Experts interpret new advances in ASCO prostate cancer immunotherapy in 2021

Sipuleucel-T is the first to be approved for the treatment of asymptomatic or mildly symptomatically metastatic castration-resistant prostate cancer (mCRPC), opening a new era of cancer immunotherapy
.

In recent years, Immune Checkpoint Inhibitors (ICI) have begun to explore the treatment of advanced prostate cancer.
Past PD-1/L1 monoclonal antibody treatments for advanced prostate cancer have been explored, whether it is KEYNOTE-028 or KEYNOTE-199.
It does not show a significant effect, so combining and moving forward has become the direction of immunotherapy for advanced prostate cancer
.

This year’s ASCO meeting reported on the preliminary results of many studies.
We have seen that the combination of immunization combined with anti-androgen therapy, chemotherapy, PARP inhibitors, radionuclide therapy and other methods has shown a trend of multi-point flowering
.

Yimaitong invited Professor Sheng Xinan and Li Siming from Peking University Cancer Hospital to review the progress of advanced prostate cancer treatment in the 2021 ASCO conference
.

1.
Immunization combined with anti-androgen therapy The KEYNOTE-199 study is a multi-cohort phase 2 clinical study, in which cohort 4 (measurable lesions) and cohort 5 (bone metastases, not measurable) included the treatment progress of enzalutamide For the later mCRPC patients, patients who have failed previous Abiraterone and Sipuleucel-T treatments were allowed to be included in the group
.

All patients received pembrolizumab 200 mg Q3w combined with enzalutamide 160 mg Qd until the completion of 35 cycles of treatment, or showed disease progression or intolerable toxicity
.

The primary research endpoint is the objective response rate (ORR) of cohort 4, and the secondary research endpoints are the duration of response (DOR) of cohort 4, the disease control rate (DCR) of cohort 4 and cohort 5, and the imaging progression-free survival time (rPFS) ), PSA remission rate, overall survival time (OS) and safety
.

The study reported preliminary results at the ASCO-GU conference last year.
The results showed that the ORR of cohort 4 was 12%, the DOR was 6.
3 months, the DCR of cohorts 4 and 5 were 51%, and the PSA remission rate was 16% and 16% respectively.
9%, the median rPFS was 4.
2 months and 4.
4 months, respectively, the median OS of cohort 4 did not reach, and the median OS of cohort 5 was 18.
8 months
.

The 2021 ASCO annual meeting updated the results of KEYNOTE-199 study cohort 4 and cohort 5, basically maintaining the previously reported efficacy data: the ORR of cohort 4 was maintained at 12%, and the PSA remission rates of cohorts 4 and 5 were 16.
3% and 9 respectively.
%, the median rPFS is still 4.
2 months and 4.
4 months
.

The median OS data was mainly updated this year.
The median OS of cohorts 4 and 5 were 17.
6 months and 20.
8 months, respectively
.

The OS data of the two cohorts of KEYNOTE-199 was significantly improved compared with the previous data of pembrolizumab single-agent treatment
.

In addition, the relevant efficacy data is roughly the same as other research data on immunization combined with anti-androgen therapy
.

In the KEYNOTE-365 study (Phase 1b/2 study), cohort C used pembrolizumab combined with enzalutamide in the treatment of mCRPC patients with previous abiraterone and chemotherapy failure, and achieved a PSA remission rate of 22% and a PSA remission rate of 12%.
ORR, median rPFS and OS were 6.
1 months and 20.
4 months, respectively
.

Studies have suggested that mCRPC cells will overexpress androgen receptor (AR) after anti-androgen therapy to adapt to the environment of low testosterone, thereby inducing resistance to anti-androgen therapy
.

Bipolar androgen therapy (BAT), which allows the rapid circulation of testosterone between high and low levels by injection of high levels of testosterone and the use of LHRH agonists, can disrupt this adaptive regulation of CRPC cells, which may reverse drug resistance1
.

