2021 ASCO-GU｜TITAN final survival data update!

*Only for medical professionals to read and refer to the latest results of the TITAN study at the 2021 ASCO-GU conference, bringing greater survival hope for mHSPC patients.

At the American Society of Clinical Oncology Symposium on Genitourinary Tumors (ASCO-GU 2021) that just ended this month, Professor Kim Chi from the University of British Columbia Cancer Center (BC Cancer) in Canada brought a new androgen receptor inhibitor Apa Tetamine combined with androgen deprivation therapy (ADT) is used in the final survival analysis of the TITAN study of metastatic hormone-sensitive prostate cancer (mHSPC).

This update is the second time that the TITAN study at the ASCO Conference in 2019 disclosed the benefit trend of imaging progression-free survival (rPFS) and median overall survival (OS).
The data of apatamide on mHSPC indications is the second time Update; Apatamide is also the first new androgen receptor inhibitor to publish final OS benefit data in the mHSPC indication.

The TITAN study marks the entry of a new era of antiandrogenic therapy for mHSPC.
The TITAN study is an international multi-center, double-blind, placebo-controlled phase III clinical study exploring the therapeutic effects of apatamide on mHSPC patients.

The study enrolled 1052 mHSPC patients (including 94 Chinese patients) between December 2015 and July 2017.
The patients were randomly assigned to the experimental group (apatamide 240mg Qd+ ADT) or the control group ( Placebo + ADT).

The primary endpoints were OS and rPFS.

TITAN study results confirmed that apatamide, as a new androgen receptor inhibitor, can significantly delay the disease progression of mHSPC patients, reduce the risk of death, and do not increase the burden of additional adverse events.

In 2019, apatamide has been listed as the standard treatment option for mHSPC by the National Comprehensive Cancer Network Guidelines (NCCN), and in 2020 it is strongly recommended for the treatment of mHSPC patients by the European Association of Urology (EAU) guidelines.

At this year's ASCO-GU conference, apatamide updated the patient's OS and other research endpoint data again, further demonstrating its excellent efficacy in the field of mHSPC treatment.

Figure 1 Professor Kim Chi of BC Cancer in Canada conducted this online sharing TITAN study reveals the huge benefits of early application of new antiandrogenic treatments for mHSPC patients▎apatamide significantly prolongs OS, reduces the overall risk of death by 35%, and early treatment gains In the final analysis this year, apatamide showed a huge therapeutic benefit compared to the control group.

After nearly 4 years of follow-up, we can see that the 4-year survival rate of mHSPC patients can reach about 65% when the more powerful new endocrine therapy drugs such as apatamide are used in the early stage.
Tamide significantly reduces the risk of death by 35%, which is consistent with the benefit data in the first interim analysis.

At the same time, the trends of these two survival curves are also different from the common clinical "curves that separate at the beginning and then gradually merge over time".
The gap between the OS curves of the experimental group and the control group has shown a trend of continuing to expand over time.
.

      Figure 2 In the final analysis of TITAN, the OS benefit of apatamide relative to the control group was based on ethical considerations.
The TITAN study was designed to allow patients in the control group to choose whether to switch after the first interim unblinding.
A new type of endocrine therapy, which allows mHSPC patients in the control group who are still using ADT to be treated with apatamide.
Therefore, 40% of the control group patients have actually received apatamide treatment in the mHSPC stage. After using the IPSW (inverse probability sensory weighting method, inverse probability weighting) method to eliminate the influence of cross-entry on the placebo group curve, we can see that: the first-line treatment of mHSPC for patients who choose ADT, the real 4-year survival rate is only The median OS was 37.
9%, and the median OS was only 39.
8 months.
After excluding cross-entry, the 4-year survival rate difference between apatamide and the control group could reach 27.
3%.

At this time, the HR value of the OS benefit of the experimental group and the control group was 0.
52, indicating that apatamide can actually reduce the patient's risk of death by up to 48%.

Figure 3 After excluding the effect of cross-entry (green), the OS benefit of apatamide (yellow) relative to the control group (white) ▎subgroup analysis further reveals that apatamide can bring benefits to all types of mHSPC patients Benefits In order to maximize the therapeutic benefits of apatamide, the TITAN study included patients with common clinical "All Comer" mHSPC, including but not limited to patients who had relapsed and metastasized after the treatment of localized prostate cancer, and those who received it in the past.
Patients who have received systemic/local treatments (such as ADT treatment, radiotherapy, radical surgery, docetaxel chemotherapy for ≤6 months), people who meet the entry criteria of the CHAARTED study (high tumor burden/low tumor burden patients) or LATITUDE Study the enrollment criteria (high-risk/low-risk mHSPC patients), etc.

The subgroup analysis of OS shows that apatamide can bring obvious or even significant therapeutic benefits to all types of mHSPC patients.

It is worth noting that, regardless of the tumor burden of mHSPC patients, apatamide can bring significant OS benefits.

