Fexapotide Triflutate (FT) injection - a new kind of focal treatment to extend time on active surveillance

FT for Prostate Cancer

A new medicine may be able to help men on active surveillance stay on it longer. The medicine, called Fexapotide Triflutate (FT), is administered just once with a thin (#22 gauge), reportedly non-painful, needle, in the prostate quadrant where GS6 cancer has been detected. It causes prostate cells, both benign and cancerous, to undergo "apoptosis" (programmed cell death). It only kills prostate tissue and not blood vessels or nerves, does not leak outside of the prostate into systemic circulation, and does not affect adjacent tissues of the rectum, bladder, urethra, or periprostatic tissue.

Shore et al. reported the results of a Phase 2 randomized clinical trial in 148 patients at 28 sites.  They were randomized to get low-dose FT (2.5 mg), high dose FT (15 mg), or active surveillance (AS). Patients and investigational staff were blinded as to FT dose, with no sham injections for AS patients. The FT patients received a single injection only into the quadrant with the cancerous core. Patients were all excellent candidates for active surveillance:

• Gleason score 6
• Stage T1c (nothing felt on DRE)
• Only 1 core with cancer
• ≤ 50% cancer in the core

They were all followed using the same protocol:

• Follow-up biopsy on Day 45 and at 18 months, 36 months, and 48 months
• PSAs every 6 months
• After the first biopsy, 18 of the 49 AS patients were allowed to opt for FT injections

After 4 years of follow-up:

• 42% of AS patients progressed, and 39% were treated for progression
• 19% of high-dose FT patients progressed, and 11% were treated for progression
• 37% of low-dose FT patients progressed, and 21% were treated for progression.
• Median biopsied tumor grade was Gleason 3+4 among those assigned to AS or low-dose FT vs Gleason 3+3 among those who received high-dose FT. At 18 months, the median tumor grade for the high-dose group was benign (no cancer detected) vs GS 3+3 in the other two groups.
• At 18 months, estimated tumor volume in the quadrant with cancer increased by 69% for AS vs decreased by 59% for FT.
• The effect of high-dose FT was greatest at 18 months, and still had an effect at 48 months.
• The effect of low-dose FT was greatest at 18 months, but was insignificant at 48 months.
• PSA reduction was maintained in both FT groups (-21%) 
• There were very few and transient side effects attributable to the injections (blood in urine, sperm or stool), diarrhea or nausea from antibiotic.
• There were no serious adverse effects - no increase in urinary symptoms
• There were no significant sexual problems associated with FT treatment

It is entirely possible that injections across the entire prostate might have improved results.

For comparison, at 5 years after AS, Johns Hopkins (which had similar stringent requirements) reported progression in only half as many patients (21%), about the same percent as in the high-dose FT group. It is unclear why progression among the AS control group was so much higher in the Shore trial.

Comparison to 5αri therapy

Dutasteride has also been used in an effort to slow progression among men on AS. Fleshner et al. reported that after 3 years, 38% of treated patients and 48% of their more liberally-assigned AS patients progressed or were treated. In the Shore trial at 3 years, 10% of high-dose FT-treated patients and 30% of the AS patients progressed and were treated. It's hard to compare these trials because the AS criteria were so different.

At one year after 5αri therapy (finasteride or dutasteride) for BPH in very-low-risk men on AS for prostate cancer, Shelton et al. reported that no cancer was found on biopsy in over half (54%) of the treated men, similar to the finding of the high-dose FT group at 18 months. Only 5% progressed to Gleason 7, similar to the high-dose FT group  (6%) at 18 months.

• 5αris are known to have sexual side effects in 20-25% of men taking them. Sexual side effects may include reduced libido, difficulty in having an erection or orgasm, or gynecomastia. 

• Hair growth is a beneficial side effect for many men. 

• They have to be taken every day. 

• They shrink benign prostate tissue, and may cut PSA in half if the PSA is due to enlargement of the entire prostate. However, in men who have BPH due to enlargement of the transition zone-only (with normal-sized prostates), their effect on BPH and PSA is unclear. Whereas PSA as a biomarker for active surveillance is already problematic, using 5αris may increase confusion and anxiety.