The 2021 ASCO annual meeting reported the results of the COMBAT-CRPC study using BAT therapy
.

The study is a multi-center, single-arm Phase 2 clinical study.
The subjects are mCRPC patients who have failed at least first-line neoadjuvant endocrine therapy (NHT) and ≤1-line chemotherapy
.

The patient received BAT therapy (i.
e.
cypionate [testosterone] 400 mg intramuscular injection of Q4w and continued LHRH antagonist treatment) for 12 weeks, and then entered BAT combined with nivolumab 480 mg Q4w for 12 weeks, until disease progression or intolerable toxicity
.

The primary endpoint of the study is PSA50 remission rate, and secondary endpoints include safety, ORR, and rPFS
.

The study enrolled 45 patients with a median age of 69 years.
Among them, 44.
4% of the patients had received taxane chemotherapy in the past, and 33.
3% of the patients had received at least 2 NHT treatments and received taxane chemotherapy
.

The overall PSA50 remission rate was 40%, and the ORR was 23.
8%.
One patient obtained CR, which lasted more than 13 months
.

The median rPFS was 5.
7 months (95%CI: 4.
9-6.
9 months), and 11.
1% of patients had no progression on imaging for more than 11 months
.

The main treatment-related adverse reactions (TRAE) and immune-related adverse reactions (irAE) are all AEs below grade 2
.

Since the study was enrolled in patients who had been severely treated in the past, this BAT combined immunotherapy method seems to be very effective at present and has a good application prospect.
Survival data needs further follow-up
.

2.
Immunity combined with chemotherapy Chemotherapy increases tumor neoantigens by killing tumor cells, interferes with the immunosuppressive pathway, and increases the immune killing effect of effector T cells2, providing a theoretical basis for ICI combined chemotherapy
.

The ASCO-GU meeting earlier this year reported the results of two ICI combined chemotherapy studies (CheckMate 9KD study cohort B and KEYNOTE-365 study cohort B).
All mCRPC patients who had not been chemotherapy and had failed NHT treatment were included.
Use nivolumab and pembrolizumab in combination with docetaxel and prednisone
.

The overall ORR was 23-40%, the PSA remission rate was 34-47%, the median rPFS was 8.
5-9.
0 months, and the median OS was 18.
2-20.
2 months
.

The results of the two studies are evenly matched, and also show the efficacy of immunotherapy combined with chemotherapy in mCRPC
.

Related Phase 3 studies (CheckMate 7DX and KEYNOTE-921 studies) are currently underway
.

This year’s ASCO annual meeting recently reported the results of a phase 1b/2 study (ARC-6 study) in which a new targeted drug Etrumadenant was combined on the basis of immunization combined with chemotherapy
.

Etrumadenant is an oral, small molecule, selective diadenosine receptor antagonist.
Preliminary studies have shown that the inhibition of adenosine axis combined with standard therapy or immunotherapy has a certain synergistic effect in mCRPC, thereby inducing continuous anti-tumor immunity
.

The ARC-6 study is a two-phase 1b/2 phase study.
This year, the results of the first phase (phase 1b study) of the study are reported
.

In the first stage, mCRPC patients who have not received taxane chemotherapy and have failed previous ADT treatments will receive EZD treatment, specifically: Etrumadenant 150mg Qd oral + Zimberelimab (a PD-1 monoclonal antibody) 360mg Q3w + doxie He is against 75mg/m2 Q3w
.

The main study endpoints are safety, PSA50 remission rate, ORR and rPFS
.

A total of 17 patients were enrolled in the Phase 1 study
.

Among them, 17 cases can be evaluated for PSA, and the PSA50 remission rate is 35% (6/17); 11 cases can be evaluated for imaging, and the ORR is 27% (3/11, including 1 case of complete remission [CR])
.

The combined ORR (CR+PR+PSA remission) was 41%
.

The most common AEs after treatment were hair loss (53%), decreased lymphocyte count (53%), and fatigue (47%)
.

