Apaziquone is an interesting drug for intravesical use in patients with nonmuscle invasive bladder cancer; however, more research is needed to prove its actual benefit. Although the apaziquone trials demonstrate the potential of this new drug, the singular phase 3 trials did not reach their primary endpoint. To date, no new trials are recruiting, so the development of apaziquone seems to have stopped.
Key points
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Apaziquone is an interesting drug for intravesical use in patients with nonmuscle invasive bladder cancer; however, more research is needed to prove its actual benefit.
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Although the apaziquone trials demonstrate the potential of this new drug, the singular phase 3trials did not reach their primary endpoint.
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To date, no new trials are recruiting, the development of apaziquone seems to have stopped.
Introduction
Bladder cancer (BC) is the second most common genitourinary malignancy worldwide and has a great impact on health care infrastructure and costs. , Worldwide, approximately 2.7 million patients have been diagnosed, treated, and followed for BC at any given time point. , Seventy-five percent of BC patients present with nonmuscle invasive bladder cancer (NMIBC). BC presents with macroscopic hematuria in most cases. Risk factors are predominantly smoking and some industrial exposures like aromatic aromines and dyes. There is a 3 to 4 to 1 male predominance.
NMIBC is characterized by a high recurrence rate, which emphasizes the need for adjuvant intravesical therapies after transurethral resection (TURBT). To date, intravesical chemotherapy for low- and intermediate-risk tumors and intravesical Bacillus Calmette-Guerin (BCG) therapy for intermediate- and high-risk tumors are the gold standards. Despite adjuvant treatment, however, up to 61% of all patients will recur within 1 year. , Particularly in patients with high risk NMIBC, the risk of progression also increases, and because of the lack of alternative conservative treatments, this may result in early cystectomy.
In low-risk patients, a single adjuvant chemotherapeutic instillation is sufficient. This advice is predominantly based on large meta-analysis, comparing transurethral resection of a bladder tumor (TURBT) alone to TURBT plus 1 immediate instillation of chemotherapy. Seven randomized trials with 1476 patients and a median follow-up of 3.4 years were analyzed. Two hundred sixty-seven (36.7%) of 728 patients recurred after TURBT and 1 instillation with chemotherapy compared to 362 (48.4%) of the 748 patients treated with TURBT alone (odds ratio [OR] 0.61, P <.0001). Patients with single tumors (OR 0.61) and multiple tumors (OR 0.44) benefited. However, because 65.2% of patients with multiple tumors had a recurrence after this 1instillation, compared to 35.8% of patients with single tumors, the authors concluded that 1 instillation alone was insufficient for multiple tumors. It is, therefore, the treatment of choice in patients with single, low-risk papillary tumors. Furthermore, no difference between the chemotherapeutic drugs used could be found. The instillation should probably be given within 6 hours after operation, but in any case within 24 hours, unless there has been a bladder perforation or extensive/deep resection.
In high-risk patients, a second TURBT is mandatory, as residual or recurrent disease within 3 months after TURBT for NMIBC can be up to 45%. Therefore, a second TURBT within 2 to 4 weeks is strongly recommended by the current guidelines.
For these high-risk patients, additional therapy consists of intravesical Bacillus Calmette-Guérin (BCG). BCG is superior to any other adjuvant intravesical drug in the prevention of recurrence of NMIBC, and it is considered to prevent and/or delay progression of NMIBC.
A large meta-analysis showed that BCG had a lower risk of tumor progression in comparison to intravesical chemotherapy. Twenty-four trials with 4863 patients and a median follow-up of 2.5 years were reported. Two hundred sixty (9.8%) of 2658 patients on BCG had progression as compared to 304 (13.8%) of 2205 patients without BCG (OR = 0.73, P =.001). This effect was similar in patients with papillary tumors and in those with carcinoma in situ (CIS), but only patients receiving maintenance BCG benefited. Limitations of this study are the overall low percentage of progression (6.4% of 2880 patients with papillary tumors and 13.9% of 403 patients with CIS) as a result of the short follow-up and relatively favorable patient profile. Last, but not least, no significant difference in disease-specific survival was found. A disadvantage of BCG is that it has more severe local and systemic adverse effects compared with chemotherapy. When patients fail on BCG, radical cystectomy is the safest option. , Adjuvant intravesical treatment in these patients remains experimental.
