PARP inhibitors - Can you see the hidden corners of the new anti-cancer trend?

At the beginning of December 2021, the National Medical Security Administration announced the "2021 New Medical Insurance Catalogue List".

The 4 masters focus on gynecological tumors: ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; the indications are also focused on platinum-sensitive recurrences: first-line maintenance, recurrence maintenance, and post-line treatment

Let’s talk about the conclusion first: the approval of drugs is not just a matter of one family.

At first, a PARP inhibitor

Looking back at the spring of that time: In 2005, when "platinum sensitivity" was the only type of synthetic lethal treatment, two articles were published in "Science" [1 2], confirming the relationship between BRCA1/2 mutation and PARP inhibition The "synthetic lethal" mode of the agent

I don't know how much expectations this drug named Olaparib had at the beginning; I don't know if it has the confidence to write the clinical consensus of mankind in the next 20 years

Like all teenage heroes, when Olaparib first appeared and filled the global market expectations, the first Waterloo also arrived as scheduled in 2011: Phase II clinical results published in the New England Journal of Medicine in patients with platinum-sensitive ovarian cancer Among them, olaparib failed to prolong overall survival [3]

Absurdity and truth are often two sides of the same coin

This dramatic reversal reinvigorated Olaparib and launched a phase III trial: maintenance therapy extended PFS by 13.

The wind is blowing, synthetic death

Fenghua Zhengmao's PARP inhibitor, with its high efficiency, high selectivity and high ductility, has created a new consensus for the world

BRCA: The FDA approved Olaparib in 2018-19 for the maintenance treatment of patients with BRCA-mutated breast cancer and pancreatic cancer recurrence;

HRR: The development of the prostate cancer market has also brought HRR-related genes (the mainstream has expanded to 17~25) into the main battlefield – the FDA granted niraparib breakthrough therapy in 2019 for the treatment of BRCA-positive mCRPC patients [10] ; Olaparib was approved in 2020 for the treatment of HRR-positive mCRPC patients [9]

HRD: In 2019, Niraparib was approved for the second-line treatment of patients with HRD-positive gynecological tumors; in 2020, Olaparib combined with Bevac was approved for the maintenance treatment of first-line HRD-positive advanced gynecological tumors

Homologous recombination repair loss (HRD) is a state of genomic instability, its evaluation is completely built in the algorithm, generally composed of three "scars" of the genome: loss of heterozygosity (LOH), telomere allelic imbalance (TAI) and Long Segment Shift (LST) calculations

The synthetic lethal mechanism is not like EGFR/PI3K/AKT, which continues to be excited, creates chaos, and makes targeted drugs chase the butt and spank; it is more like a pre-Qin ranger, quiet and forbearance, maintaining deterrence, and waiting for the master (PARP inhibitor) to arrive, He jumped up and drew his sword to seal his throat

The approval of HRD also confirms one thing: the era of algorithm-based biomarker diagnosis in the mainstream market has begun

Too late to explain, get in the car!

Each targeted indication must have its own "Companion Diagnostics" (CDx) method, which is co-developed and co-approved with the drug

The approval process is so strict, so it goes without saying that the standard use: Whenever Olaparib is clinically prepared to treat BRCA-mutated ovarian cancer patients, BRACAnalysis CDx should be used to detect the BRCA mutation status

Looking back at the NMPA-approved targeted drugs, each biomarker-related indication has its own CDx reagent approved (or in the process of being approved)
.
For PARP inhibitors, the currently approved CDx products around the world are concentrated in the "troika", namely: Foundation Medicine in the United States, Myriad Genetic Laboratories in the United States and Aide Bio in China
.

The information comes from the official website of FDA and the official website of China National Medical Products Administration (NMPA).

Decentralized accurate detection, China is at the forefront of the world

Compared with the two "Ocean Horses", this "dark horse" from China has actually been deeply involved in precision medicine in the tumor business for many years, and has cultivated its own fertile soil
.

In February 2019, the world's first kit-based BRCA detection kit was approved by NMPA for marketing - Aide Bio Human BRCA1/2 Gene Mutation Detection Kit (NGS)
.
This kit is only half a year after olaparib was first approved by NMPA, and it is the only companion diagnosis of olaparib in China so far
.

In addition to the BRCA-approved kit, the development of Aide's HRD detection CDx kit is also remarkable in the industry
.
Based on the self-developed ADx-GSS core algorithm, in the head-to-head study on HRD performance jointly conducted by AZ and MSD, the agreement rate between the ADx HRD kit and myChoice CDx (the current standard) is excellent, which is higher than that of FoundationOne®CDx[12]
.
More importantly, because the core algorithm holds completely independent intellectual property rights, it does not conflict with any existing HRD algorithm, which greatly promotes the global registration process of the Aide HRD kit, and has also received high attention from various multinational pharmaceutical companies
.

Table: With Myriad myChoice CDx as a comparison reference, both the positive coincidence rate and the overall coincidence rate of Aide HRD Panel are higher than those of FoundationOne®CDx[12]
.

Today, the consensus on diagnosis and treatment in China is growing rapidly, and the level of supervision goes hand in hand.
Self-built molecular testing platforms have become the most favored growth drivers for central hospitals
.
Looking at the whole country, "molecular diagnostic centers" are rising, and the companion diagnostic kits that are separated from the central laboratory will definitely become a stable demand under this wave of "normalization of in-hospital diagnosis"
.

