Phase I Study of the Prolactin Receptor Antagonist LFA102 in Metastatic Breast and Castration-Resistant Prostate Cancer

Abstract

Lessons LearnedDespite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising.Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels.Background.Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity.Methods.Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3–60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.Results.A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected.Conclusion.Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested.

Preclinical Activity of the Novel Anti-Prolactin Receptor (PRLR) Antibody–Drug Conjugate REGN2878-DM1 in PRLR-Positive Breast Cancers

“…We therefore generated REGN2878-DM1, comprised of a fully human anti-PRLR antibody, REGN2878, and the cytotoxic drug DM1. We found high expression of PRLR in approximately 25% of breast cancers across previously established molecular subtypes defined by HER2, ER, and PR expression, in agreement with other published reports (12,24). Of note, we found that that PRLR may be expressed in some triple-negative breast cancers (TNBC), as these tumors remain in need of novel targeted therapeutics.…”

“…Subsequently, this antibody was conjugated to the auristatin MMAE to form the ADC Adcetris (brentuxmab vedotin) that has demonstrated significant antitumor activity in Hodgkin's Lymphoma and Anaplastic Large Cell Lymphoma clinically (52). Perhaps similarly, the anti-PRLR antibody LFA102 was recently observed not to have sufficient activity in clinical testing against PRLR-positive cancers despite its inhibition of PRLR signaling (24). Doses of LFA102 up to 60 mg/ kg did not show dose-limiting toxicities, suggesting that blocking PRLR is well tolerated, although the tolerability of anti-PRLR ADCs will have to be assessed in appropriate toxicology studies.…”

“…Recently, antibodies to PRLR such as LFA-102 and 005-C04 have demonstrated the ability to inhibit PRL-mediated signaling in vitro and in vivo (14,15,23). In a phase I study of LFA-102, doses of up to 60 mg/kg were tolerated, although they did not result in significant antitumor efficacy (24). This weak antitumor effect suggests that inhibiting PRLR signaling alone is insufficient for potent clinical activity.…”

Rheumatoid arthritis and psoriatic arthritis synovial fluids stimulate prolactin production by macrophages

“…Because dopamine is unable to down-regulate PRL production in extrapituitary tissues, alternative therapeutic approaches have been developed to block PRLR-mediated signaling rather than PRL production in target cells [54,55]. A phase I clinical trial with PRLR neutralizing antibodies in patients with breast or prostate cancer, however, showed no antitumor activity when used as monotherapy [56]. Still, the results presented here support the rationale to test this approach in chronic inflammatory diseases.…”

Truncating Prolactin Receptor Mutations Promote Tumor Growth in Murine Estrogen Receptor-Alpha Mammary Carcinomas

“…Since truncated PRLR expression is preferentially increased in ERα+ breast cancer and FL/T PRLR heterodimers display constitutive activation as shown in our current study, it would be of interest to examine whether LFA102 is able to block heterodimerization of full-length and truncated PRLR in future studies. Unfortunately, LFA102 failed to show antitumor efficacy in a recent Phase 1 clinical trial for metastatic breast cancer (Agarwal et al, 2016). Direct inhibition of Jak2 using small molecule inhibitors will also be worthy of investigation in breast cancers with Prlr activation.…”