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Comment on interim DARRT-1 data announced February 6, 2019

I understand the complexity around the DARRT concept, what we expect to come of the DARRT-1 study, and what the data means that we are reporting on as we move through the study. Boosting the effectiveness of radiotherapy with an immuno-oncology drug is an entirely new area of cancer therapy, so there are no yardsticks to measure us by. The only relevant yardstick is current therapeutic options and whether we can improve on them.

I understand the complexity around the DARRT concept, what we expect to come of the DARRT-1 study, and what the data means that we are reporting on as we move through the study. Boosting the effectiveness of radiotherapy with an immuno-oncology drug is an entirely new area of cancer therapy, so there are no yardsticks to measure us by. The only relevant yardstick is current therapeutic options and whether we can improve on them.

Hopefully this note will shed some light on this.

The journey
It might help to put some perspective around the recent DARRT-1 interim clinical data by understanding the kind of journey a patient of the type in the DARRT-1 study might go through.

  1. The journey starts with a diagnosis of metastatic cancer. Mostly these are men where the cancer has broken through the gland’s capsule at the time of diagnosis and therefore is considered inoperable. The cancer is assumed to have spread out to neighbouring tissues (bowel, bladder), almost certainly the locally draining pelvic lymph nodes, and possibly even along the prostatic nerve to the spine.
  2. Initial treatment generally involves radiotherapy to the prostate and the tissues surrounding the prostate. This can be a fairly destructive process using high dosages of radiation. The aim is to kill as many cancer cells as possible, although complete eradication is rare. The prostate gland is usually effectively destroyed in this process.
  3. Then it is a matter of waiting for recurrence of the cancer, measured by a rise in PSA (Prostate-specific antigen) levels. This typically occurs anywhere between 6 months to 3 years later. The cancer at this stage is referred to as metastatic hormone-sensitive prostate cancer (mHSPC). Metastatic because the prostate gland has been destroyed and any PSA must be coming from secondary cancer cells; hormone-sensitive because the cancer cells are growing in response to testosterone. About 38,000 men in the U.S. develop mHSPC each year.
  4. Treatment then is aimed at blocking the body’s production of testosterone. This is medication called chemical castration or androgen ablation therapy. It has the same effect as surgically castrating a man, which was the older method of treating this disease. Testosterone is fuelling the cancer growth, hence the aim to stop the body making testosterone.
  5. The benefit of chemical castration generally lasts several years before the PSA starts rising again. Because the cancer is now regrowing in the absence of testosterone, it now is known as metastatic castration-resistant prostate cancer (mCRPC).
  6. mCRPC is end-stage disease because treatment is now aimed at prolonging life, not curing the disease. The disease at this stage generally is associated with multiple secondaries, the bulk of which are in the skeleton. Prostate cancer does spread to soft tissues (eg. bladder, rectum, lungs, lymph nodes, brain), but overwhelmingly it spreads to bone, eventually leading up to dozens or even hundreds of small lesions in the ribs, pelvis, hips, leg bones, spine and skull. Bone lesions are painful, and men with mCRPC generally are on high dosages of pain medication.
  7. Standard treatment at this stage is a chemotherapy called Taxotere (docetaxel). About one-third of men respond, although the benefit is modest, with an overall survival benefit of several months.
  8. The penultimate treatment step is anti-androgen therapy involving the drugs enzalutamide (Xtandi) or abiraterone (Zytiga). These drugs seek to shut off any response by the cancer cells to even residual levels of testosterone. The survival benefit offered by these drugs is measured in several months.
  9. The final treatment step is palliative radiotherapy, where a low dosage of radiation is given to 1 or 2 larger lesions in an attempt to relieve pain.

Palliative radiotherapy
The men in the DARRT-1 study have been through this journey and have exhausted all treatment options. They have end-stage disease, most are experiencing significant pain, and  most will have a life expectancy of about 3-6 months.

