FDA has approved Relugolix (Orgovyx) for advanced PCa.

[pjoshea13]

"The approval of the GnRH receptor antagonist is based on data from the phase 3 HERO study, which showed that 96.7% of patients randomized to relugolix maintained castration through 48 weeks, compared with 88.8% of patients receiving leuprolide (P <.001).1 The benefit with relugolix was sustained across all major secondary end points (P <.001).

Relugolix was also associated with a 54% lower risk of major adverse cardiovascular events compared with leuprolide (HR, 0.46).

Of note, relugolix did not improve castration resistance–free survival through 48 weeks versus leuprolide acetate in patients with metastatic prostate cancer.2 Overall, 74% of men who received relugolix were castration-resistance free through 48 weeks versus 75% of patients who received leuprolide (HR, 1.03; P = .84)

“Today’s approval marks the first oral drug in this class and it may eliminate some patients’ need to visit the clinic for treatments that require administration by a health care provider,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated in a press release.

“This potential to reduce clinic visits can be especially beneficial in helping patients with cancer stay home and avoid exposure during the coronavirus pandemic," added Pazdur.

The open-label international phase 3 HERO trial included 930 patients treated at 155 clinical sites. The median patient age was 71 years (range, 47-97), with 28.6% of patients being aged ≥75 years. Overall, 31.7% of patients had metastatic disease, 15.5% of patients had a Gleason score of 5-6, 38.6% of patients had a Gleason score of 7, and 43.1% of patients had a Gleason score of 8-10. Half (50.2%) of patients had evidence of biochemical or clinical relapse after local primary intervention with curative intent.

The median PSA level at baseline was 10.8 ng/ml and the average testosterone level at baseline was 427.5 ± 156.2 ng/ml. The ECOG performance status was 0 in 88.1% of patients, 11.9% of patients, had prior androgen-deprivation therapy, and 30.3% had prior radiotherapy.

Patients were randomized in a 2:1 ratio to relugolix at 120 mg orally once daily or leuprolide injections every 3 months. Treatment was administered for 48 weeks, with a primary end point of sustained testosterone suppression to castrate levels (<50 ng/dL) through 48 weeks.

On day 4 of treatment, 56% of the relugolix cohort had castrate levels of testosterone versus 0% of the leuprolide group. On day 15, the rates were 98.7% versus 12%, respectively. Also on day 15, 79.4% of the relugolix arm had a confirmed PSA response, compared with 19.8% of patients on the leuprolide arm (P <.001).

Among a subgroup of men followed for testosterone recovery (n = 184), the mean testosterone levels 90 days following discontinuation of treatment were 288.4 ng/dL versus 58.6 ng/dL, respectively.

The incidence of adverse events (AEs) was similar across the study arms. In the relugolix group, all-grade AEs occurred in 92.9% of patients compared with 93.5% in the leuprolide arm. Grade 3/4 AEs occurred in 18% versus 20.5% of the 2 arms, respectively. There were 7 AE-related deaths in the relugolix cohort compared with 9 in the leuprolide arm.

The most common AE across all grades in both arms was hot flash, occurring in 54.3% and 51.6% of the relugolix and leuprolide cohorts, respectively. There was a higher incidence of all-grade diarrhea with relugolix at 12.2% versus 6.8% with leuprolide. All diarrhea cases were grade 1/2 and did not lead to any patient discontinuations.

Major adverse cardiovascular events occurred in 2.9% of the relugolix arm compared with 6.2% of the leuprolide cohort. The study defined major adverse cardiovascular events as nonfatal stroke or myocardial infarction, or death due to any cause."

References

1. Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382(23):2187-2196. doi: 10.1056/NEJMoa2004325.

2. Myovant Sciences Announces Results of Additional Secondary Endpoint of Castration Resistance-Free Survival from Phase 3 HERO Study of Relugolix in Advanced Prostate Cancer. Myovant. Published online September 29, 2020. Accessed September 29, 2020. bit.ly/3iiHtLs.

urologytimes.com/view/fda-a...

-Patrick

[treedown]

Anything on its interactions with other drugs like Zytiga compared to Luprons interactions with said drug or is the risk profile assumed to be the same?

[pjoshea13 in reply to treedown]

There is a clinical trial in the works for Zytiga:

clinicaltrials.gov/ct2/show...

