Changes in the drug market for advanced prostate cancer: AR and PARP inhibitor market expands, PSMA potential increases

Prostate cancer is a male androgen-dependent tumor.
Patients with metastatic prostate cancer are commonly treated with medical castration (ADT).
The initial response rate can reach 80-90%, but almost all patients eventually progress to metastasis after castration.
Castration-resistant prostate cancer (mCRPC), the 5-year survival rate of such patients is only 30%
.

Figure 1 Changes in the prostate cancer drug treatment market

From the perspective of the prostate cancer drug market predicted by Nature, the overall prostate cancer drug market volume will increase by nearly two times and will reach 30 billion US dollars in 2029.

Among them, the use of traditional castration therapy ADT will be reduced, with the blockbuster drug Zytiga (Abiraterone acetate) and Xtandi (Enzalutamide)-based androgen receptor (AR) antagonists have overturned the treatment pattern of metastatic prostate cancer, the market share will continue to increase, PARP inhibitors and PSMA radiation Ligand therapy has a chance to gain a place, and kinase inhibitors, including Akt inhibitors, will also have an effect on subdivided groups

AR antagonists lead the market expansion

Johnson & Johnson’s Zytiga and Astellas/Pfizer’s Xtandi were approved by the FDA in 2011 and 2012 respectively.

They are both AR antagonists, but the former reduces androgen biosynthesis by inhibiting CYP17, while the latter prevents androgen receptors.

Johnson & Johnson occupied the dominant position in metastatic prostate cancer by listing two AR antagonist drugs
.

One is abiraterone, and the other is apalutamide purchased from Aragon Pharmaceuticals in 2013.

Table 1 Four second-generation anti-androgen drugs marketed by the FDA

Enzalutamide will now be the first and only oral treatment approved by the FDA for three different types of advanced prostate cancer-non-metastatic and metastatic castration-resistant prostate cancer (CRPC) and mCSPC
.

Bring Astellas and Pfizer into the first echelon of prostate cancer treatment

In the same year, Astellas spent $765 million to buy Xtandi (enzalutamide) from Medivation (later acquired by Pfizer) the commercial interests of Xtandi (enzalutamide) other than the United States, and the United States' sales were equally divided
.

Astellas has a market foundation in genitourinary.
In 2004 and 2012, the first generation of antiandrogen drugs, Eligard (leuprolide acetate) and Gonax (degarelix), were launched in Europe and Japan respectively in 2004 and 2012.
, Has also marketed several products also for genitourinary system drugs

Bayer finally entered the main treatment market six years after launching Xofigo (Radium-223) for prostate cancer bone metastasis
.

The main advantage of dalolutamide over the second-generation anti-androgen drugs on the market is to reduce possible adverse reactions, and it can reduce CNS-related adverse reactions through the low blood-brain barrier

PARP inhibitors join the competition for prostate cancer

At present, PARP inhibitors are not as competitive as ovarian cancer in the prostate cancer market
.

In 2020, two PARP inhibitors were first approved by the FDA for mCRPC after AR antagonist treatment, olaparib and lucapani, the former being used to treat patients with homologous recombination repair (HRR) genetic changes Patients, accounting for about 20-30% of the mCRPC population, the latter being used for patients who progressed after chemotherapy with taxanes and carrying DDR gene defects (BRCA1/2), accounting for about 12% of the mCRPC population

Olapali is the first new drug approved by AstraZeneca in the field of prostate cancer in the past 10 years.
Two first-generation androgen receptor inhibitors, Zoladex (goserelin) and Zoladex (goserelin), were launched in the 1990s.
Casodex (bicalutamide)
.

Lynparza (Olapali), a PARP inhibitor developed in cooperation with Merck, is the PARP inhibitor with the most approved indications so far.

Lukapanib is the second PARP inhibitor approved in the United States and the first PARP inhibitor approved for the treatment of prostate cancer.
The approved indications include ovarian cancer and prostate cancer
.
The current market performance is average, and annual sales have not exceeded 200 million US dollars
.

Figure 2 Sales of three major PARP inhibitors

Table 2 Phase II/III trials of PARP inhibitors for mCRPC

In view of the proven efficacy of PARP inhibitors on the back-line, the associated use of PARP inhibitors is also being explored
.
Including PARP inhibitors + AR antagonists may have a synergistic effect.
Whether the first-line/post-line treatment of mCRPC with the combination of PARPi + AR inhibitors can further improve survival, trials such as niraparib or olaparib + abiraterone are ongoing
.
In addition, both talazopanib and niraparib are also undergoing trials in combination with AR antagonists in mHSPC populations
.

