TOOKAD Powder for solution for injection Ref.[7650] Active ingredients: Padeliporfin

Pharmacotherapeutic group: Sensitizers used in photodynamic/radiation therapy,
ATC code: L01XD07

Mechanism of action

Padeliporfin is retained within the vascular system. When activated with 753 nm wavelength laser light, padeliporfin triggers a cascade of pathophysiological events resulting in focal necrosis within a few days. Activation within the illuminated tumour vasculature, generates oxygen radicals (•OH, •Ο₂^-) causing local hypoxia that induces the release of nitric oxide (•NO) radicals. This results in transient arterial vasodilatation that triggers the release of the vasoconstrictor, endothelin-1. Rapid consumption of the •NO radicals, by oxygen radicals, leads to the formation of reactive nitrogen species (RNS) (e.g. peroxynitrite), in parallel to arterial constriction. In addition, impaired deformability is thought to enhance erythrocyte aggregability and formation of blood clots at the interface of the arterial supply (feeding arteries) and tumour microcirculation, results in occlusion of the tumour vasculature. This is enhanced by RNS-induced endothelial cell apoptosis and initiation of self-propagated tumour cells necrosis through peroxidation of their membrane.

Pharmacodynamic effects

In patients with localised prostate cancer who received TOOKAD-VTP, necrosis was observed by Magnetic Resonance Imaging (MRI) at day 7. There was a correlation between the total energy delivered and the volume of necrosis observed at day 7. The LDI corresponds to the ratio of the cumulative length of illuminated fibre tips (cm) to the volume (cc) of the targeted zone to be treated. The targeted zone corresponds to the lobe containing the positive biopsies. Its volume is measured after prostate delineation using the treatment guidance software. In Phase II studies, treatment conditions corresponding to an LDI ≥1 were associated with a mean rate of necrosis of the targeted zone at day 7 of 89% ± 20.75 for unilateral treatment. An LDI ≥1 appeared to be associated with a greater volume of necrosis on Day 7 MRI and greater share of patients with negative biopsy at 6 months compared with an LDI <1 (see section 4.2).

There was no significant correlation between the percentage of prostate necrosis on Day 7 MRI and the likelihood of a negative prostate biopsy at follow-up.

Clinical efficacy and safety

Phase III Study (PCM301)

The pivotal open-label Phase III study (PCM301), conducted in 10 European countries, randomised 413 patients to TOOKAD-VTP arm or AS arm.

The main inclusion criteria were low-risk prostate cancer with Gleason 3 + 3 prostate adenocarcinoma as a maximum, two to three cores positive for cancer and a maximum cancer core length of 5 mm in any core (at least 3 mm for patients with only one positive core), clinical stage up to T2a, PSA ≤10 ng/mL, prostate volume equal or greater than 25 cc and less than 70 cc. The main exclusion criteria were any prior or current treatment for prostate cancer, any surgical intervention for benign prostatic hypertrophy, life expectancy less than 10 years, medical conditions which preclude the use of general anaesthesia.

The VTP procedure consisted of a 10 minutes IV injection of 4 mg/kg of TOOKAD followed by 22 minutes 15 seconds of illumination with 753 nm laser light at 200 J/cm of fibre delivered using interstitial optical fibres, inserted transperineally into the prostate gland. In case of unilateral disease, focal treatment of one lobe was to be applied. In case of bilateral disease (discovered at entry or during follow-up), bilateral treatment was to be applied, either simultaneously or consecutively. Retreatment of lobes found positive for cancer at 12-months follow-up was allowed.

AS involved serial absolute PSA measurements and ultrasound-guided prostatic biospy at 12 and 24 months.

The study had two co-primary endpoints for TOOKAD-VTP in comparison to AS:

• A: The rate of absence of definite cancer based on histology at 24 months,
• B: The difference in rate of treatment failure associated with observed progression of disease from low to moderate or higher risk prostate cancer. Moderate/higher risk prostate cancer was defined as any of the following: >3 cores definitively positive for cancer; Gleason primary or secondary pattern ≥4; at least 1 cancer core length >5 mm; PSA >10 ng/mL in 3 consecutive measures; T3 prostate cancer; metastasis; prostate cancer-related death.

All patients had Gleason score ≤ 3 + 3 at baseline.

In each table are also presented the results of patients meeting the indication criteria (patients with unilateral low-risk localised prostate cancer excluded the very low-risk)

Table 2 gives baseline characteristics by arm.

Table 2. PCM301 – Baseline characteristics by arm for the Intention-To-Treat (ITT) population and patients meeting the indication criteria:

Of the 206 subjects randomised TOOKAD-VTP, 10 did not receive treatment for various reasons including study withdrawal, meeting exclusion criteria, non-compliance and other medical events.

Table 3 describes the co-primary efficacy endpoints in the whole prostate gland and in the treated lobe (ITT population and patients meeting the indication criteria).

Table 3: PCM301 – Co-primary efficacy endpoints – Whole prostate gland and treated lobe(s)* – ITT population and patients meeting the indication criteria:

^g Adjusted Hazard Ratio (95% CI) = 0.34 (0.24; 0.46); p value≤0.001
^h Adjusted Hazard Ratio (95% CI) = 0.31 (0.20; 0.50); p value≤0.001
ⁱ Adjusted Hazard Ratio (95% CI) = 0.17 (0.12; 0.27); p value≤0.001
^j Adjusted Hazard Ratio (95% CI) = 0.11 (0.05; 0.25); p value≤0.001
* The treated lobe(s) in the AS arm was defined as the lobe(s) with disease at baseline.

A secondary objective was to determine the difference between the two arms with regard to the rate of subsequent radical therapy for prostate cancer. Of 58 patients that progressed in the TOOKAD-VTP arm, only 11 underwent radical therapy, 18 patients underwent a second VTP procedure and 29 had not received further treatment at the end of the study. Of 121 patients that progressed in the AS arm, 54 underwent radical therapy and 67 had not received any active treatment at the end of the study. Patients in the AS arm were not offered subsequent VTP. In assessing overall tolerability by Month 24, post enrolment patients who underwent a radical therapy were also counted in the scoring of prostate symptoms and erectile function.

Table 4. PCM301 – Number of subjects with radical treatment at 24 months – ITT population and patients meeting the indication criteria:

Effect on urinary morbidity (IPSS) and erectile function (IIEF) following TOOKAD-VTP

As shown in Table 5, in PCM301 study, the International Prostate Symptoms Score (IPSS) showed, a moderate increase 7 days after the VTP procedure, in both the ITT population and in patients meeting the indication criteria. Those results were improved at Month 3 and back to baseline values at Month 6, with further improvement until Month 24. In the Active Surveillance arm, the IPSS score slightly worsened over time until Month 24.

Table 5. PCM301 – Effect on urinary morbidity (IPSS) – ITT population and patients meeting the indication criteria:

* Scores at Month 24 include patients who underwent radical therapy

As shown in Table 6, in the VTP arm of PCM301 study, erectile function domain scores of the 15-question International Index of Erectile Function (IIEF-15) questionnaire showed a marked decrease, 7 days after the VTP procedure followed by a subsequent improvement in the following months up to Month 24, in the ITT population and in patients meeting the indication criteria.

Table 6. PCM301 – Effect on erectile function (IIEF) – ITT population and patients meeting the indication criteria:

* Scores at Month 24 include patients who underwent radical therapy.