• FT, on the other hand, has no sexual side effects

• works well for transition zone tumors, and 

• has a smaller effect on PSA (-21%)

• is a pain-free, "one and done" treatment. 

• It is unknown what the relative costs will be.

Other potential therapies

In a retrospective study at Cleveland Clinic, statin use was not associated with reduction of progression among men on active surveillance.

There are other medicines in ongoing clinical trials to delay progression in men on AS:

• 2-hydroxyflutamide (intra-tumoral injection)
• apalutamide
• green tea catechins
• curcumin
• Prostatak
• Provenge
• Proscavax

Patients are cautioned against using supplements that may be masking their true PSA (see this link) in the hope of prolonging AS. "Treating PSA" rather than treating the underlying cancer can lead to mismanagement.

This small study suggests that FT injections can delay progression for men on AS, without any side effects. This is different from focal ablation therapy (see this link).  There must still be periodic biopsies, although their frequency may be safely reduced. The cost and whether insurance will cover that cost may be a consideration. If it gets approved for BPH (see below), and considering that many men with prostate cancer also have symptomatic BPH, this may be available "off-label" within the next couple of years.

FT for BPH

Benign Prostatic Hyperplasia (BPH) plagues most older men with Lower Urinary Tract Symptoms (LUTS). LUTS symptoms include getting up many times at night to pee (nocturia), bothersome urinary frequency and urgency, urinary retention (incomplete emptying), weak/interrupted stream, and dribbling. Cialis, alpha blockers, and Proscar or Avodart are effective in some men. The most invasive therapies are radical prostatectomy and Trans-Urethral Resection of the Prostate (TURP). TURPs sometimes have to be re-done and carry risk of erectile dysfunction (ED), incontinence, and retrograde ejaculation. Somewhat less invasive is Holmium Laser Enucleation of the Prostate (HoLEP), with perhaps diminished risks. Both require catheterization during healing. Both may make future treatments for prostate cancer problematic. Several mechanical solutions have been tried (see this link) with varying degrees of success.

The advantage of FT is it is minimally invasive - only two injections with a thin needle are given, one in each side of the transition zone of the prostate. It can be easily re-done, if needed. And it has no effect on non-prostatic tissue (e.g., nerves or blood vessels) so side effects are expected to be minimal.

Shore et al. (and here) reported on a trial of 995 men with BPH treated at 72 sites in the US. The treatment consisted of:

• 5 ml of FT solution injected in each lobe (2.5 mg FT in 10 ml total)
• using a thin (22 G) needle 
• into each lobe of the transition zone 
• under transrectal ultrasound guidance.

The Phase 3 trials were randomized and double-blinded. Follow-up was double-blinded, and continued for up to 6.5 years. From 18-39 months after the first blinded injection, 344 patients received an (unblinded) injection of FT (half had a second injection, half a first).

Adverse Events

• There were no cases of infection or sepsis
• Mild side effects of the injection (blood in semen, urine or stool) were transient and similar for treatment and placebo.
• Transient side effects attributable to the antibiotic were the same for treatment and placebo.
• No FT detected in plasma.
• No anti-FT antibodies were created
• No differences in semen.
• Improvement in patient-reported sexual function of FT-treated vs worsening of placebo group
• Improvement in patient-reported urinary function of FT-treated vs worsening of placebo group
• In the first year, peak urine flow rate was no different in the FT group compared to the placebo, but the placebo (buffered saline+antibiotic) itself created a significant improvement
• Reduced use of TURP among FT-treated vs placebo group
• Reduced use of TURP among FT-treated vs placebo group who used oral medications 
• Acute Urinary Retention in 1% of FT-treated vs 5% of placebo group

Other Measures

• PSA did not change
• Exterior prostate volume reduced by 2% in treatment group only. 
• Prostate cancer detected in 1% of FT-treated vs 5% of placebo group

Unlike systemic treatments like 5αris, alpha blockers, and bladder anti-spasmotics, FT has no global effects. It requires only a single pain-free, non-invasive, treatment, and it may allow one to postpone, perhaps indefinitely, more invasive treatments. 

When used for BPH, it does not interfere with PSA as a biomarker for prostate cancer. It reduces the need for prostate cancer treatments, and probably does not add to the side effects of those treatments if needed.

With these large phase 3 trials completed, the FDA may approve its use within the next couple of years.