For the largest group of patients, the intermediate-risk group of NMIBC, intravesical chemotherapeutic instillations can reduce the risk of recurrence. However, in the long term, it only causes a modest reduction of the risk of recurrence, without reduction in the risk of progression. In a combined analysis of individual patient data from previously performed EORTC (European Organisation for Research and Treatment of Cancer) and Medical Research Council (MRC) randomized trials, including a total of 2535 patients, the effect of adjuvant intravesical chemotherapy or adjuvant oral agents on several endpoints in TaT1 NMIBC was calculated. Only the disease-free survival was significantly prolonged after adjuvant treatment compared with no adjuvant treatment ( P <.01). Still, the differences were modest. For example, the disease-free estimate at 8 years was 44.9% in the treatment group, versus 36.7% in the no treatment group. No significant or relevant advantage was shown for progression to invasive or metastatic disease, or duration of (progression-free) survival. In case of recurrent intermediate-risk NMIBC, additional chemotherapeutic instillations or instillations with BCG are advocated. ,
In conclusion, initial therapy of NMIBC is TURBT, followed by intravesical therapy with chemotherapeutic drugs or BCG. The choice of drugs, frequency, and schedule used for these additional intravesical instillations are defined by guidelines. However, therapy is not without toxicity, and a substantial percentage of treated patients still experience tumor recurrences or progression to muscle-invasive bladder cancer (MIBC), so several unmet needs remain.
This article reports on the developments of new intravesical therapies and strategies, with a main focus on the mitomycin (MMC)-derivative apaziquone. In 2008, the first review considering apaziquone was published in Expert Opinion on Investigational Drugs by the same research group. New data and insights are added considering the current status of apaziquone in 2019.
The Impact on Health Care
Botteman and colleagues looked at health economics related to BC. They calculated that BC is the fifth most expensive cancer, but considering the (life) long surveillance, the per patient costs for BC from diagnosis until death appeared to be highest of all cancers.
In conclusion, NMIBC is a highly recurrent disease with a tremendous impact on patients, doctors, and health care costs.
New intravesical treatments for nonmuscle-invasive bladder cancer
The high amount of recurrence in NMIBC patients stresses the need for new intravesical therapies and strategies. Several new therapies are under study; however, none has been implanted as standard therapy yet. In this article, the authors focus on the relatively new agent apaziquone.
Bacillus Calmette-Guerin Failures
In the European Association of Urology (EAU) guidelines, BCG treatment failure is defined as
Muscular invasion, detected during follow-up
The presence of high-grade NMIBC at both 3 and 6 months after initial treatment
Any deterioration of the disease under BCG treatment, such as a higher number of recurrences, higher T stage or higher grade, or the appearance of CIS, despite an initial response
In daily practice, a subdivision of BCG failure patients into 4 groups can be used:
1. Patients intolerant because of adverse effects
2. BCG resistance that includes recurrence/persistence of lesser disease and which resolves with further BCG
3. BCG-relapsing patients, which means recurrence after initial resolution
4. BCG-refractory disease (those patients primarily not improving or even worsening under BCG treatment)
BCG intolerance is inevitable, with various clinical studies reporting recurrence rates of 20% to 53% within 5 years and progression rates of up to 28%. In BCG-intolerant patients, certainly in those who never completed the induction course, intravesical therapy with another drug at the time of recurrence is worth trying.
BCG induces a 70% initial complete response rate, which remains in 50% after long follow-up. Around 40% to 60% of the initial nonresponders will respond to a second course of BCG. Real failures are those patients having a recurrence during BCG treatment or those who are not achieving a complete response. Unfortunately, one cannot to predict BCG failure accurately on an individual basis. However, with clinical and histologic parameters, risk groups can and should be identified, because the window of opportunity is limited; in case of tumor progression to MIBC, the survival rate drops dramatically, and the outcome is far worse than in primary MIBC patients. In a recent systematic review of 19 trials (total of 3088 patients), progression to MIBC was seen in 21%, of which 14% died of BC after a follow-up of 48 to 123 months. Hence, the long-term cancer-specific survival after progression was as low as 37%.