From the preliminary results of this immune + chemotherapy + targeted therapy study, both PSA remission rate and ORR are not low, but compared with previous immune + chemotherapy studies (CheckMate 9KD, KEYNOTE-365) data, it seems that the target The addition of drugs did not significantly improve the efficacy
.

On the one hand, the number of enrolled cases in this phase 1b study is still small, and on the other hand, the survival data is not yet mature; the subsequent phase 2 study will randomize EZD treatment with docetaxel chemotherapy, and the results are worthy of attention
.

3.
Immunization combined with PARP inhibitor therapy studies have shown that PARP inhibitors can increase TMB levels, up-regulate PD-L1 expression, and increase immune cell infiltration to TME by increasing unrepaired DNA damage (especially in patients with DDR mutations).
Improve the efficacy of ICI3
.

The final results of cohort A1 in the CheckMate 9KD study were reported at this year's ASCO annual meeting
.

This cohort will enroll mCRPC patients who have failed previous 1-2-line taxane chemotherapy and ≤2-line NHT treatment failed, and will be treated with nivolumab 480mg Q4w combined with PARP inhibitor rucaparib 600mg Bid
.

The primary endpoint was ORR and PSA50 response rate, and secondary end points were rPFS OS, DOR, security and so on
.

The study also included biomarker analysis, including homologous recombination repair defect (HRD) status
.

A total of 88 patients were enrolled in the study, with a median age of 66 years.
Among them, 34.
1% of patients had visceral metastases, 29.
5% of patients had received 2-line chemotherapy, and 30.
7% of patients had received two NHT treatments, suggesting enrollment The patient’s previous multi-line treatment status
.

The results showed that the overall ORR was 10.
3%, the PSA50 remission rate was 11.
9%, and the median rPFS and median OS were 4.
9 (3.
7-5.
7) months and 13.
9 (10.
4-15.
8) months, respectively
.

If you distinguish the HRD status and analyze it, you can see from the waterfall chart below that almost all patients with reduced target lesions and PSA decline after treatment are HRD+ patients, especially BRCA2 gene mutations (orange bars)
.

The ORR of HRD+ and HRD- patients was 17.
2% vs.
3.
4%, and the PSA50 remission rate was 18.
2% vs.
5.
0%
.

BRCA2 mutation patients benefit more significantly, with confirmed ORR as high as 37.
5% and PSA50 remission rate as high as 45.
5%
.

In addition, the median rPFS of HRD+ and HRD- patients was 5.
8 months vs.
3.
7 months, and the median OS was 15.
4 months vs.
9.
4 months
.

In comparison, HRD+ patients can benefit more from immunotherapy combined with PARP inhibitors, while BRCA mutation patients are worthy of further study by expanding the sample size
.

It is worth noting that cohort A of the KEYNOTE-365 study also used ICI (pembrolizumab) in combination with olapa for the treatment of mCRPC.
The results showed that the median rPFS was 4.
3 months, the median OS was 14 months, and the PSA The remission rate was only 9%, and the ORR was only 8%
.

But the study did not distinguish gene mutation status when it was enrolled
.

It can be seen that this combination of immune therapy with PARP inhibitors is more important for the selection of patients at the molecular level (such as DDR mutations, HRD status, BRCA mutations)
.

IV.
Immunization combined with radionuclide therapy In the two years of ASCO or ASCO-GU conferences, there have been research reports on immune combined with radium 223 radionuclide therapy
.

It is believed that Radium 223 may increase the immunogenicity of mCRPC patients with bone metastases and thereby increase the anti-tumor activity of ICI
.

However, last year's ASCO annual meeting and this year's ASCO-GU meeting successively reported the results of two PD-1/L1 monoclonal antibodies combined with radium 223 in the treatment of mCRPC, and did not see the improvement in efficacy brought about by the introduction of immunotherapy
.

177Lu-PSMA-617 (Lutetium 177) is a newer radionuclide therapy that targets prostate-specific membrane antigen (PSMA), which has significantly reduced PSA ability and OS benefit in mCRPC
.

