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Prostate cancer is a male androgen-dependent tumor. Androgen stimulates the growth of prostate cancer cells and induces disease progression. Metastatic prostatectomy (ADT) is commonly used in patients with metastatic prostate cancer. The initial response rate can reach 80%-90%, but almost all patients will eventually progress to metastatic castration-resistant prostate cancer (mCRPC) after castration.

In the past decade, research on metastatic prostate cancer has progressed quite a lot. The first cancer treatment vaccine Provenge, the second-generation anti-androgen drugs such as the blockbuster drugs Zytiga and Xtandi, have been subverted, and the treatment pattern of metastatic prostate cancer has been subverted. .
In the future, PARP inhibitors and PSMA inhibitors will have a chance to gain a place. CDK4/6 inhibitors and Akt inhibitors are also exploring possible segments of the population, and the competitive landscape of each company is also apparent.

 

Second-generation antiandrogen drugs are still the mainstream

The second-generation antiandrogens, Zytiga and Xtandi, were approved by the FDA in 2011 and 2012, respectively. The former reduced androgen biosynthesis by inhibiting CYP17, which prevents the androgen receptor from being transported to the nucleus.

Johnson & Johnson takes over the market for metastatic prostate cancer through two second-generation antiandrogens (Zytiga and Apalupamide). 2018 is a year of Zytiga’s sorrow and joy. On the one hand, its US patent protection expires, on the other hand, ADT+Prednisone is expanded and approved for the transfer of people at higher risk, although there are not many people with high risk transfer. The trial showed that continuous medication for more than 30 months may ease the impact of generics on sales.

Johnson & Johnson Apalupamide, purchased from Aragon Pharmaceuticals in 2013, is the first FDA approved drug for non-metastatic castration-resistant prostate cancer.
Prior to this, there was no standard treatment option for CRPC patients with elevated prostate specific antigen (PSA) but no metastasis after ADT treatment. This year, Apalupamide was approved by the FDA in combination with ADT for the treatment of metastatic castration-sensitive prostate cancer through the real-time tumor review program, which will become the main force in the post-Zytiga era.

 

Xtandi brings both Anstel and Pfizer to the first echelon of the prostate cancer market. Anstel spent $765 million from Medivation (later acquired by Pfizer) to buy Xtandi (Xtandi) commercial interests outside the US, while US sales were equally divided. After receiving Xtandi, Pfizer has almost an all-star lineup of small molecule anticancer drugs, including the renal cell carcinoma drug Sunitinib (multi-target TKI), non-small cell lung cancer Crizotinib (JAK), breast cancer drug Pipersil (CDK4/6), etc. The next listing may be the acquisition of Medivation’s prostate cancer drug talazoparib (PARP). If successful transfer of sex hormone-sensitive prostate cancer (mHSPC), Xtandi will be the first full-line treatment for advanced prostate cancer. European and American patents will expire in 2027 and 2028, and will be two companies. The important support for the next five years in the field of prostate cancer.

Bayer has finally entered the main treatment market six years after the prostate cancer bone metastasis drug Xofigo (Ra-223). The main advantage of darolutamide over the previously marketed second-generation antiandrogen drugs is that it lowers the blood-brain barrier and reduces CNS-related adverse reactions, while darolutamide is not a CYP inhibitor, and drug-drug interactions are reduced.

PARP inhibitors are coming out

30% of mCRPC patients have genetic mutations (including BRCA1/2) that directly or indirectly affect DNA damage homologous repair (HRR), and thus have a worse prognosis. PARP inhibitors can block the DNA repair of cancer cells, and are more suitable for tumors carrying mutations that affect HRR, and thus become the development direction of mCRPC.

From the current clinical data, the results of ORR and PSA reduction were similar in the mCRPC population in which Niraparib and Rucaparib were treated with paclitaxel chemotherapy and second-generation antiandrogen therapy. Olaparib’s R&D is the fastest progress, and the PROfound study is the first phase III trial to include a broad range of HRR-deficient mutation genotypes, showing significant survival benefits over re-use of second-generation antiandrogens, especially BRCA1. /2 + ATM mutation queue.

 

Regardless of whether Olapali is first marketed to this mutant population through the PROfound clinical data application, genetic screening for prostate cancer treatment is currently uncommon, and PARP inhibitors are used in combination to all populations that do not require genetic screening. Two Phase III trials for all populations are underway, one of which is codenamed PROPEL, which evaluates Olapali +Zytiga vs Zytiga, another codenamed TALAPRO-2, and Talazoparib+ Xtandi vs Xtandi. The answer is the fastest to wait until 2020.

