According to the disproportionality analysis, the most common and significant AEs reported were gastrointestinal disorders (SOC) which was in line with a previous network meta-analysis, demonstrating that rucaparib had higher risk for gastrointestinal toxicities compared with other PARP inhibitors8. Among the SOC of gastrointestinal disorders, AEs with the highest number of reports were nausea, diarrhoea, constipation, vomiting, abdominal pain, which had been reported in the label. Furthermore, other AEs in gastrointestinal disorders (SOC) were also discovered as strong disproportionality signal such as small intestinal obstruction, intestinal mass, intestinal obstruction, abdominal pain upper, abdominal discomfort, abdominal distension, flatulence. Among them, small intestinal obstruction (10 [5%] patients), as well as malignant neoplasm progression (10 [5%] patients) were reported to be common serious adverse events in a clinical trail under the treatment of rucaparib9, which was consistent with our findings. Similarly, abdominal mass was identified as strong disproportionality signal in disproportionality analysis of olaprib (as the first PARPi)10, which is similar to intestinal mass discovered in our study. In addition, a phase 3 trial manifested that intestinal obstruction (three [2%] patients) was the most common serious adverse events in the olaparib group, compared to intestinal obstruction (two [2%] patients) in the placebo group11. In summary, clinicians should be aware of these new and unexpected AEs such as small intestinal obstruction, intestinal mass, intestinal obstruction, although there is not enough evidence to support they are adverse events of rucaparib or due to disease progression.
Multiple studies had shown that hematotoxicity of PARPi such as hemoglobin decrease, anemia, thrombocytopenia/platelet count decrease, especially acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) attained more and more attention12–13. Among them, thrombocytopenia/platelet count decrease was the most frequent AE that led to treatment discontinuation. In this study, hemoglobin decrease, anemia, thrombocytopenia/platelet count decrease were identified as strong disproportionality signal, which were consistent with the label. Signal strength for AML and MDS significantly increased, which is consistent with the real-world observations by Ma14 and Matsuo15. A meta-analysis also showed that PARPi significantly increased the risk of MDS and AML with a delay of probably 17.8 months16. It is possible that PARPi leads to acquired mutations with clonal hematopoiesis via the DNA damage response and triggers off-target epigenetic changes by potential clonal hematopoietic transformations, consequently increasing the risk of MDS and AML17.
AEs such as malignant neoplasm progression, recurrent ovarian cancer, recurrent cancer, increased carbohydrate antigen 125 levels, and increased tumor marker levels were most likely due to disease progression, drug resistance and recurrence and not due to rucaparib treatment in patients with cancer.
Elevations in creatinine (grade 1 or 2) levels were observed in 15–20% of patients in the first weeks of rucaparib treatment, although levels stabilized within normal ranges over time18–19. Coincidentally, an increase in blood creatinine level, abnormal renal function test results, and decreased glomerular filtration rate were detected with a strong signal strength in our study. Creatinine elevation had been linked to inhibition of the renal transporters MATE 1 and MATE2-K, as PARP inhibitors were known to affect these transporters in vitro20–21. Since rucaparib is mainly cleared by the liver and intestines, renal impairment is unlikely to affect on the PK of rucaparib. A study showed that mild-to-moderate renal impairment(CLcr ༞ 30 mL/min) had no clinically significant effect on the PK of rucaparib, indicating that dose adjustment is not required for these populations 22. Available data in patients with severe renal impairment (CLcr 15 to 29 mL/min) and end-stage renal disease (CLcr < 15 mL/min) are limited, therefore rucaparib is not recommended for use in these patients. A case report demonstrated that treatment with rucaparib at a dose of 200 mg twice daily was well tolerated and effective in a patient with ESRD undergoing dialysis23. Although there is evidence that increased serum creatinine levels may not be correlated with renal toxicity in patients receiving PARPi 24, rucaparib may need to be discontinued and sufficient attention should be given to alternative causes of renal dysfunction (e.g. obstruction, dehydration, concomitant medication) through appropriate assessments if creatinine levels rise substantially (e.g. grade 3 or higher)25. To avoid continued usage with potential safety hazards, alternative methods for assessing renal function such as nuclear medicine GFR scan could be conducted to gain a more accurate evaluation of renal function when the estimated glomerular filtration rate based on serum creatinine levels is greatly decreased.
Skin and subcutaneous tissue disorders were rare AEs of PARPi. Photosensitivity reactions, sunburn and were discovered with relatively strong signal strengths of disproportionate reporting in our study, although they were not described in the label. Dermatological adverse events had been reported with rucaparib in a double-blind phase 3 trial26. In another double-blind phase 3 clinical trial, 17% of the patients receiving rucaparib experienced photosensitivity11. In a phase II study assessing rucaparib maintenance, 13% of the patients receiving rucaparib reported photosensitivity, 2% rash, 7% dry skin, 2% dry mouth, and 2% pruritus, all of which were wholly grade 1–2 27.
