(318) Risk of Oligospermia with Tyrosine Kiase Inhibitors: A Disproportionality Analysis from Vigibase and AERS Databases

Saturday, August 27, 2022

8:00 AM – 6:00 PM CEST

Location: Hall C

Publication Number: 992

Presenting Author(s)

Luis G. Velez-Nandayapa, MD
– PhD Student in Pharmacoepidemiology, University of Basel, University of Basel, Z�rich, Z�rich, Switzerland

Co-Author(s)

Anusmita Das
– Safety Signal Detection & MQM, Novartis, India
Vishaka Parulekar, MD
– Patient Safety Oncology, Novartis, Hyderabad, India, India
Naveen Chhabra, MD
– Patient Safety Oncology, Novartis, Hyderabad, India, India
Miguel Izquierdo, MD
– Clinical Development Oncology, Novartis, Basel, Switzerland, Switzerland
Maria Nicolaides, MD
– Patient Safety Oncology, Novartis, Basel, Switzerland, Switzerland
Pierre de Zeeuw, MD
– Patient Safety Oncology, Novartis, Basel, Switzerland, Switzerland
Alicia Rossiter, MD
– Patient Safety Oncology, Novartis, New Jersey, USA, United States
Johannes Eisinger, MD
– Patient Safety Oncology, Novartis, Basel, Switzerland, Switzerland
Christiane Michel, MD, MSc
– Safety Signal Detection & MQM, Novartis, Switzerland

Background:
Advances in the treatment of cancer in young patients have led to great improvements in life expectancy. However, treatment with chemo or radiotherapy causes reduction of sperm counts often to azoospermic levels that may persist for several years or be permanent.

Objectives:
To quantify disproportionate reporting (Disp-Rep) for the risk of drug-associated oligospermia/azoospermia for 41 clinically approved tyrosine kinase inhibitors (TKIs) in 2 groups: 1) Anti-angiogenic (AA) TKIs; 2) Non-anti-angiogenic (NAA) TKIs.

Methods:
We used the AERS and VigiBase databases, with data up to Dec 2021 and Mar2022 for analysis respectively. Cases of oligospermia and azoospermia were identified using MedDRA (v24.1) and the high-level-term (HLT) ‘Spermatogenesis and semen disorders’ (SSD). Empirical Bayes Geometric Means (EBGM) with 90%CI were calculated to quantify Disp-Rep. We considered the lower bound of the 90% CI, EB05 > 2 as the threshold for claiming an observation of Disp-Rep. We studied 3 groups of drugs: 1) Positive control group (non-TKIs associated with oligospermia/azoospermia: sulfasalazine, colchicine and cisplatin) and two groups of TKIs: 2) AA TKIs & 3) NAA TKIs. Drugs were identified by non-proprietary name.

Results:
We retrieved 104 SSD cases in AERS and 83 in VigiBase. In AERS, Disp-Rep with EBGM [90%CI, EB05-EB95] was confirmed for the positive control group: cisplatin 4.32 [3.29-5.64], and colchicine 3.80 [2.40-5.97] and in VigiBase for sulfasalazine 3.15 [2.05-4.68]. In AERS, Disp-Rep was confirmed for only 1 of 25 NAA TKIs: ibrutinib 3.52 [2.37-5.13]. No Dis-Rep was found for the rest of NAA TKIs: afatinib, alectinib, avapritinib, bosutinib, brigatinib, ceritinib, crizotinib, dabrafenib, dasatinib, entrectinib, erlotinib, fostamatinib, gefitinib, gilteritinib, imatinib, lapatinib, lorlatinib, nilotinib, osimertinib, pemigatinib, pexidartinib, pralsetinib, tucatinib and zanubrutinib. No Dis-Rep was found for any of the 16 AA TKIs: acalabrutinib, axitinib, cabozantinib, dacomitinib, lenvatinib, neratinib, nintedanib, pazopanib, ponatinib, regorafenib, ripretinib, selpercatinib, sorafenib, sunitinib, tivozanib and vandetanib. The analysis in VigiBase database yielded similar results.

Conclusions:
Ibrutinib (NAA TKI) was the only drug among the 41 different TKIs studied with Disp-Rep for oligospermia/azoospermia in both databases. Our results however, should be interpreted with caution as disproportionality analyses are hypothesis generating rather than hypothesis testing.