Chinese people have always advocated a gentleman and pragmatism, and there are local "leading enterprises" in all walks of life.
Their unique "pragmatic + low-key" makes them seldom actively show their achievements, but at the same time, they can make great achievements in their own vast world
.
Aide Bio, founded in Xiamen, Fujian, belongs to such a type of enterprise:

23 NMPA-approved Class III medical device diagnostic products; China's first registration certificate for polyoma NGS panel (lung cancer + intestinal cancer 10-gene detection); China's first BRCA gene NGS panel registration certificate; Lung cancer 11-gene PCR panel as a variety of The CDx of the drug is included in the medical insurance of Japan and South Korea; the genetic testing in the Chinese tumor hospital occupies a leading market position; the registration and commercialization network of companion diagnostic products covers the world
.

In the past 40 years, China's industry has experienced so much chaos and bleakness, pain and quest
.
Time tells us two things: to be an enterprise, we must do things that are beneficial to the fundamental interests of the people; every step of "going out" must be solid
.

Work hard, it is better to accompany hand in hand

It's not easy to make medicine, everyone knows it
.
After two years of carnival, with the successive promulgation of the guidelines and policies represented by the "Guidelines for Clinical Research and Development of Antitumor Drugs Oriented by Clinical Value", it is foreseeable what kind of big waves will be in the next two years
.
The hustle and bustle of capital games is gradually ebbing, and returning to the essence of medicine can cure diseases is the last word for the survival and longevity of enterprises
.

In China's medical industry, reviewing every great drug is basically "three good students": good efficacy, good compliance, and good channels
.

Needless to say, the efficacy of the drug is good.
If it can't be Me-better, even the company may be suspended
.

Good compliance requires continuous investment in policy principles and system norms
.
As far as CDx development is concerned, whether a collaborator is reliable or not depends on its various qualities: quality system, product research and development capabilities, experience in applying for certification, communication efficiency with regulatory authorities, and more importantly, the cognition of personnel level
.
How many star drugs that have attracted worldwide attention, the diagnosis has not been selected, and the first-in-class cannot be obtained; how many potential drugs are in the works, and the cooperative diagnostic companies are gone.
.
.
Everyone has a pen in his eyes, and what happened Things will not be forgotten
.
The choice of CDx partners reflects the level and pattern of pharmaceutical companies: you can choose the right one, not the cheap one, give up illusions, and seek truth from facts
.

Having achieved the first two steps, commercial capability is the core competitiveness of medicines
.
In the context of simultaneous listing of drugs + diagnosis, medical insurance requires medication for indications, and testing requires access to the hospital system, and whoever channels drugs and CDx to pull their hips will become a big problem
.
Avoid cooperating in a flash and promote crematoriums
.

Making medicine is not easy, some people work hard, some people work hard; some people are already on the right path, doing "horse killing chickens" with their collaborators, hand in hand, and go to the new chapter
.

end

Twenty-three years ago, the first targeted drug Herceptin was launched, and people realized that the treatment of tumors could be more precise; later Gleevec and Iressa made humans believe that tumors can be cured
.
The growth of PARP inhibitors is like a spring breeze, which has warmed the consensus of biomarker diagnosis and treatment, and has also opened up the common mechanism between solid tumors
.
With the wide application of CDx, the original hidden corners have become more and more clear
.
Biomarker-driven synthetic lethality and interventional therapy have just begun, and we look forward to the next legend
.

references:

[1] Bryant HE, Schultz N, Thomas HD, et al.
Specific killing of BRCA2-deficient tumors with inhibitors of poly(ADP-ribose) polymerase[J].
Nature, 2005, 434(7035): 913-917.
DOI :10.
1038/nature03443

[2] Farmer H, McCabe N, Lord CJ, et al.
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
[J].
Nature, 2005, 434(7035): 917-921.
DOI: 10.
1038/ nature03445

[3] Ledermann J, Harter P, Gourley C, et al.
Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer[J].
New England Journal of Medicine, 2012, 366(15): 1382-1392.
DOI: 10.
1056/ NEJMoa1105535

[4] Ledermann J, Harter P, Gourley C, et al.
Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial[J].
The lancet Oncology, 2014, 15(8): 852-861.
DOI: 10.
1016/S1470-2045(14)70228-1

[5] Pujade-Lauraine E, Ledermann JA, Selle F, et al.
Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind , randomised, placebo-controlled, phase 3 trial[J].
The Lancet Oncology, 2017, 18(9): 1274-1284.
DOI: 10.
1016/S1470-2045(17)30469-2

[6] Sisay M, Edessa D.
PARP inhibitors as potential therapeutic agents for various cancers: focus on niraparib and its first global approval for maintenance therapy of gynecologic cancers[J].
Gynecologic oncology research and practice, 2017, 4(1): 18.
DOI: 10.
1186/s40661-017-0055-8

[7] Moore, Kathleen N et al.
“Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial.
” The Lancet.
Oncology vol.
20,5 (2019): 636-648.
doi: 10.
1016/S1470-2045(19)30029-4

[8] Ray-Coquard, Isabelle et al.
“Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer.
” The New England journal of medicine vol.
381,25 (2019): 2416-2428.
doi:10.
1056/NEJMoa1911361

[9] de Bono, Johann et al.
“Olaparib for Metastatic Castration-Resistant Prostate Cancer.
” The New England journal of medicine vol.
382,22 (2020): 2091-2102.
doi:10.
1056/NEJMoa1911440

[10] https:// Accessed October 2019.

[11] https:// Weichert W, Lukashchuk N, Yarunin A, et al216An evaluation of the performance of molecular assays to identify homologous recombination deficiency-positive tumors in ovarian cancerInternational Journal of Gynecologic Cancer 2021;31:A366.