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Key Studies in Genitourinary Cancers: CCO Independent Conference Highlights of the 2021 ASCO Annual Meeting
  • CME

Daniel P. Petrylak, MD
Elizabeth R. Plimack, MD, MS
Released: September 7, 2021

Key Studies in Prostate Cancer

PEACE-1: Study Design

Daniel P. Petrylak, MD:
Treatments are being moved up earlier in the course of disease for hormone-sensitive prostate cancer, and the PEACE-1 study is a 4-arm trial that asked some interesting questions.21-22 PEACE-1 was a multicenter, European, randomized, open-label phase III trial that enrolled patients (N = 1173) with metastatic castration-sensitive prostate cancer who had distant metastases by ≥1 lesion on bone scan and/or CT scan and had started androgen-deprivation therapy (ADT) ≤3 months prior to enrollment.

In this trial, patients were randomized to 1 of 4 arms. Arm 1 was abiraterone plus radiation therapy plus SoC with ADT with or without docetaxel, arm 2 was abiraterone plus SoC, arm 3 was radiation therapy plus SoC, and arm 4 was SoC by itself. SoC in this trial initially included continuous ADT before an amendment in 2015 to allow docetaxel 75 mg/m2 Q3W for 6 cycles. Then, in 2017, the trial was amended again to make docetaxel a mandatory part of SoC.

The coprimary endpoints were radiographic PFS (rPFS) and OS with a 2 x 2 factorial design with hierarchical testing. The secondary endpoints were castration resistance–free survival, time to next skeletal-related event, PSA response rate, time to pain progression, quality of life, and safety.

PEACE-1: Baseline Characteristics

Daniel P. Petrylak, MD:
The median age for patients in the PEACE-1 study was 67 years, and the median time from diagnosis was 2.3 months. Of the patients randomized to receive abiraterone plus SoC (with or without radiotherapy) or SoC (with or without radiotherapy), 81% had bone metastases without visceral metastases, 11% had visceral metastases, and 8% to 9% had lymph node only metastasis. The rate of visceral metastasis was a bit lower than what we have seen in other studies, such as LATITUDE, where 15% to 19% of patients had visceral disease.23 In this trial, 57% of patients had high disease burden. For the type of SoC, approximately 60% of patients received docetaxel as a part of SoC, with 39% receiving no docetaxel.21

PEACE-1: rPFS (Coprimary Endpoint)

Daniel P. Petrylak, MD:
In this analysis, the data were assessed using 2 subsets of patients: the overall patient population and those who received ADT plus docetaxel as part of SoC therapy. In both populations, the median rPFS was improved in patients who received abiraterone vs SoC alone (with or without the addition of radiotherapy). In the overall population, the median rPFS was 4.5 years (95% CI: 3.5 to not estimable) with abiraterone compared with 2.2 years (95% CI: 2.0-2.6) without abiraterone (HR: 0.54; 95% CI: 0.46-0.64; P <.0001). In patients who received ADT plus docetaxel, the median rPFS was 4.5 years (95% CI: 3.1 to not estimable) with abiraterone vs 2.0 years (95% CI: 1.8-2.3) without abiraterone (HR: 0.5; 95% CI: 0.40-0.62; P <.0001).

PEACE-1: CRPC-Free Survival

Daniel P. Petrylak, MD:
Castration-resistant prostate cancer (CRPC)-free survival also was superior for abiraterone plus SoC (with or without radiotherapy) vs SoC (with or without radiotherapy). In the overall population, the median CRPC-free survival was 3.8 years (95% CI: 3.1-4.5) with abiraterone compared with 1.5 years (95% CI: 1.4-1.6). Similarly, the median CRPC-free survival was 3.2 years (95% CI: 3.0-4.5) with abiraterone vs 1.4 years (95% CI: 1.3-1.6) in the ADT plus docetaxel patient population. The HR was 0.40 (95% CI: 0.35-0.47; P <.0001) in the overall population and 0.38 (95% CI: 0.31-0.47; P<.0001) in the ADT plus docetaxel population.

PEACE-1: Clinical PFS

Daniel P. Petrylak, MD:
Clinical PFS had the same pattern as rPFS in the PEACE-1 trial. The HRs for the overall population and the ADT plus docetaxel population were similar to those for rPFS, with HRs of 0.54 (95% CI: 0.46-0.63; P <.0001) and 0.50 (95% CI: 0.40-0.62; P <.0001), respectively, favoring abiraterone plus SoC (with or without radiotherapy).