Therefore, the EAU treatment guidelines recommend the consideration of cystectomy after initial BCG failure in patients with high-grade recurrences. The advantage is obvious, as early cystectomy in BCG failure patients is associated with a recurrence-free 5-year survival rate of 80% to 90%. On the other hand, some of these patients will be overtreated, and become disadvantaged by the comorbidity, mortality, and impaired quality of life associated with this procedure.
Apaziquone
Apaziquone, a quinone-based bioreductive drug, was originally developed by the Netherlands Cancer Institute. Its preclinical and systemic early clinical studies were conducted within the EORTC framework.
Despite reports of 3 partial responses in phase 1 studies, no responses were seen in phase 2 clinical trials with intravenous apaziquone. It was hypothesized that the rapid pharmacokinetic elimination and relatively poor penetration of the drug could have compromised drug delivery to tumors following systemic administration.
If this is the case, these unfavorable pharmacokinetic properties of intravenous administration could be turned to an advantage for apaziquone in the treatment of cancers in third compartments like the urinary bladder. Subsequent studies confirmed that NMIBC cases have elevated levels of the activating enzyme DT-diaphorase (DTD). Apaziquone (EOquin) is a prodrug that is activated by DTD and other reductases to generate cytotoxicity that leads to apoptosis. Apaziquone has potent antitumor activity, proven in both in vitro and in vivo tumor models. ,
Apaziquone is chemically composed as 5-(aziridin-1-yl)-3-(hydroxymethyl)-2-[(1 E )-3-hydroxyprop-1-enyl]-1-methyl-1 H -indole-4,7-dione. Its molecular formula is C 15 H 16 N 2 O. The molecular weight of apaziquone is 288.30 kDa. The drug product EOquin (apaziquone for intravesical instillation) is supplied as a sterile, nonpyrogenic lyophilized product in clear glass vials. It contains 4 mg apaziquone, as well as mannitol and sodium bicarbonate. The recommended storage temperature is 2° to 8°C. Prior to intravesical instillation, the EOquin vial is reconstituted with 20 mL of “Diluent for EOquin” (a propylene glycol solution for intravesical instillation), to yield 0.2 mg/mL of apaziquone. This solution is further diluted with 20 mL of sterile water for injection, resulting in 40 mL of the instillation solution containing 0.1 mg/mL of apaziquone.
Preclinical activity
The antitumor activity of apaziquone has been evaluated in murine tumor models and in human tumor lines, both in vitro and in vivo.
Cytotoxicity against various tumor cell lines was evaluated by different investigators. Apaziquone is highly cytotoxic against a broad spectrum of cell lines, and it inhibits the growth of most cell lines tested at nanomolar concentrations. Of note, in vitro apaziquone potency was a multiple of that of MMC in most solid tumors, achieving a mean 50% growth inhibitory concentration of 17 nm against 710 nm for MMC.
In the cytotoxicity studies, the mean graphs of apaziquone show a characteristic pattern with clusters of sensitive cell lines derived from colon, melanoma, and central nervous system (CNS) tumors. Unlike MMC, apaziquone showed preferential cytotoxicity against solid tumors and was much less active or inactive against most leukemia. This was also evident from the Corbett 2-tumor assay. No activity in leukemias was seen in the human tumor line screen either, where apaziquone was assayed over a broad concentration range against a panel of 56 cell lines and displayed substantial potency in most of the available sensitive lines of colon, melanoma, renal, and CNS tumors. Noteworthy is the lack of significant differences in apaziquone sensitivity between MCF-7 (breast adenocarcinoma) and its derivative expressing the multidrug resistance phenotype MCF-7/ADR.
Continuous exposure of cells from subcutaneously growing human tumors in a colony-forming assay in nude mice showed high sensitivity to apaziquone in breast, colon, nonsmall cell lung and kidney cancer lines.