Disproportionality analysis of FAERS manifested that disproportionality signals of skin and subcutaneous tissue disorders(SOC) with rucaparib and niraparib were stronger among PARP inhibitors7. The mechanism of dermatological toxicity of rucaparib might involve an indole chromophore in its structure, thereby supplementing the effect of the active fraction of solar light that can trigger photosensitivity reactions28. Interestingly, niraparib, compared with other members of PARPi, had an indazole ring which was similar to the indole chromophore in rucaparib. Anticancer treatments have been identified as one of the top five classes of drugs associated with photosensitivity, making up around 12% of reported photosensitizers29. Targeted anticancer therapies as well as conventional chemotherapyhave all been reported to induce photosensitive dermatitis 30. Therefore, we suggest that during treatment of rucaparib, patients should avoid direct sunlight and take protective measures such as systematically applying broadspectrum sunscreens and wearing UV-protective clothing, hats and sunglasses to keep away from dermatological adverse events.
In the SOC of nervous system disorders, dysgeusia, taste disorders, and peripheral neuropathy showed a high correlation with strong signals. Dysgeusia, mainly grade 1–2, as one of the most common adverse reactions, occurred in 20% of patients receiving rucaparib31. Higher RORs of dysgeusia (ROR = 10.786) and taste disorders (ROR = 27.447) were found in our study, which was consistent with the ROR of dysgeusia (ROR = 27.06) for rucaparib7 (Tian et al., 2022). Taste disorders were seen in half of patients after gynecological cancer chemotherapy32. Furthermore, antineoplastic medications were found to account for 21.6% of olfactory and gustatory ADRs33. The most generally accepted mechanism of dysgeusia in cancer patients is that systemic therapy induces taste and odor changes due to cytotoxic damage to the rapidly dividing taste and smell receptor cells34. There are various other mechanisms of taste alterations including reduced sensitivity to taste, disturbed perception of taste and phantom tastes35. Thus, patients should maintain adequate oral hygiene care or change their diet for dysgeusia management.
Peripheral neuropathy was a new and significant AE of rucaparib and was not included on the label. A meta-analysis including 843 patients treated with veliparib or olaparib showed that the overall relative risk of neuropathy with PARPi was 1.06 (95% confidence interval (CI): 1 to 1.4)36. Similarly, another PARPi, niraparib, had been reported to cause neurologic AEs, such as initial insomnia, memory impairment, neuropathy, peripheral dysgeusia, and balance disorders7. The mechanism of peripheral neuropathy caused by rucaparib may be the inhibition of dopamine transporters by rucaparib, although its off-target efficiency was not known7.
Elevated liver transaminase levels were common during rucaparib treatment. Elevations in alanine aminotransferase/aspartate aminotransferase levels were rarely associated with elevations in bilirubin levels with signs of hepatotoxicity. In our study, an increase in blood bilirubin level was discovered as a new signal in addition to an increase in hepatic enzyme levels. A clinical study involving 46 patients showed that the incidence of increased blood bilirubin levels was 26% after rucaparib treatment27. In addition, the white blood cell count decreased in 4 of the 46 patients in the study mentioned above, which was in line with our findings. Hence, it is important for physicians to closely monitor liver function in patients during rucaparib treatment.
In the present study, the median time-to-onset was 32 days (IQR, 15–88 days), and most of the AEs occurred within the 1 (48.95%), 2 ( 17.72%), or 3 (9.40%) months of treatment with rucaparib. Similarly, the median time to onset across settings was within 30 days for the majority of frequently reported AEs after rucaparib treatment by a previous integrated safety analysis with 937 patients37 (R.S. Kristeleit et al.,2019). Our study suggested small intestinal obstruction and abdominal pain upper occurred at 32.5 and 31 days after rucaparib treatment, which is in line with the results of a previous study25 ( Lorusso et al., 2020). A real-word analysis following PARPi of FAERS discovered that the median times to MDS and AML events of PARP inhibitor (only including olaparib and niraparib) were 211 days and 355 days, respectively38. Here, we discovered time-to-onset of AML and MDS were 525 and 522.5 days of rucaparib, which was much longer than olaparib and niraparib, warning clinicans pay more attention to serious hematological toxicities after long-term treatment of rucaparib. Moreover, our study identified that time-to -onset of photosensitivity reaction and sunburn were 44 and 62 days, and for neuropathy peripheral and taste disorder, time-to-onset were 49.5 and 60.5 days. Therefore, we should not only concentrate on AEs occurred within the first month after rucaparib treatment, but also keep an eye on long-term AEs detected in the study.