"This study is being conducted to assess the safety and tolerability of relugolix in combination with abiraterone plus prednisone during a 12-week treatment period in men with metastatic prostate cancer, either metastatic castration-sensitive prostate cancer (mCSPC) or metastatic castration-resistant prostate cancer (mCRPC)."

Can't find anything for Xtandi.

-Patrick

[treedown in reply to pjoshea13]

Looks like we won't know for a year. I hope to be off treatment at that time and taking a vacation while my T returns. There's a rumor my MO is thinking of taking me off Zytiga next week so this may be an option at that time. I plan to ask about this as an option if the runmor is true as 3 month Lupon is still on backorder and even though Eligard is the same drug and I can't say specifically why I think it was different it felt different. More so at first. Thanks!

[cesces]

So about half the adverse cardiovascular events.No need for injections.

But about the same efficaciousness. With about a year of data so far.

Do I have that right?

Are there any other major attributes I missed?

Probably it's going to more expensive. Probably most Medicare drug plans will exclude it from their formulary I would expect.

That injections are covered by one part of a plan and ingested medications by another will likely have some real life impact. Though it isn't to clear to me what that will look like. Does anyone have any insights to this.

[MateoBeach in reply to cesces]

You have summarized it quite well. Only other factor is faster Testosterone recovery after stopping. That may be beneficial in IADT cycling.

[cesces in reply to MateoBeach]

"IADT" ?????Are you talking about bipolar androgen therapy?

[pjoshea13 in reply to cesces]

"I" = Intermitent.

I agree that it should add to QoL on IADT. The off-phase of IADT is often a continuation of castrate levels for a while.

When T recovers from castrate levels, PSA will tend to rise. It often settles down when the "Saturation" level is reached - ~250 ng/dL from what I have read from Morgentaler (Myers says at least by 350 ng/dL, the hypogonadal cut off.) But some may panic & rush back to ADT.

-Patrick

[MateoBeach in reply to cesces]

Intermittent ADT So when you go off ADT the testosterone recovers to normal much more quickly. Would also be applicable or similar to BAT but would be physiological T instead of Supra T.

[cesces in reply to MateoBeach]

Could you explain a little more about the difference between bat and iadt?

And why you would choose one over the other?

And the difference between "physiological T " and "Supra T."

Thanks

[MateoBeach in reply to cesces]

Sure. Just my take as an overview from one person’s perspective. Normal adult male Testosterone levels are around 300 to 600 nG/dL but varies with labs. This would be “physiologic” or normal T. ADT therapies lower T levels to castrate levels which is ideally <20 nG/dL ( and certainly <50). Intermittent ADT (IADT) utilizes castrate levels to suppress PC growth for a time until a very low PSA level is achieved. Then it is stopped to allow T levels to recover to normal for a time. This lets the body recover from adverse effects of ADT and relief from symptoms. Though T recovery from Lupron like drugs can be very slow. IADT has been shown to be “not inferior” to continuous ADT. When the PSA starts rising again to a preselected level then the ADT is started again.

BAT therapy takes this strategy much higher and is still quite Controversial Only small early trials have been done so far and it works beneficially for some patients and not at all well for others. So it must be done with very careful monitoring and supervision as in a clinical trial. The principle is that very high T levels also suppress PC cancer growth. Levels above the normal range are called Supra-physiologic testosterone, SPT.

This is known as the bi-phasic response of PC to Testosterone. It is at the in-between zone above castrate and below high-normal that prostate cancer growth is most strongly stimulated. The BAT clinical trial used continuous ADT then inserted a big shot of injectable testosterone once a month in cycles. This effectively gives 2 weeks of SPT alternating with 2 weeks of castrate levels. This is a form of adaptive treatment attempting to keep complete testosterone independence from emerging by changing the selective pressures on the cancer.

I think this is very promising and hope it is further developed while I can take advantage of it. Some on this forum are trying it with their MOs. Others are also doing quite well on continuous high testosterone regimens (continuous SPT). It can be difficult to find a physician willing to authorize these strategies due to the old and out of date blanket view that testosterone is always bad and contraindicated in PC.

[Don_1213 in reply to cesces]

You missed that it was much more effective sooner than Lupron. I don't see a downside to it except I'm sure it's going to be costly, and most "help" plans by drug manufacturers exclude Plan-D Medicare participants even when their plans won't pay for any part of the drug.

Luckily I'm done with ADT.. (at least for now..)