Apatamide can significantly reduce the 30% risk of death in patients with high tumor burden and 48% in patients with low tumor burden.
For newly diagnosed patients with only bone metastases, apatamide can significantly reduce the risk of death by 50%.
For patients who are newly diagnosed with localized prostate cancer (M0), apatamide can even reduce the risk of death by 61%. Figure 4 Subgroup analysis shows that apatamide can bring OS benefits to different types of mHSPC patients.
The first-line use of apatamide can bring long-term follow-up treatment benefits.
The 4-year PFS2 progression-free rate exceeded 60% in this time.
In the final analysis, the experimental group also showed significant differences in the time to second disease progression (PFS2) and castration resistance compared with the control group.

The PFS2 study endpoint explains the common clinical, early application of more powerful treatments will overdraw the follow-up treatment benefits, showing the use of apatamide treatment at the beginning, and actively follow-up treatment when the disease progresses mHSPC patients The overall benefit of its two-line treatment is still significantly better than the survival benefit of patients who only use traditional endocrine at the beginning until the subsequent disease progresses and then use strong follow-up treatment.

The PFS2 of mHSPC patients who only used traditional endocrine at the beginning was only 44 months, while the patients who used apatamide at the beginning had a PFS2 rate of more than 60% at 4 years; the first-line treatment of apatamide for mHSPC did not Follow-up treatment benefits for patients with overdrafts.

Figure 5 The benefits of apatamide relative to the PFS2 (left) and the time to CRPC (right) of the control group.
On the other hand, with the deepening of advanced prostate cancer research, we have become more and more aware that advanced prostate cancer The real focus of patient treatment is not how long a single drug can benefit from castration-resistant prostate cancer (CRPC), but to delay the patient’s disease progression to the terminal stage of CRPC as long as possible.

The median time to CRPC in mHSPC patients who used traditional endocrine therapy was 11.
4 months (all enrolled patients included both high and low tumor burden), while patients in the apatamide group had not reached CRPC after 4 years of follow-up Median time to CRPC; apatamide significantly delayed the progression risk of CRPC by 66%.

▎Apatamide can maintain the quality of life of patients with stable and reliable safety data.
In addition to the definite efficacy, apatamide treatment can also preserve the quality of life of patients to the greatest extent.

Under longer-term follow-up observation, apatamide treatment still did not increase the risk of patients' quality of life, and its safety data were consistent with the first interim analysis.

Figure 6 Apatamide can maintain the quality of life of patients.
In terms of adverse event (AE) data, apatamide did not increase the incidence of treatment-related adverse events (TEAE) in patients as a whole, whether it is the overall AE incidence or It is the incidence of grade 3 to 4 AE, and apatamide is consistent with the control group.

Among them, the common AEs of apatamide, such as skin rash, are mostly grade 1-2, indicating that apatamide has better safety and is relatively controllable in adverse event data.

Figure 7 The safety data of apatamide is basically the same as that of the control group, and the common adverse events are controllable.
In summary, we can think that the final data of this TITAN study clearly shows that apatamide, a new anti-androgen, is in mHSPC The treatment has satisfactory efficacy and safety, and there is sufficient evidence to prove that apatamide has the potential and ability to become the standard treatment for mHSPC in the future.

Expert comment 1 For a long time, clinicians' treatment concept for metastatic prostate cancer has always been to use traditional endocrine therapy first, and then actively use new endocrine therapy such as abiraterone for intervention after the disease progresses to mCRPC; although Some doctors will combine a generation of antiandrogens on top of pure ADT.
However, multiple meta-analyses have also confirmed that traditional combined androgen blockade (CAB) has no more than 5% of long-term OS compared with pure ADT.
Benefits, the first-line treatment of prostate cancer requires a more intensive treatment plan.

Since abiraterone was approved for the indication for high-risk mHSPC in 2017, many doctors have begun to try new endocrine drugs to treat mHSPC.
However, does the new endocrine therapy have significant benefits for all mHSPC patients, or is it just like chemotherapy? For patients with high tumor burden or high-risk metastatic prostate cancer, it is only beneficial, but it has become an unsolved problem because the clinical study of abiraterone did not enroll patients with low tumor burden.

The uniqueness of the TITAN study of apatamide is that its enrolled patients include as far as possible all types of mHSPC patients commonly seen in the clinic, and the final analysis results show that apatamide can significantly reduce the death of patients with simple bone metastasis by 50% Risk.
For patients with low tumor burden, the benefit of apatamide is further expanded to 48%.
Whether the patient is high-risk/low-risk/high-tumor/low-tumor, apatamide has a significant OS benefit. Therefore, apatamide combined with ADT, as a more potent new generation of combined anti-androgen regimen, can completely replace traditional endocrine therapy such as simple ADT or CAB, and become a common standard treatment option for mHSPC patients.
It can be applied earlier and can be used for patients.
Bring greater long-term benefits.