In an in vitro test against 4 small-cell lung cancer cell lines, both with 1-hour incubation and with continuous exposure, a small increase in potency with increased exposure time suggested that apaziquone activity is not cell cycle specific.
Aerobic cytotoxicity analysis of apaziquone and MMC against EMT6 mouse breast cancer line after either 1 hour or continuous exposure was done by MTT dye reduction. Apaziquone was tenfold to 20-fold more potent than MMC against this cell line. Apaziquone cytotoxicity under hypoxic versus oxic conditions was compared in a clonogenic assay in EMT6 mouse mammary tumor cells using a 3-hour exposure experiment. Concentrations required to reduce cell survival to 10% of control were 3 and 10 ng/mL (ratio 3.3) for hypoxic and oxic cells, respectively.
In human tumor xenografts, apaziquone induced tumor regression in gastric cancer GXF 97 and ovarian cancer MRI-H-207. A single intravenous injection of 2 mg/kg MMC, however, caused tumor regression in GXF 97 (T/C 5.3%), and in MRI-H-207, 2 weekly intravenous injections of 5 mg/kg induced complete remissions A third injection of apaziquone in MRI-H-207-bearing nude mice induced almost complete remissions. Growth delay in breast cancer MAXF 449 and marginal activity in the nonsmall cell lung cancer LXFL 529 were seen. No antitumor activity was found in the renal cancer RXF 243.
In conclusion, apaziquone is a potent cytotoxic agent preferentially active in solid tumor lines.
Pharmacokinetics and metabolism
Pharmacokinetics of intravenous injection in rodents and dogs using a high-performance liquid chromatography (HPLC) method show that clearance is rapid and the half-life short (1.9 minutes in the mouse, 3 minutes in the rat at nontoxic doses and 4–14 minutes in the dog). The half-life is linear in the mouse and rat, but not the dog, in which it shows a beta phase. Area under the curve increased with the dose, and maximal plasma concentrations after intravenous administration of 0.41 to 1.64 mg/kg were in the 0.6 to 1 μg/mL range in the dog. Two major metabolites appear in the plasma, along with several minor peaks. Apaziquone was not found in the urine, which contained numerous metabolites. In any case, the drug is extensively and rapidly metabolized.
In the human studies of intravenous administration, the pharmacokinetics of apaziquone were determined in 32 and 28 patients, treated in phase 1 studies of apaziquone given every 3 weeks or weekly. , The recommended doses reached were 22 mg/m 2 every 3 weeks and 12 mg/m 2 weekly. The plasma curve fit a 2-compartment model. Pharmacokinetic parameters varied widely between patients; the half-life, however, was almost uniformly short (mean 10 minutes).
Intravesical instillation in animal studies
Apaziquone at a concentration 4 and 16 times higher than that used in the human phase 2 trial (0.1 mg/mL) was instilled into the urinary bladder of 4 Beagle dogs in a range-finding pilot toxicology study in 2 dogs at each of the 2 levels. The maximum plasma concentration reached with the higher dose concentration of 1.6 mg/mL was 21 ng/mL as detected by liquid chromatography/mass spectrometry (LC-MS). This level is considerably lower than the maximal concentrations that had been reported after administration of nontoxic intravenous doses to Beagles.
A second study in dogs, with 6 weekly instillations at drug concentrations of 0.0125, 0.05, and 0.2 mg/mL, used the same analytical methods, with a lower limit of quantitation of 5 ng/mL in the dog plasma. Out of 237 samples drawn after the start of instillation, 7 showed apaziquone levels above the lower limit of quantitation (5.4–75.5 ng/mL) and none above 20 ng/mL (lower limit of quantitation) for metabolite EO5a. It was concluded that penetration into the blood flow from the intact bladder is absent or minimal.
Phase 1/2 safety studies
During the phase 1/2 study of intravesical instillation 2 weeks after TURBT, blood and urine were collected in all instillation treatments in the 6 patients of the first intrapatient dose escalation cohort and in the 6 patients of the fixed-dose treatment cohort during and after the first and last instillations only.