After the FDA approved the PD-1 inhibitor K drug (Pembrolizumab) for solid tumors with MMR missing, the NCCN guidelines recommend that mismatch repair deficiency (dMMR) be screened by detecting mismatch repair and microsatellite instability.
) And microsatellite instability-high (MSI-H) prostate cancer patients are then treated with K drugs.
This type of population is very small in mCRPC, accounting for only 2-5%, so PARP inhibitors are also also Trying to combine with PD-1 inhibitors may broaden the indications
.
From a mechanism point of view, tumor mutation burden is related to DDR deficiency, especially hypermutated tumors often carry mutations including BRCA1/2.
DNA damage mediated by PARP inhibition can also increase the infiltration of T cells into tumor cells by activating cGAS-STING
.
Olaparib+durvalumab, olaparib+Pembrolizumab, lukapanib+nivolumab, talazopanib+avelumab, etc.
are all undergoing mCRPC trials
.

PSMA targeted therapy and other kinase inhibitors

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein.
It is expressed in more than 80% of primary and metastatic prostate cancers.
It has a proliferation-promoting effect.
Its overexpression can also make prostate cells get rid of Dependence on androgen
.

Although Novartis has no products in the field of prostate cancer, it hopes to seize the opportunity in radioligand therapy
.
Through the acquisition of Advanced Accelerator Applications and Endocyte in 2017 and 2018 to obtain targeted radiotherapy products, ASCO announced this year's Lutetium-177 PSMA 617 Phase III trial results.
Compared with the best standard treatment alone, mCRPC patients received 177Lu-PSMA- 617 combined with the best standard treatment reduces the risk of death by 38% (median OS benefit 4 months), and its imaging progression or death risk is reduced by 60% (median rPFS benefit 5 months).
U.
S.
and EU regulatory agencies submit new drug registration applications
.

Figure 3 The results of the Phase III trial named VISION

In addition to entering the second-generation antiandrogen drug market in the current mCRPC main market, Bayer has also deployed PSMA-targeted radiation and cooperated with Amgen to develop double antibodies
.
In June 2021, Bayer announced that it would acquire two companies focused on the development of radioligand therapy, namely Noria Therapeutics and PSMA Therapeutics
.
Through the acquisition of Bayer, it will obtain the right to develop differentiated alpha particle therapy based on the isotope actinium-225 (actinium-225)
.

Table 3 PSMA targeted therapy in main clinical stages

Other kinase inhibitors that have developed relatively quickly in clinical development are Akt inhibitors and Cabozantinib, and these two types of drugs are also facing different challenges
.

Akt is at the core of the PI3K/Akt/mTOR signaling pathway in the cell survival pathway.
It is closely related to the occurrence, growth and metastasis of tumor cells.
In 40-60% of mCRPCs, it has been found that PTEN loss will lead to the activation of the PI3K/AKT pathway.
It can promote the growth of prostate cancer cells without relying on the androgen receptor pathway, so Akt inhibitors may be effective for mCRPC patients
.
The current advanced clinical stage is mainly Roche's ipatasertib and AZ's capivasertib (AstraZeneca)
.

Roche is not a player of prostate cancer.
Akt inhibitors have not been marketed for many years.
However, ESMO announced last year that ipatasertib + abiraterone + prednisone versus abiraterone + prednisone were used for mCRPC patients, and 1101 patients were included.
The results showed that although rPFS was significantly improved in all populations, the median rPFS of the ipatasertib group and placebo group were 18.
5 months and 16.
5 months (HR=0.
77, P=0.
0335) in PTEN-deficient patients
.
Capivasertib is currently being used in combination with abiraterone for the mHSPC population trial of PTEN deletion (CAPItello-281)
.
At present, the application of Akt inhibitors in mCRPC will be limited by PTEN detection
.

The VEGFR, MET, and AXL multi-target inhibitor Cabozantinib is currently undergoing a phase III trial (CONTACT-01) in combination with Roche's PD-L1 inhibitor atezolizumab to compare AR antagonists in mCRPC patients treated with AR antagonists
.
At present, data from the prostate cancer cohort in the solid tumor trial (Cosmic-021) of the two combined use has been published.
The data of 36 patients were published at the ASCO meeting last year.
The ORR reached 33%, compared with the 101 cases announced by the company this year.
For patient data, the independent review committee assessed ORR of only 18%, which is not much different from the results of PD-1 single drug.
Whether this valid data can support accelerated review remains to be verified
.