They have reached the final treatment step – palliative radiotherapy - which involves applying radiation from a standard external source to 1 or 2 individual lesions that are causing symptoms. Mostly the symptom is pain, usually coming from tumours in bone, but symptoms range from a blockage of the bowel through to paralysis coming from pressure of tumour in the backbones pressing on the spinal cord.

The aim of palliative radiotherapy is temporary relief of symptoms and making the end of life as comfortable as possible. There would be no realistic expectation of the treatment altering the course of the disease or the patient living any longer. Palliative dosages of radiotherapy are about one-third that of a dosage of radiation that might be used earlier in the disease. In this way, harm is minimised while still delivering a dose of radiation that might provide some temporary relief.

The purpose of using Veyonda®
The main purpose in using Veyonda® in the DARRT-1 study is to stimulate the body’s innate immune system to boost the anti-cancer response to radiotherapy.

Innate immune cells are first-line defence cells that conduct immuno-surveillance. They are meant to detect and kill abnormal cells such as cancer cells before they get established. Cancers thrive because they are able to deactivate these cells, and successful treatment of cancer with both radiotherapy or the new checkpoint inhibiting drugs is now known to depend on reactivating the innate immune cells within each and every tumour. Not surprisingly, there currently is a race on within the international pharmaceutical industry to find a drug that does this effectively and safely.

Some of the shrinkage a tumour undergoes after receiving radiation certainly comes from  some of the cancer cells being killed in a direct fashion by the radiation. But, that general tissue damage also acts as a trigger that reactivates the previously inactive local innate immune cells within the tumour. Once reactivated, those immune cells then attack and kill remaining cancer cells.

If the trigger is strong enough to cause the immune response within the irradiated tumour to wipe out the irradiated lesion, and then even spill over into the blood so that it reaches other tumours elsewhere in the body that haven’t been irradiated, then those distant non-irradiated tumours will also have their local innate immune cells activated and hopefully deliver an anti-cancer effect. This off-target anti-cancer effect is called an abscopal response.

So, why doesn’t radiotherapy produce this effect in everyone? Why doesn’t every tumour that is irradiated disappear completely and never recur? And why doesn’t everyone experience an abscopal response to some extent?

A likely explanation is the double-edged sword nature of radiotherapy – yes, it is killing cancer cells, and the more cancer cells that can be killed, the more likely the innate immune cells are to be reactivated. But, radiotherapy is also killing healthy cells, and this includes the innate immune cells within the tumour. The result? The more you try to kill cancer cells with radiation, the more likely you are not going to get an immune response being triggered.

Veyonda® is aiming to overcome this problem. Veyonda® is designed to boost the ability of radiation to kill cancer cells without having the same effect on healthy cells such as immune cells. Which means that if you drop the dosage of radiotherapy enough (eg. with palliative radiotherapy), then we believe a Veyonda® + palliative radiotherapy combination means you should be able to maximise the number of cancer cells being killed, while minimising the damage to the immune cells. But we also believe Veyonda® goes one step further and actually activates innate immune cells in its own right, independent of what it is doing alongside radiotherapy. This is the unique dual-acting effect of Veyonda® that we refer to.

The overall aim is to increase the likelihood of triggering a potent local immune response, which hopefully boosts the likelihood of the irradiated tumour responding, and hopefully spills over to all other tumours in the body.  

The aim of DARRT-1
The simple aim of DARRT-1 is to shift a palliative outcome towards a curative outcome.

We don’t expect to see all men respond – that is a function of something called genomics (amongst many other factors), which is the unique makeup of an individual patient and individual tumours that influences how any medication works. No other anti-cancer drug works 100% of the time, and Veyonda® will be no different.

We also don’t expect that every single tumour in the one patient is going to respond identically. Again, this comes down to genomics. Cancer cells are constantly undergoing mutations to the extent that secondary tumours in different parts of the body can be quite different in their genetic make-up. What this means is that a metastatic cancer cannot be regarded as a single disease where all the tumours will show the same response to treatment. That is the situation with current therapies, and we anticipate that it will be the case with Veyonda®.

