#xofigo

Several men have asked us if they are better off having 177Lu-PSMA-617 (Pluvicto) or Xofigo, a radiopharmaceutical drug that treats bone metastases. There is no simple answer, and the answer is not the same for each of us. Making a sound decision can be helped by understanding the mode of action and the limits of each treatment. 

Like some other radiopharmaceuticals, both of these treatments have two components, a drug that delivers, or targets, the therapy to the cancer cells and a radioactive particle that treats or destroys the cancer cells after they have been delivered to the Mets.

In the case of 177Lu-PSMA-617, the delivery vehicle (ligand) is PSMA-617 (aka, vipivotide tetraxetan), a drug that latches onto a protein called PSMA that is often found at high levels on the surface of prostate cancer cells. The protein, PSMA, is present in bone and soft tissue prostate cancer Mets, but only in around 80 to 90 percent of men. 

The radioactive component or the actual treatment drug is lutetium-177. 

 For a more in-depth explanation see:

cen.acs.org/pharmaceuticals...

The delivery vehicle for Xofigo mimics calcium, and calcium goes (targets) bones. So, Xofigo specifically goes to the bones, and the attached radiation treatment treats the Mets in the bones; Xofigo will not treat soft tissue Mets.   

 One treatment is not better than the other; they are different. Pluvicto and Xofigo have different targeting abilities. Pluvicto targets PSMA, but not all men express the protein PSMA. If you do express PSMA, verified by a positive PSMA scan, then Pluvicto can treat both bone and soft tissue Mets. If you do not express PSMA, Pluvicto will not treat your Mets. For men with only bone, Mets Xofigo will target and treat the Mets.

After this discussion, we do need to add some additional complications.

• You cannot get Pluvicto soon after Xofigo, but you can get Xofigo after Pluvicto. I am unaware of a good reason for this - it was just how Pluvicto was tested and approved.

• Xofigo combines well with some other medicines:

prostate cancer.news/2021/02...

• PSMA expression can be heterogeneous, so even one tumor part could express PSMA (and be treated), and part might not express PSMA and not be treated.   

Theranostics has been around for a while; however, it is a relatively new word in our lexicon for those of us with prostate cancer. 

What is Theranostics other than a cool sounding word and a thing that happens in Germany?

The concept behind Theranostics is pretty simple; it is using the same or similar drugs for both diagnosis and therapy. In prostate cancer, theranostics involves using the same radioisotope to identify or diagnose where the prostate cancer is located and also to use it to treat the disease.  

ASCO recently provided an educational presentation you might be interested in reviewing, which offers a good description of Theranostics (see it here). 

Theranostics has been in medical use in other clinical care areas long before its use in prostate cancer. The treatment of thyroid cancer is one of the oldest examples where the use of the radioisotope radioiodine is common. Radioiodine, which is taken up by the thyroid gland, thus allowing metastases to be visualized in a scan. If you also inject additional radioiodine amounts, it will also be taken up by the thyroid gland, making the thyroid gland “hot” enough to kill the cancer cells.

In prostate cancer, Radium 223, approved in prostate cancer treatment as a treatment known as Xofigo, is a radioisotope that mimics calcium. Like calcium, Xofigo seeks bone, and where there is more bone turnover and remodeling as happens at the site of bone metastases, more Radium 223 accumulates at these sites. 

Radium 223 (Xofigo), landing in bone, specifically at the bone metastases, emits alpha particles that will kill cancer cells. The beauty of Xofigo is that alpha particles have a short reach and kill the cancer cells, but will not penetrate and damage the healthy bone marrow.  

The hottest new Theranostics topic in prostate cancer is 177Lutetium (177Lu). 177Lu is an isotope that, when bound to PSMA, allows both diagnoses (visualization on a scan) because it emits gamma radiation for detection and high energy beta radiation that can kill cancer cells. 

177Lu shows considerable promise for treating prostate cancer, but it is not yet approved for use in most countries. Several completed trials of 177Lu-PSMA have demonstrated that this Theragnostic can increase overall survival in men with progressing castrate-resistant prostate cancer.  

For more details on 177Lu-PSMA treatment, this is an excellent recent review from the European Society of Radiology.

On July 29, 2018, we published a post, Xofigo (Radium-223)- Cautionary Information where we urged men to be very cautious and talk to their doctors before using Xofigo (Radium-223) in combination with Zytiga.  We also indicated that we were concerned about using Radium in combination with any of the other second-line hormone agents.  Our concern came from evidence that men taking a combination of Radium and Zytiga were experiencing very high rates of severe fractures. 

A presentation about data from two separate studies that were presented at the 2019 ASCO conference demonstrates that if a man is also taking a bone protecting agent like Zoledronic acid or denosumab, the fracture risk we expressed concern about that is associated with Enzalutamide and Zytiga in combination with Ra223 for Prostate Cancer is eliminated. 

These findings strongly reinforce the need to be sure that you are following the guidelines regarding bone health monitoring and use of bone-protecting agents when receiving Radium Therapy.  Generally, the guidelines say that before using Radium, a man should start one of the bone-strengthening medications at least six weeks before Radium use.

The ERA-223 study (a company-sponsored registration trial) shows that the administration of a bone-protecting agent before initiation of radium-223 dichloride (Radium-223), when used in combination with Zytiga (abiraterone), eliminates the increased risk of fracture among men being treated for metastatic castration-resistant prostate cancer. 

Similar results were reported from the EORTC -1333-GUCG/PEACEIII (European Organization for Research and Treatment of Cancer), study for the combination of Radium-223 and Xtandi (enzalutamide).  