 Expert Profile Professor Zhang Xu Chief Physician, Professor, and Doctoral Supervisor Director of the Department of Urology, General Hospital of Chinese People's Liberation Army General Hospital of the People's Liberation Army General Hospital Designate Chairman of the Chinese Medical Association Urology Branch Leader of the Robotics Group of the Chinese Medical Association Urology Branch Deputy Chairman of the All Army Urology Association Beijing Vice Chairman of the Municipal Society of Urology, Vice Chairman of the Beijing Society of Urology and Leader of the Robotics Group, Winner of the National Outstanding Youth Fund, 863 Chief Expert, National Prize for Progress in Science and Technology, Winner of the National Government Special Allowance for Science and Technology Leading Talents in the Army The editor-in-chief expert comment of the Journal of Urology 2 For the drug treatment of advanced tumors, whether choosing a more effective treatment plan from the beginning will overdraw the benefits of subsequent treatment is a question that is often asked by clinicians and patients.

The TITAN study answers this question from three aspects: Time to CRPC: The real focus of the treatment of advanced prostate cancer patients is not how long a single drug can benefit after CRPC, but to delay the patient’s disease progression to CRPC as long as possible.
The terminal stage of the disease.

Apataamide can significantly delay the time for patients to enter CRPC, and postpone the risk of CRPC by 66%.
At a median follow-up of 4 years, patients in the trial group still did not reach the median CRPC time.

It can be said that apatamide has reached the treatment goal of long-term survival of mHSPC patients.

PFS2: In the final analysis, compared with the control group, apatamide significantly reduced the risk of PFS2 by 38%.
The PFS2 curve expanded and expanded over time to prove that the choice of first-line treatment of apatamide can continue to benefit subsequent treatments.
And for the follow-up treatment options for overdraft. PFS2 stratified data: patients who choose apatamide for first-line treatment and choose other new endocrine treatments after disease progression, their PFS2 benefit (HR 0.
684, p=0.
0326) and apatamide for first-line treatment and chemotherapy after disease progression The PFS2 benefit of patients (HR 0.
634, p=0.
0062) remained consistent, suggesting that the choice of first-line treatment of mHSPC may not affect the choice of subsequent treatment drugs.

Therefore, the mechanism (more potent and complete androgen receptor inhibition) and efficacy data of apatamide (significantly reduce the risk of death by 48%, significantly reduce the risk of imaging progression or death by 52%, and reduce the risk of disease by 66%) Progress to CRPC risk), safety (basically the same as the control group), and follow-up treatment options (follow-up benefits of no overdraft, and subsequent treatment options that affect follow-up treatment options) have shown satisfactory results, and have been included in EAU and NCCN.
According to the recommendations of the international authoritative guidelines in China, I believe that apatamide can benefit and benefit more mHSPC patients in the future.

 Expert profile Professor Xing Nianzeng Doctor of Medicine, Professor, Chief Physician, Doctoral Supervisor, National Cancer Center/Tumor Hospital of Chinese Academy of Medical Sciences, Member of the National Committee of the Chinese People's Political Consultative Conference, Member of the National Committee of Science, Education, Health and Sports of the Chinese People's Political Consultative Conference.
In 2017, he was named the "Hundred Million Talent Project" Grade-level candidate, national “young and middle-aged expert with outstanding contribution”, enjoys special allowance from the State Council, deputy leader of the technical expert group of urology endoscopy, National Health and Family Planning Commission, chairman of the Urology branch of the Chinese Medical Association, deputy chairman of the Urogenital Committee of the Chinese Medical Promotion Association Member of the Urology Branch of the Chinese Medical Association Deputy Chairman of the Urology Branch of the Beijing Medical Association and Leader of the Urology Minimally Invasive Expert Group Deputy Editor-in-Chief of Chinese Journal of Endoscopic Urology, Chinese Medical Journal, Chinese Journal of Urology, and Clinical Journal of Urology" Editorial Board 2021 POST ASCO GU Prostate Cancer Symposium will be held from February 11th to 14th, local time in the United States.
ASCO-GU will be held in the form of an online conference in 2021.

This conference gathered a number of cutting-edge research in the field of urinary tumors, among which the research of new endocrine drugs, accurate diagnosis, and imaging progress for prostate cancer are the hot spots of this conference.

The 2021 POST ASCO GU prostate cancer seminar will be held from 18:00-20:40 on March 5th.
The major research content in this meeting will be shared and discussed, and the latest theories and clinical practices will be shared with everyone.
, Including blockbuster studies of the limited and advanced stages of prostate cancer, and presenting you the latest research summary of precision research, imaging research and new endocrine drugs that you are concerned about. Thank you for your attention to this conference, and we invite you to take the time to attend and share this academic feast! References: [1] Chi KN, Agarwal N, Bjartell A, et al.
Apalutamide for metastatic, castration-sensitive prostate cancer.
New England Journal of Medicine 2019; 381:13-24.
[2] Chi KN, Chowdhury S, Bjartell A et al.
Final analysis results from TITAN: A phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT).
Journal of Clinical Oncology 39, 2021 (Suppl 6; abstr 11).
[3] Mohler JL, Srinivas S, Antonarakis ES, et al.
National Comprehensive Cancer Network.
(2019).
Prostate cancer (version 3.
2019).
[4] Mottet N, Cornford P, Briers E, et al.
EAU – ESTRO – ESUR – SIOG Guidelines on Prostate Cancer.
Edn.
presented at the EAU Annual Congress Amsterdam 2020.