Putting these two variables together, we expect to see Veyonda® + palliative radiotherapy produce the following possible spectrum of responses in decreasing order of benefit:

  • complete remission, or what is known as no evidence of disease (NED)
  • a partial response extending life by months-several years
  • a modest survival benefit but with considerably less pain and a better quality of life
  • no effect at all.

As to whether any of this would bring Veyonda® to market, it’s worth looking at enzalutamide, one of the last drugs to be approved for the treatment of late-stage prostate cancer, and the penultimate treatment prior to palliative radiotherapy. Enzalutamide was approved for use in men with mCRPC on the basis of a study in about 1200 men where enzalutamide produced a mean overall survival outcome of 18.4 months versus 13.6 months in the placebo group.

Currently, palliative radiotherapy is offering little more than temporary relief of pain and discomfort. If we could achieve an abscopal response in just 30-40% of end-stage mCRPC patients to the extent of slowing down the rate of cancer growth of most lesions, and in so doing, provide significant pain relief and a modest survival benefit, then Veyonda® should transform the management of late-stage prostate cancer, as well as providing justification for using it in earlier stage prostate cancer where its effectiveness might reasonably be expected to be greater.

The latest DARRT-1 data
So, now we finally come to the data we announced recently.

This was 12-week data involving the first 12 patients in this study. These patients are in the first arm of this study which was intended to look at the risk: benefit ratio of three different dosages of Veyonda®. It was asking two prime questions: (1) is the combination of Veyonda® and radiotherapy providing any evidence that non-irradiated tumours are responding and are doing so in a well-tolerated manner?, and (2) is there any evidence of a dose-response effect that would suggest the appropriate therapeutic dose of Veyonda®?

We were able to announce:

  • that we have seen evidence that non-irradiated tumours have responded
  • that we have identified our preferred therapeutic dosage of Veyonda® , and
  • that Veyonda® + palliative radiotherapy is well tolerated.

As I noted in the ASX release, these are just small numbers of patients, so let’s not get too carried away with statistical significance. DARRT-1 is a pilot study intended to give us confidence to go on in terms of safety and efficacy, as well as guidance on the appropriate dosing schedule.

So, what is the basis of our confidence that we are seeing evidence of a potential off-target anti-cancer effect? The reason is that these are men with metastatic disease with multiple lesions throughout their bodies, particularly in their skeleton. Their pain is coming mainly from the lesions in the skeleton, and their PSA levels reflect their total tumour load from all the metastatic lesions. In normal circumstances, applying radiotherapy to a single lesion, in most cases to an enlarged lymph node in the pelvic cavity, is going to have little or no effect on bone pain levels, and just a minimal effect on the overall PSA level.

There was a total of 8 patients in the 800 mg and 1200 mg dose groups:

  • Scans on these patients at 12-weeks showed that 6/8 had stable disease or better (remembering that these patients came into the study with rapidly progressive disease and only 1 lesion received radiation)
  • 5/8 had a significant (>30%) lowering of pain
  • 4/8 had significant (>50%) falls in PSA levels.

We feel confident in interpreting this as potential evidence of off-target (abscopal) activity in about half of the men. Interestingly, in a number of these responders, PSA levels declined from week 6 to 12-week, suggesting that the anti-cancer response might be ongoing, something that will be assessed at 24-weeks.

We currently have an additional 12 men undergoing treatment with 1200 mg Veyonda® which will give us a total of 20 men at ‘therapeutic’ doses when we include the current 8 (800 mg and 1200 mg) subjects. We believe that’s a reasonable number to be able to make some inference later this year about the potential significance of DARRT therapy in mCRPC.

The final readout of DARRT-1 data later this year will coincide with advanced data from our LuPIN-1 study. Both studies are using patients at exactly the same stage of mCRPC and we will be able to compare the relative benefits of both approaches in terms of response rates and likely survival benefits. This is a unique dual approach to the treatment of late-stage prostate cancer that maximises the opportunity to do something transformative with Veyonda®.