PARP inhibitors are also being tried in combination with PD-1 inhibitors. From a mechanical point of view, tumor mutation load is associated with DDR defects. In particular, hypermutated tumors often carry mutations including BRCA1/2. PARP inhibition-mediated DNA damage also increases T cell infiltration into tumors by activating cGAS-STING. Cells, and therefore PARP inhibitors may be synergistic with immunotherapy, and the following drug combinations have been clinically tested in prostate cancer, including Olapali + Devaluzumab, Olapali + Pabolizumab, Rucaparib + Nivolumab, talazoparib + Avelumab.

AstraZeneca was originally a veteran of the prostate cancer field. In the 1990s, two first-generation androgen receptor inhibitors, Zoladex and Casodex, were launched. Olapali is expected to be the first new drug approved by AstraZeneca for more than 10 years in the field of prostate cancer. Rucaparib is the only drug listed by Clovis. Compared to the wealthy AZ, it is trying to expand Olaparib to a larger population of HRR-deficient mutations. Clovis only wants to extend Rucaparib to prostate cancer indications as soon as possible.

 

PSMA targeted therapy close layout

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is expressed in more than 80% of primary and metastatic prostate cancers and has a proliferative effect. Its overexpression can also remove prostate cells. Androgen dependence.

Although Novartis has no products in the field of prostate cancer, it hopes to take the lead in targeted radiotherapy. In 2017 and 2018, Advanced Accelerator Applications and Endocyte were acquired to obtain targeted radiotherapy products. Among them, Lutetium-177 PSMA 617 is in stage III. In the published phase II results, 64% (32/50) of patients with mCRPC including chemotherapy and androgen inhibitors have a PSA level of ≥ 50%. Among the 27 patients with lesions, the ORR was 56%. Drug-related common grade 1-2 adverse reactions were dry mouth, nausea, fatigue, drug-related thrombocytopenia, and anemia were uncommon.

At the same time, Usman Azam, former head of Novartis Cell Therapy, became the CEO of Tumnity, which develops PSMA CAR-T cell therapy that blocks TGF-β. In addition to entering the current second-generation anti-androgen drug market in the main market of mCRPC, Bayer also deployed PSMA targeted radiation and developed a double antibody in cooperation with Amgen.

 

Can a breakthrough be made in CDK4/6 or Akt inhibitors?

Estrogen receptor-positive (ER+) metastatic breast cancer usually exhibits excessive CDK4/6 activity, CDK4/6 binds to cyclin D, phosphorylates retinoblastoma gene (Rb) and then releases The transcription factor E2F promotes transcription of cell cycle-related genes and promotes tumor cell growth. In 25% of mCRPCs, the proportion of Rb1 phosphorylation inactivation is increased, so CDK4/6 inhibitors are effective in this population, but the results from Pipersil+ADT vs. ADT for Rb-positive newly diagnosed mHSPC are Disappointing, there was no difference in the proportion of patients who achieved PSA <4 ng/mL on the 28th week, and 90% of patients still had Rb expression, and PFS data had not been published.

Phosphorylation of Rb is often present in mCRPC, perhaps one of the reasons for the low sensitivity of CDK4/6 inhibitors in the mHSPC population. It is a challenge to explore a population of patients with adequate cell cycle abnormalities. Currently, some CDK4/6 inhibitors are Clinical trials in the mCRPC population are ongoing, including Zytiga± abemaciclib, Xtandi± ribociclib in the Rb expression population, and so on.

AKT is at the core of PI3K/Akt/mTOR, which is closely related to the occurrence, growth and metastasis of tumor cells, and the loss of PTEN in 60% of mCRPC leads to activation of PI3K/AKT pathway, which can be independent of The androgen receptor pathway promotes the growth of prostate cancer cells, so Akt inhibitors may be effective in mCRPC patients.

Roche is not a player for prostate cancer. There have been no significant advances in the development of Akt inhibitors for many years, but now based on the positive phase II results of ipatassertib+Zytiga for mCRPC, the first phase of the IPATunity130 trial was initiated. In the phase II trial, ipatastertib-400mg+Zytiga vs. Zytiga had no survival advantage (rPFS=8.2 vs 6.4 months, OS=18.9 vs 15.6 months, but in the PTEN-deficient population, the ipatasterib-400 mg group showed better efficacy (rPFS = 11.5 vs 4.6 months)

At present, the drug treatment of metastatic prostate cancer is mainly based on the androgen receptor signaling pathway. The exploration of other targets is an opportunity and a challenge.

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