Clinical trials have shown that antibody-drug conjugates or ADCs are an emerging class of cancer therapies that have demonstrated favorable activity both as single agents and as components of combination regimens. Phase II testing of an ADC targeting prostate-specific membrane antigen or PSMA in advanced prostate cancer has shown specific antitumor activity. A study by Jose Murga, Sameer Moorji, Amy Han, Wells Magargal, Vincent DiPippo and William Olson, published in the October 18, 2014 online edition of The Prostate, examined PSMA ADC used in combination with potent antiandrogens (enzalutamide and abiraterone) and other compounds.
In this study, the antiproliferative activity and expression of PSMA, prostate-specific antigen and androgen receptor were evaluated in the prostate cancer cell lines LNCaP and C4-2. The researchers tested cells for susceptibility to antiandrogens or other inhibitors, used alone and in combination with PSMA ADC. Potential drug synergy or antagonism was evaluated using the Bliss independence method.
The study results demonstrated that enzalutamide (Xtandi®; Astellas Pharma) andabiraterone (Zytiga®; Janssen Biotech) offers a robust, statistically significant synergy when combined with PSMA ADC. Largely additive activity was observed between the antiandrogens and the individual components of the ADC (free drug and unmodified antibody). Rapamycin (known as sirolimus – Rapamune®; Pfizer) also synergized with PSMA ADC in certain settings. Synergy was linked in part to upregulation of PSMA expression. In androgen-dependent LNCaP cells, enzalutamide and abiraterone each inhibited proliferation, upregulated PSMA expression, and synergized with PSMA ADC. In androgen-independent C4-2 cells, enzalutamide and abiraterone showed no measurable antiproliferative activity on their own but increased PSMA expression and synergized with PSMA ADC nonetheless. PSMA expression increased progressively over 3 weeks with enzalutamide and returned to baseline levels 1 week after enzalutamide removal.
Based on these outcomes, the researchers believe that these findings support exploration of clinical treatment regimens that combine potent antiandrogens and PSMA-targeted therapies for prostate cancer.
Published in: The Prostate