to something inherent to the drug-conjugate.
https://www.mdpi.com/1420-3049/24/10/1855/htm
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