[ragnar2020]

A while ago, I watched a gathering of MOs at a Grand Rounds presentation discuss Relugolix. Dr. Shore had made a presentation.

It was enlightening how two of the concerns with an oral ADT drug seemed to be centered around the potential lost of patient control if the patient were able to walk into CVS and purchase their ADT drug and possibly maybe miss a daily dose.

Another voiced concern was the possible lost of a revenue source to a urology practice if patients weren’t required to make office visits for ADT drug injections. Two of the MOs mentioned how their nursing staff administered the ADT injections and the lost of that revenue source was concerning.

I found these two concerns disheartening, but I shouldn’t have. This is medicine today. New treatments are approved very slowly for many reasons that are not immediately apparent to the patients.

Jeff

[pjoshea13 in reply to ragnar2020]

Before Medicare put a stop to it, offices were getting $1,000 to administer the shot. Very lucrative. From a urologist I know: "We were all doing it!" Nowadays "it's almost not worth the trouble."

The cash cow that needs to be taken away from them is the 80% of unnecessary biopsies. IMO.

-Patrick

[ragnar2020 in reply to pjoshea13]

Hi Patrick,

It was probably my naïveté but during another round table discussion between MOs and urologists I found it interesting how what ADT drug the docs often chose for their patients were dictated not by them but instead by the business manager at their practice who had negotiated the best price for a particular drug with the drug salesmen hounding their office.

One doc at a larger academic practice said that if he really felt a different ADT drug would cause a better outcome

for his patient he’d “push back against the business office and force them to let me use the one I wanted.”

I had hoped that the drug that I was given was dictated by what would help me and not by what made the medical

practice the biggest profit margin.

Jeff

[cesces in reply to ragnar2020]

That's why it is good always to get second opinions and ask lots of questions.

[cesces in reply to pjoshea13]

"The cash cow that needs to be taken away from them is the 80% of unnecessary biopsies. IMO."

Lol yup

[noahware in reply to ragnar2020]

So Jeff, think about your observations here in the context of the fact that oral bicalutamide NEVER got an approval for monotherapy by the FDA, as it did in nearly every other country on the planet! (So not just "very slowly" but not at all.)

One headline I saw regarding Relugolix made it sound like it was the first oral PC agent ever released, while really it is either only the first of its type or the first with an FDA blessing. I wouldn't be surprised if there are two stories behind the non-approval of bicalutamide: the official one, and the real one.

Bicalutamide was of course also quite expensive when first released, costing more than Lupron, but was FDA-approved for use only ALONG WITH an agent like Lupron. Once it became less expensive and widely used around the globe, I gather that some docs in the US prescribed it off-label as monotherapy to a certain subset of patients: those who could not afford the prevailing standard of care.

[pjoshea13 in reply to noahware]

For my BAT-like protocol I chose DES (Diethylstilbestrol). It is taken orally - so no outings for injections. A 3-month supply is shipped to me from a compounding pharmacy in NJ for under $50!

It's a synthetic estrogen so I keep an eye on D-dimer. No negative effects on bone.

One can imagine the arm-twisting that occurred 35 years ago, when Lupron was approved by the FDA. There must have resistance to giving up DES (a cheap drug that had been around for 45 years) for an expensive drug that had to be injected.

-Patrick

[noahware in reply to pjoshea13]

Some resistance to giving up a cheap drug, but not too much, so long as everything gets paid for with Other People's Money. For the ones without access to that, good old castration was still pretty cheap.

Considering the FDA declared DES a carcinogen in the same year they approved Lupron, the arm-twisting was probably a bit easier. I gather 3-5 mg is where the risk goes up in terms of CV risk. What dose do you take?

[pjoshea13 in reply to noahware]

I began DES at 1mg but was on a monthly cycle (i.e. testosterone cypionate injected on the first of each month.) This allowed a lesion at S1 to progress & cause pain. I went to 2mg on a 2 month cycle & pain went, but felt tired on 2mg. In the current cycle, which ends on Dec 31st, I am using 1.5mg DES & feel pretty good. If the PSA is good, I will try 1mg.

-Patrick

[V10fanatic]

This is good news for us all.

[Patrick-Turner]

So what is the average benefit to a man with advanced Pca whose ADT with Lucrin etc has not worked for years and if he changes to Relugolix ? Just what this approved new potion does seems entirely obscured by Medispiel.

Patrick Turner.