Blood was collected before treatment, and 30 and 55 minutes after the start of instillation. Bladder contents were drained at the end of the instillation and the samples buffered and frozen. Analysis of the samples was by HPLC with a lower limit of quantitation of 20 ng/mL. No apaziquone or its metabolite EO5 was detected in the plasma samples. Apaziquone was found in the bladder contents at the end of the 1-hour instillation, and its concentration increased linearly with the dose. The pH of bladder contents was relatively consistent (6.80 ± 0.84–7.66 ± 0.59), and percentage drug recovery after 1 hour was similar for all doses administered, accounting for 57.1 plus or minus 27.6 to 72.0 plus or minus 3.67% of the dose administered. The volume of bladder contents at the end of each instillation varied considerably, with values ranging from 112.5 plus or minus 40.6 to 240.0 plus or minus 112.2 mL. This may be dose-dependent, although considerable variation in the volume of instillation occurs at all doses administered.
During the pilot study of immediate post-TURBT instillation, blood samples were collected from 6 of the 23 patients, before instillation and at 5, 15, 30, 45, and 60 minutes from its start. The samples were analyzed by a sensitive LC-MS method with a lower limit of quantitation of 5 ng/mL.
The possibility of intravesical instillation reaching toxic levels of apaziquone or metabolites in the blood seems low, considering that the total dose recommended for instillation, 4 mg, is the equivalent of 20% of the tolerated weekly intravenous dose in an average patient with 1.7 m 2 BSA.
In conclusion, apaziquone was ineffective by systemic administration probably because of its rapid elimination; it is not absorbed from the bladder even when instilled within 6 hours from TURBT, and its toxic potential, even if entirely absorbed, remains low.
Dose-finding/marker lesion studies
In preclinical research the concentration of apaziquone needed to achieve 50% cell kill at 37°C was 6 to 78 times lower than that of MMC depending on the cancer cell line used.
In a dose-finding study, Puri and colleagues determined the dose of apaziquone that could safely be administered in the bladder in patients with NMIBC. Six patients with multifocal, Ta/T1, and G1/G2 urothelial cell carcinoma received escalating doses of apaziquone (0.5 mg/40 mL up to 16 mg/40 mL) weekly for 6 weeks after resection of all but 1 lesion (the marker lesion). An additional 6 patients received weekly apaziquone in the highest nontoxic dose established. Pharmacokinetic parameters were determined in urine and blood, and the pharmacodynamic markers NQO1 (reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase-1) and glucose transporter 1 were also characterized. Local toxicity (grades 2 and 3 dysuria and hematuria) was observed at doses of 8 and 16 mg/40 mL, but 4 mg/40 mL were well tolerated with no systemic or local adverse effects. Urinary apaziquone increased linearly with the dose, but no apaziquone was detected in plasma. In 8 of 12 patients, complete macroscopic and histologic disappearance of the marker lesion occurred. A correlation between response and pharmacokinetic measurements could not be found.
Van der Heijden and colleagues performed a subsequent phase 2 marker lesion study on 46 patients with Ta-T1 G1-G2 NMIBC undergoing TURBT, with the exception of 1 marker lesion of 0.5 to 1 cm. Six weekly intravesical EOquin instillations of 4 mg/40 mL were administered. The adverse effects of EOquin in this study were comparable to other chemotherapeutic agents used against NMIBC, and the histologically proven complete response 2 to 4 weeks after the last instillation was 67% (30/45 patients). The remaining patient, who did not receive all 6 instillations, also had a compete response of the marker lesion.
In conclusion, these 2 initial studies clearly show that apaziquone is safe and has a marked effect on marker lesions.
