Ann: SECuRE trial update, page-151

64Cu-SAR-bisPSMA + Enzalutamide: The SECURE Trial Extension

KNOW WHAT YOU ARE INVESTED IN – for fewer heartaches when the share price gyrations threaten to throw you overboard!

DID YOU KNOW?

• The SECURE trial started as a dose-determining study to find the right treatment dose. In these early trials, patients are usually those who have exhausted all other treatment options. They take on unknown risks in the hope of finding something that might help them - or simply to contribute to advancing science for the benefit of others.
• Failing many lines of therapy makes it much harder to respond to new treatments! Every patient in SECURE v1 had already failed multiple treatments! These patients are among the toughest to treat, and the likelihood of success is low from the outset.
• However, for Clarity and its investors, there is still huge value in such a trial: identifying a safe dose that does not harm patients.
• Efficacy, if achieved, is a bonus!

In short, SECURE is just the beginning! Understand this, and you won’t be alarmed when trial changes occur, or when a patient’s PSA rises again after one or three doses. The key point is he is still alive and can receive further doses - helping generate more valuable data in the process.

CONTEXT is KEY!

When evaluating the SECURE trial results, we should keep in mind:
a) The trial’s goals – as explained above.
b) The patient group – these individuals had already failed multiple treatments and were expected to be the hardest to treat, with low chances of success.
c) FACT: While early localized prostate cancer is curable (through surgery or radiation), advanced prostate cancer is not curable with current treatments. However, existing therapies can prolong survival and control the disease for years.

A complete response is not the same as a CURE! Time will tell!
Key Results So Far

1) Optimal Dose Identified: The best balance between effectiveness and safety was found at 8 GBq. While 12 GBq remained safe, 8 GBq was selected as the preferred dose. (Hopefully, 12 GBq isn’t discarded forever!)

2) Strong Effectiveness in Heavily Treated Patients: The treatment worked well even in men who had already failed multiple treatments, including androgen receptor pathway inhibitors (ARPIs), Pluvicto (Lu-177 PSMA Beta), and Actinium (Ac-225 PSMA Alpha) therapies.

---
Next Steps: Expanding the Trial with Cu-67 and Enzalutamide

Somehow, this didn’t excite the market. If anything, it seems to have disappointed some investors (judging by posts on HotCopper).
Biotech investing is about finding promising stocks while they are still underappreciated. It’s about recognizing hidden gems, setting up camp, and staying the course.
There’s nothing wrong with expanding to include Enzalutamide (Enza). In fact, some might argue this should have happened earlier. More on that below.
Let us not forget: Clarity will need to plan a Phase 3 trial sometime in the near future! To design a trial properly, you need some previous data which is used as a guide, on everything including endpoints as well as sample sizing calculations!
-

Why Combine Cu-67 SAR-bisPSMA with Enzalutamide?

First, lets understand Enzalutamide: Its an Androgen Receptor Inhibitor (ARPI). It blocks testosterone from fuelling prostate cancer growth. Unlike treatments that lower testosterone levels - Androgen Deprivation Therapy (ADT) or surgery (chemical or surgical castration), Enzalutamide works even when testosterone production has been suppressed. It doesn’t matter where residual testosterone comes from - Enza blocks it (alongside its other cancer-killing mechanisms).
# A man always finds another way to harm himself: Even after castration, the body and cancer itself find ways to keep producing testosterone - which is why we have Castration-Resistant Prostate Cancer (CRPC).

-
Radiation + Enza: A Proven Synergy!

Preclinical studies and real-world data show that combining Enza with radiation therapy improves prostate cancer outcomes.

• External Beam Radiation (EBRT) + Enza – Enhanced tumor control.
• Radium-223 (Xofigo) + Enza – Synergistic effects seen in bone metastases.
• Pluvicto (Lu-177 PSMA) + Enza – Undergoing trials for earlier treatment lines. Loise Emmet's group found great results with this combination. [Loisse pushed for Clarity to do the same trial being debated].

For targeted radiation therapies like Pluvicto and Cu-67 SAR-bisPSMA, the mechanism is clear to all of us here: PSMA (Prostate-Specific Membrane Antigen) is found in high amounts on prostate cancer cells. This is what Illuccix, Pylarify, 64Cu-SAR-bisPSMA (for imaging), and Pluvicto & Cu-67 SAR-bisPSMA (for therapy) target.
Enzalutamide increases PSMA expression on cancer cells, making them easier to target with PSMA targetting radiopharmaceuticals. This enhances treatment effectiveness.
Among ARPIs, Enza is the most commonly used. It is 1st line in nmCRPC, mCRPC, and mHSPC. (n = non, m = metastatic, CR = Castration Resistant, HS = Hormone Sensitive, PC = Prostate Cancer). It is frequently used alongside other therapies (ADT, etc.) to improve treatment response.

Some results from Louise Emmet's ENZA-p study (ASCO 2025).



# 96 deaths reported after a median follow-up of 34 months: 53 from enzalutamide-alone and 43 in enzalutamide + LuPSMA group.
# Overall survival was longer in the enzalutamide + LuPSMA group than the enzalutamide-alone group: median 34 months versus 26 months (HR 0.55, 95% CI 0.36 to 0.84; p = 0.005):

-
First-Line Therapy: A Bigger Opportunity!

First-line therapy is a much larger market than what SECURE originally targeted. Even Pluvicto is aiming for first-line approval, using the same strategy of combining with Enzalutamide.
If science already knew its so good - why didn't secure start with the combination? Perhaps because Clarity needed to prove that 67Cu-SAR-bisPSMA was safe in humans before expanding its use!
Now that the dose determination phase is complete, and there is some efficacy data, it is possible to tell a patient about to start Enzalutamide:
"This new treatment is safe, and science suggests it will improve your response to Enzalutamide."
That’s a great strategic move.

---
Potential Benefits of the Combination (In Short)!

# Greater Efficacy – Studies show radiation + Enza works better than Enza alone. The expectation here is that Cu-67 SAR-bisPSMA will be even more effective when paired with Enza.
# Safety Profile – While Cu-67 SAR-bisPSMA has shown excellent safety so far, Enza does have notable side effects, particularly CNS (central nervous system) effects. Using Cu-67 SAR-bisPSMA with Enza might allow for Enza dose adjustments, improving tolerability.
----

Final Thought: Enza Is Not the End-All, Be-All

Enzalutamide is NOT a cure for prostate cancer! It delays disease progression but does not eliminate prostate cancer.The need for more effective therapies remains.
There are other ARPI's such as Darolutamide, which is more effective and has less adverse effects than Enza - but Enza is in number one position at the moment!
Anyhow, Cu67-SAR-bisPSMA will be used with ARPI's that are in use, and likely wont specify which when getting to the Phase 3 trials.

Expanding SECURE to include Cu-67 SAR-bisPSMA + Enza is an important step forward!

Below - SECURE trial - selected.




---

Below - PSMAfore results (selected)

--

Below (form a study combining radium 223 with Enza)


REFERENCES

ASCO GU 2025: Overall Survival and Quality of Life with 177Lu-PSMA-617 plus Enzalutamide Versus Enzalutamide Alone in Poor-Risk mCRPC in ENZA-P (ANZUP 1901)

ASCO 2024: PSMAfore: HRQoL and Pain in a Phase 3 Study of 177Lu-PSMA-617 in Taxane-Naïve Patients with mCRPC

ESMO 2024: Radium-223 and Enzalutamide in Asymptomatic or Mildly Symptomatic Patients with Bone Metastatic Castration-Resistant Prostate Cancer: First Results of EORTC-GUCG 1333/PEACE-3