The ASCO presenter, Dr. Tombal MD, Ph.D., of Cliniques Universitaires Saint Luc and Université Catholique de Louvain in Brussels, Belgium, pointed out that bone protecting agents, “have been registered for years and are recommended by most guidelines.” 

He also said, “However, only one-third of patients receive these treatments regularly. (These findings) should reinforce the message that patients should be monitored for bone health at regular intervals. … and (bone protecting agents should be) used earlier in that setting.”

YOUR TAKE HOME

Last year on this blog we posted important warnings about using abiraterone (Zytiga) in combination with Xofigo (Radium 223).  The warnings were around a finding from a clinical trial (ERA 223) that men with prostate cancer who used both Zytiga and Xofigo in combination were found to be at an increased risk of developing severe bone fractures when compared to men who did not receive both of these treatments in combination (the control group). 

 These findings led to the FDA indicating that the use of Xofigo in combination with abiraterone (Zytiga) is contra-indicated.  Additionally,  the European Medicines Agency (EMA) recommended that the use of Xofigo (Radium-223) be restricted so that Xofigo can only be used after two other treatments have been taken; when other therapies cannot be used and not in combination with other 2nd line hormone therapies. 

There has been some exciting follow-up subgroup analysis that has indicated that the men who had Xofigo and Radium-223 in combination and suffered these bad fractures tended to be men who were not also on bone-targeted therapies like Zometa or Xgeva.  The men who were on these bone-targeted therapies did experience an increased risk for these fractures when compared to the control group. 

Does this finding have any immediate clinical value for us?  

Listen to an interview between Drs. Philip Koo and Charles J. Ryan discuss this finding.  

There are two phase 1 and 2 clinical trials reporting about a new PSMA targeting alpha emitting investigational radiation treatment.  The trials are evaluating Ac-225-PSMA-617.

 The first trial evaluated a cohort of men with end-stage (meaning they have failed many other treatments and had a life expectancy of 2 to 4 months) with advanced prostate cancer.

The trial report by Kratchowil et al. indicated that 40 men received three cycles of this treatment at the University of Heidelberg in two-month intervals.  They reported the following results:

1-     Eleven (11) men did not complete three cycles, - five (5) discontinued due to non-response; four (4) stopped due to xerostomia (dry mouth), and two (2) did not survive eight (8) weeks.

2-    There were thirty-eight (38) surviving men with 87% experiencing some PSA decline; 63% had a PSA decline greater than 50%; tumor control lasted a median of nine (9) months; five (5) men had a response lasting more than two (2) years.

 For comparison purposes prior therapies with abiraterone lasted ten (10.0) months, docetaxel lasted for six and one half (6.5) months, enzalutamide for six and one half (6.5) months, and cabazitaxel for six (6.0) months.

 Since the subject men were end-stage these outcomes are very impressive. 

 In the other early trial which was reported by Sathekge et al., seventeen (17) men who were chemotherapy-naive with metastatic prostate cancer were treated with Ac-225-PSMA-617 in South Africa. 

Most of the men had three (3) treatment cycles (every two months). Subsequent doses were lowered to control side effects. PSA and metastatic activity were tracked using Ga-68-PSMA-617 PET scans.  They found that:

1-    Sixteen (16) men responded to treatment

2-    In fourteen (14) men, PSA declined by over 90%

3-    In seven (7) men, PSA became undetectable after two (2) or three (3) treatments

4-    Fifteen (15) men had greater than 50% regression of their metastases

5-    Eleven (11) men had a complete resolution of their metastases

6-    Xerostomia (dry mouth) occurred in all of the subjects, but it was not severe (all Grade 1 or 2)

7-    Grade 3 anemia occurred in one (1) man who had extensive bone marrow metastases

8-    Grade 4 renal toxicity occurred in one (1) man with pre-existing Grade 3 renal failure

9-    Men reported a significant reduction in their bone pain

This study suggests that the investigational treatment Ac-225-PSMA-617 can be beneficial in men who have not been heavily pre-treated. It also demonstrates that the side effect, xerostomia (dry mouth) can be mitigated by reducing the subsequent doses and that for most patients, side effects are not severe enough to stop treatment. 

We have no way to compare this investigational treatment to the already approved beta radiation treatment Xofigo, or to the experimental therapy Lu-177 PSMA which is already in phase 3 clinical trials in the United States.   The possible advantage of the two PSMA treatments might be that Xofigo only targets cancer in bones, while the two PSMA treatments attack prostate cancer in both bone and soft tissue.

We now await the phase 3 clinical trials for Ac-225-PSMA-617.

Xofigo, Obat Baru Kanker Prostat dari Bayer Kini Hadir di Jepang

Xofigo, Obat Baru Kanker Prostat dari Bayer Kini Hadir di Jepang. Bayer mengumumkan (29/3) bahwa Kementerian Kesehatan, Tenaga Kerja dan Kesejahteraan ( Ministry of Health, Labour and Welfare/MHLW) Jepang telah memberikan izin edar untuk Xofigo® (radium-223 diklorida, radium-223) untuk pengobatan pasien dengan castration-resistant prostate cancer dan metastasis tulang (bone metastases).

Produk…

Cabazitaxel funciona mesmo em AR-V7-positivos

Há poucos meses foi descoberta a importância de uma variante de um receptor de andrógenos chamada (AR-V7). A presença desse receptor em células cancerosas (CTCs) circulando no paciente desestimula o uso de abiraterona e da enzalutamida, medicamentos recentes aos que recorremos nos casos de canceres muito avançados. Esses pacientes ficavam quase sem opções. Não obstante, um estudo recente mostrou…