Phase 2/3 efficacy trials (2009–2018)
In 2009, an update the 2 year follow-up was published of this phase 2 marker lesion study by Hendricksen and colleagues. The objective was to study the time to recurrence and duration of response of the same cohort from Van der Heijden and colleagues in 2006. Routine follow-up was performed at 6, 9, 12, 18, and 24 months from the first apaziquone intstillation. The authors found that in an intention-to-treat analysis (2 complete response patients dropped out during follow-up) 49.5% of the complete responders remained recurrence free at 24 months of follow-up. The median duration of response was 18 months. Of the 15 nonresponders, only 2 had additional prophylactic instillations after TURBT. Of the nonresponders, 26.7% were recurrence free without additional intravesical therapies except for the additional TURBT to remove the remaining marker lesion. One nonresponding patient progressed to muscle-invasive disease. Adverse effects did not exceed grade 3, and no clinical meaningful changes were found by blood chemistry and/or urinalysis.
The same research group presented a new phase 2 study in 2012. In this multicentre prospective phase 2 trial that was conducted in 3 Dutch hospitals, the efficacy and safety of multiple adjuvant apaziquone instillations were studied in patients with high-risk NMIBC. Fifty-three patients with high-risk NMIBC were enrolled and underwent TURBT of all lesions and 6 weekly adjuvant intravesical apaziquone instillations of 4 mg in 40 mL. Follow-up with cystoscopy, cytology, and adverse events was executed every 3 months, for 18 months in total. In the intention-to-treat analysis, 34.7% and 44.9% of the patients recurred at 12 and 18 months, respectively. One patient had progression to muscle-invasive disease at the 9-month follow-up. Adverse effects were mild, with mostly grade 1 to 2 reported by the investigators. No systemic toxicity was observed.
Noteworthy, the guideline definitions of intermediate- and high-risk BC changed during the conduct of this study. Although all patients were high risk according to the definitions when included in this trial, according to the most recent guideline criteria, 80% of the population would now be considered intermediate risk.
In 2018, 2 parallel phase 3, double-blind, placebo-controlled multinational trials were published in 1 extensive paper. These studies were performed following a Special Protocol Agreement with the US Food and Drug Administration (FDA). These 2 nearly identical trials (SPI-611 and SPI-612) were conducted between April 2007 and January 2012. Their objective was to evaluate the 2-year recurrence rate on time to recurrence in a Ta,G1-G2 randomized cohort receiving complete TURBT plus apaziquone versus TURBT plus placebo. A single intravesical instillation of apaziquone (4 mg/40 mL) or placebo was administered within 6 hours after TURBT.
Researchers enrolled 1614 patients, of whom 1146 patients met the histologic inclusion criteria after TURBT. In both studies, the primary endpoints were not met, although the studies showed 6.7% and 6.6% reduction recurrence in the apaziquone group (not significant compared with the placebo group). When combined, the pooled analysis did show a significant reduction in the 2-year recurrence rate of 6.7% (OR 0.76; P =.0218). In both studies, the time to recurrence showed improvement in the apaziquone group. In the SPI-611 study, this improvement was significant; in the SPI-612 study it was not. Pooled data for time to recurrence, again, did show significant improvement of time-to-recurrence (hazard ratio [HR] 0.79; P =.0096). The authors performed a post hoc analysis that showed that apaziquone instilled within 30 minutes after TURBT provided no benefit in reducing recurrence in either study. The explanation for this finding was the amount of red blood cells in the bladder within 30 minutes after TURBT. The red blood cells could inactivate apaziquone, as was observed in previous preclinical intravenous administration of apaziquone.
Safety and tolerability
Apart from evaluation for intravesical use, apaziquone has undergone clinical evaluation when used systemically against a range of tumor types in the past decades, but it has failed to demonstrate activity when administered intravenously. Reasons for the absence of tumor response could be the rapid removal from the blood stream (short half-life time) and poor penetration through avascular tissue. Although these properties are a problem in terms of treating systemic disease, they can be ideal for treating cancers that arise in an anatomically accessible site such as the bladder. Drug delivery is not a problem, as drugs are instilled in the bladder through a catheter. Any drug reaching the blood stream would be rapidly removed, , making the risk of effects to other tissues low. Furthermore, apaziquone is a bio-reductive drug, so it requires activation by cellular reductase enzymes. As discussed earlier, in the case of apaziquone the enzyme DTD plays a central role in activating the drug. Several tumors have high levels of DTD activity compared with normal tissue, suggesting that selective toxicity against tumor cells may be achieved. In more than 40% of patients suffering from BC, the level of DTD in bladder tumor tissue is higher compared with normal tissue. Another reason to assume systemic toxicity of apaziquone is a minor problem is the fact that systemic absorption through an intact bladder wall into the blood stream is limited because of the molecular weight of 288. Indeed, apaziquone and known metabolites were consistently undetectable by HPLC in the 12 patients of a phase 1 study, 30 and 60 minutes after the start of intravesical instillation with doses ranging from 4 mg to 16 mg in 40 mL, and no hematological changes were noted in the phase 2 study. Finally, apaziquone can be potentiated under acidic extracellular pH (eg, pH 6.0) conditions, but may lose activity in the blood stream because of an increase in extracellular pH to 7.35 to 7.45.