This year's ASCO reported the results of the group A study of the phase 1b study of 177Lu-PSMA-617 combined with pembrolizumab in the treatment of mCRPC
.

The subjects of the study were mCRPC patients who had not received chemotherapy and had at least one NHT progression.
Patients were required to have at least 3 metabolic uptake metastases in 68Ga-PSMA-11 imaging
.

All patients were treated with a single dose of lutetium 177 (7.
4GBq) combined with pembrolizumab 200mg Q21d until disease progression or intolerable toxicity
.

The study also carried out different scheme designs for the timing of the administration of lutetium 177 in group A: Scheme 1, give lutetium 177 treatment first, and then pembrolizumab; Scheme 2, on the day of pembrolizumab C1D1 administration Lutetium 177 treatment was performed at the same time; Plan 3, Lutetium 177 treatment was performed at the same time on the day of pembrolizumab C2D1 administration; 6 patients were planned to be included in each plan
.

A total of 18 patients are currently enrolled in group A, with a median age of 64 years, including 39% of visceral metastases, 89% of lymph node metastases, 78% of bone metastases, and 17% of soft tissue metastases
.

The results showed that the overall ORR was 44% (8/18, of which 5 cases achieved sustained remission> 8 months), and the PSA50 remission rate was 28% (5/18)
.

This report did not disclose the effect of different administration timings of lutetium 177 on the efficacy, but the current "Lutetium 177 treatment first, followed by pembrolizumab treatment" plan 1 has begun to be further evaluated in the B group study
.

Moreover, the survival data did not see the report this time, and we need to wait for follow-up reports to disclose
.

However, based on such visceral metastases, the ORR of 44% is still considerable, and the related Phase 2 study is worth looking forward to
.

V.
Summary Through the progress of this year's ASCO annual meeting, we can see that immune checkpoint inhibitors have been combined with various treatments for prostate cancer in an all-round way
.

More choices are the most commonly used treatments for mCRPC: anti-androgen therapy and chemotherapy
.

From the data point of view, the ORR (approximately 23-40%) and PSA50 remission rate (approximately 35-45%) of immunization combined with chemotherapy are higher, PFS is longer (approximately 8.
5-9.
0 months), and immunotherapy combined with anti-androgen therapy The ORR is about 12%, the PSA remission rate is about 10-20%, and the PFS is about 4.
0-6.
0 months
.

However, the median OS of the two therapies is similar at present, basically between 18-20 months
.

Among other combinations, what needs attention is the combination with PARP inhibitors, especially those with BRCA gene mutations whose ORR and PSA remission rate after treatment are significantly improved.
Therefore, more emphasis may be placed on the priority of patients based on the distinction of HRD status.
In order to achieve the maximum benefit
.

Another combination method that needs attention is the combination of immunity and bipolar androgen therapy (BAT).
The ORR and PSA remission rates achieved in previously severely treated patients are high, but follow-up survival data must be paid attention to
.

Of course, what we must face is that most of the above immunotherapy studies for prostate cancer are phase 1/2 studies, so we still have to be cautiously optimistic about the results of the research
.

However, this mode of immune combination therapy and the identification of predictive markers for combination therapy in the later period, and even the development of new immunotherapy drugs, may still be an important research direction for mCRPC in the next few years
.

References: 1.
Denmeade SR, Wang H, Agarwal N, et al: TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer.
J Clin Oncol 39:1371-1382, 20212.
Galluzzi L, Buque A, Kepp O, et al: Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents.
Cancer Cell 28:690-714, 20153.
Peyraud F, Italiano A: Combined PARP Inhibition and Immune Checkpoint Therapy in Solid Tumors Cancers (Basel) 12, 2020 Recommended reading 1.
Expert interpretation | ASCO renal cancer treatment progress in 2021 2.
Expert interpretation | ASCO advanced urothelial cancer treatment research progress in 2021