ON HISTOPATHOLOGY / BIOPSIES!
"Clarity now faces the challenge of having to prove thelesions detected are not false positives by biopsy against the current SOC which was created and now determined by Illucix, Pylarify etc."Can Clarity prove that the lesions detected are TRUE POSITIVES (not false positives)? To prove this requires histopathology assessment of a biopsy of the lesion detected (so, this is a biopsy after being told the cancer has spread). A post mortem will do too but that has other challenges.
Here are TWO trials that should help us with this information;
1) The COBRA Trial (this is on BCR, and directly informs the design of AMPLIFY)
a) The COBRA Trial protocol: Fortunately, we have the full document:
https://cdn.clinicaltrials.gov/large-docs/27/NCT05249127/Prot_000.pdfb) The ASCO GU 2025 presentation (a well timed question):
https://www.claritypharmaceuticals.com/pipeline/scientific_presentations/2) CLARIFY trial
a) Clinical trials.Gov
b) ASCO GU 2025 has that as well! Great timing.
# Let us remember that the design of the FDA approved Diagnostic pivotal (Phase 3) trials (CLARIFY and AMPLIFY), were both directly informed by PROPELLER and COBRA! So, on a question of possibility - its safe to say that what proved possible the early trials, is indeed possible, and can still be done in later trials - if required! If the FDA says - NO NEED! Great!
The FINDINGS - in SUMMARY!
1a) The COBRA Trial Protocol has Histopathology!
Here is more wording on Histopathology thats marked above: Section 7.4 (page 44)
7.4 Histopathology - Where clinically feasible, histopathology (from image-guided biopsy or surgery [e.g., salvage pelvic lymph node dissection]) should be obtained for as many 64Cu-SAR-bisPSMA PET positive lesions as possible based on the local interpretation of the 64Cu-SAR-bisPSMA PET/CT scans. If clinically feasible, the Investigator should make every effort to obtain histopathology for at least one 64Cu-SAR-bisPSMA PET-positive lesion per region. The biopsy or surgery specimens will be processed and analyzed locally. The local pathologist evaluating the samples will be blinded to the 64Cu-SAR-bisPSMA PET/CT results. The procedure, date of assessment, imaging modality used to guide biopsy (if applicable) and local histopathology result will be recorded on the eCRF.
- For participants undergoing image-guided needle biopsy, the needle biopsy images (e.g., CT, transrectal ultrasound-MRI, ultrasound) of the procedure will be sent to central reading center. The instruction for capturing biopsy images and directions for submitting the images to the central reading center is specified in the Image Acquisition Manual. All histopathology results (and any associated images) acquired within 180 days (±15 days) of Day 0 must be transferred to the central reading center.
1b) We even have HISTOPATHOLOGY RESULTS from COBRA! - it was done!
BUT: This group is made up of BCR (recurrence) patients, and they are all
post definitive therapy (some were-prostatectomy)! Sampling of nodes is not part of standard management when the patient already had cancer treated but now shows signs its back: PSA and Radiology are enough! This is different from PROPELLER and AMPLIFY (the pre-definitive treatment groups).
B) CLARIFY STUDY PLAN - has histopathology post treatment. Its the Standard of Truth. Its an FDA Approved trial design!
ClinicalTrials.Gov
On the illustration below - per information on the ASCO GU 2025 Poster; Step 5 is Histopathology!
But note: CLARIFY is being trialled in the
pre-prostatectomy patients, so the histopathology is automatic in this case.
' ... CLARIFY is a multi-center, single-arm, non-randomized, open label, Phase 3 study of 64Cu-SAR-bisPSMA PET in patients with untreated, histopathology-confirmed PC with high-risk features, who are proceeding to radical prostatectomy with pelvic lymph node dissection (RP-LND)...'
IN CONCLUSION- Clarity can certainly include histopathology in their trials. This is already part of the CLARIFY trial design (it is automatic for patients who proceed from imaging to to having a prostatectomy).
- COBRA, which was on BCR (Biochemical Recurrence), has just provided histologies - so it can certainly be done in AMPLIFY as well (its the same group that COBRA trialed).
- However (My Opinion): This will be very imperfect anyway - esp with AMPLIFY. Patients who already have metastatic cancer are less likely to want to have a biopsy as an additional test due to risks for not a lot of gain!
Finally: You may have a point, even if the wording may be off target! With the personalities at Clarity, I can quite easily imagine them insisting on doing head-to-head as a Phase 3, to prove the science! I can understand: ".... we've built a SUPERIOR PRODUCT!" No prizes for guessing who said those words!
Anyhow: the FDA will not require more from Clarity than what they (the FDA) require from others. So it may have been made clear to Clarity that whatever additional data they provide (such as by doing head to head trials) - the FDA will not issue Gold medals or A+ grades to anyone! Its a PASS if you pass!
However: proof of superiority is not a lost cause: that's what showcases a product as Best In Class - but the FDA does not care about that! Keytruda is having to slog it out with second rate products!
REFSCOBRA protocol (full);
https://cdn.clinicaltrials.gov/large-docs/27/NCT05249127/Prot_000.pdfCLARITY Scientific Presentations:
https://www.claritypharmaceuticals.com/pipeline/scientific_presentations/CLARIFY: Positron Emission Tomography Using 64Cu-SAR-bisPSMA in Participants With High-risk Prostate Cancer Prior to Radical Prostatectomy; ClinicalTrials.gov ID NCT06056830;
https://clinicaltrials.gov/study/NCT06056830https://www.claritypharmaceuticals.com/wp-content/uploads/2024/07/ASCO-2024-CLARIFY-Final-scaled.jpg
(20min delay)