In conclusion, several properties of apaziquone make systemic toxicity unlikely and subsequent intravesical use theoretically safe.
Summary
NMIBC is a common disease with a wide range of oncological outcomes. The optimal treatment has not yet been found, as NMIBC is associated with high rates of recurrence and sometimes progression. Every patient is initially treated with a TURBT, and most patients require adjuvant intravesical instillations of chemotherapeutic or immunotherapeutic drugs. However, as it is common in cancer therapy, instillation therapy is not without toxicity, and even with optimal therapy many patients experience recurrences or even progression.
Progression is a real concern in high-risk patients, especially when they fail standard intravesical therapy with BCG. In these patients failing BCG, the standard therapeutic recommendation is radical surgery, and no conservative treatment is accepted as an alternative.
Nowadays, There are some new promising intravesical therapies/strategies available. Of these newer drugs, gemcitabine seems especially promising, but more studies are needed. CHT shows promising results too, even in patients failing BCG therapy. However, longer follow-up and confirmative randomized data are strongly needed.
Apaziquone is a potent cytotoxic drug. It is activated in the cell with the help of DTD in oxic conditions, or, in its absence, in hypoxia, acting through the redox cycle or DNA breaks. Apaziquone is preferentially active in solid tumor lines. However, it has been ineffective after systemic administration, probably because of its rapid elimination. After intravesical use it is not absorbed from the bladder even, when instilled within 6 hours from TURBT.
Several properties of apaziquone, such as the molecular weight, its metabolic activation, and degradation, make systemic toxicity unlikely; therefore intravesical is considered to be safe.
To date, data of several phase 2 and 2 phase 3 have been published within this field. Although these studies demonstrate the potential of apaziquone, the singular phase 3 trials did not reached their primary endpoint. When their data were pooled, the primary endpoint did reach significance, and a combined post hoc analysis suggested that the instillation should be given at least 60 minutes after TURBT. All studies published in the field of apaziquone reported mild adverse effects, comparable to other intravesical drugs, and no systemic adverse effects were noted.
To the authors’ best knowledge, there are currently no new trials recruiting. Consulting Clinicaltrials.gov , 1 new phase 3, randomized, multicenter, multiarm, placebo-controlled, double-blind study of apaziquone ( NCT02563561 ) was found. However its recruitment status is “active, not recruiting.” Considering the fact that no new trials are recruiting at this moment and current data are insufficient to change any guideline on NMIBC, it seems that the development of apaziquone for NMBIC has stopped. In an FDA Oncological Drugs Advisory Committee (ODAC) meeting of September 14, 2016, the FDA concluded that with the available data apaziquone has not shown substantial evidence of a treatment effect over placebo. This FDA document could be the reason for the study sponsor (Spectrum Pharmaceuticals, Inc.) to focus on other new medicines in its pipelines.
Disclosures: Dr J.A. Witjes was a previous advisor of Spectrum Pharmaceuticals (until 2017) and primary investigator in apaziquone studies.
References
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Predictors of Response to Intravesical Therapy
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Immuno-Oncology Approaches to Salvage Treatment for Non-muscle invasive Bladder Cancer
Role of Indoleamine-2,3-Dioxygenase Inhibitors in Salvage Therapy for Non-Muscle Invasive Bladder Cancer
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