PEACE-1: Grade 3-5 AEs in ADT Plus Docetaxel Population

Daniel P. Petrylak, MD:
The rates of grade 3-5 neutropenia and febrile neutropenia reported within the first 6 months were higher with the addition of abiraterone (10% and 5%, respectively, in the abiraterone plus SoC arms of the trial). The rates of each were similar in the SoC-only arms at 9% and 5%. These rates were a bit higher than what has been reported with docetaxel in the metastatic setting, but it is consistent with what we have experienced in prior studies. Grade 3-5 hypertension was higher with abiraterone (12%) than SoC (8%), but again, that was not unexpected. Grade 3-5 fatigue and gastrointestinal AEs were low at 2% for the abiraterone arms and 4% for the SoC alone arms. Also, the rate of grade 5 events was <1% in both arms.

PEACE-1: Conclusions

Daniel P. Petrylak, MD:
In the PEACE-1 study, the addition of abiraterone to ADT plus docetaxel improved rPFS; this is not a surprising finding. The secondary endpoints such as CRPC-free survival and symptom-free survival also were superior with the addition of abiraterone to ADT plus docetaxel. However, the OS data are immature. There also were no meaningful additional short-term toxicities.

The investigators concluded that adding abiraterone to ADT plus docetaxel is a potential new SoC.

Unfortunately, this trial did not have an abiraterone-only arm, which would have been important for really understanding what additional efficacy is accomplished with the combination of chemotherapy and abiraterone. For our patients, I think you must discuss the addition of abiraterone based on the data from the PEACE-1 trial. However, I think it could be less relevant in today’s practice, because only approximately 20% of my patients currently receive ADT plus docetaxel, as opposed to ADT plus a next-generation androgen receptor inhibitor.

Elizabeth R. Plimack
I agree. I think these data are compelling. However, the questions I think we are asking clinically when we look at this are: Can we get away with not giving docetaxel? And how important is radiation?

I think there is a clue here, but it does not definitively answer these questions. The rPFS is almost identical in the docetaxel population compared with the ITT population. So, although that is not a great way to look at whether docetaxel is needed, I would conclude that it is not. I really prefer not to give docetaxel if we can get the same efficacy with abiraterone. That reinforces our SoC in this space, which for me is ADT plus abiraterone/prednisone or one of the other oral next-generation androgen receptor inhibitors.

Daniel P. Petrylak, MD:
Abiraterone has some associated cardiac toxicity, and this is something we need to be concerned about with these next-generation antiandrogens. Some patients also do not want to be on a pill for a long period of time and would rather just receive a round of chemotherapy and be done. So, it is important to have a discussion with the patient and consider their overall medical condition and preferences. There were not many cardiac events in this trial, but that is always a consideration for me.

I also think we need a randomized trial of up-front abiraterone vs up-front docetaxel and then various combinations thereof. I do not think it will be done, but still there is evidence that there may be some cross resistance between docetaxel and abiraterone.

VISION: Study Design

Daniel P. Petrylak, MD:
The VISION trial is a very exciting study. We have tried targeting PSMA with antibody–drug conjugates and other isotopes, with disappointing results. The VISION trial is the first time we have seen any sort of signal with PSMA.

The VISION study was a randomized, open-label phase III study.24-25 Men (N = 831) with mCRPC who had previous treatment with ≥1 anti-androgen receptor pathway inhibitor and ≤2 prior taxane regimens were enrolled in this trial. All enrolled patients had an ECOG PS of 0-2 and a life expectancy of >6 months. Patients were randomized to 177-Lu-PSMA-617 with protocol-permitted SoC that did not include chemotherapy, IO, radium-223, or investigational drugs. So, the SoC was basically second hormonal manipulations.

The primary endpoints for the VISION trial were rPFS and OS, and there were 2 analysis sets: OS in the fully randomized population and rPFS in a subset of patients after dropout reduction measures were implemented.

This trial had issues with accrual because of the randomization to SoC, which could be another antiandrogen such as abiraterone or enzalutamide. Many patients did not want that, so they would enter the trial and drop out if they were randomized to the SoC arm. A high dropout rate was initially a problem, so the investigators went back to the FDA and subsequently increased education of investigators at the study site and put enrollment caps in place. This helped to reduce the dropout rate.

VISION: Baseline Characteristics

Daniel P. Petrylak, MD:
The trial arms were well balanced. The median age was approximately 70-72 years, most patients had an ECOG PS of 0-1, and the percentage of patients with liver metastases was 11% to 14%. The arms also were well balanced with respect to race. Unfortunately, Black patients and Asian patients were underrepresented in this study.

The patients in the VISION trial were prescreened based upon their PSMA PET scan results, and 126 patients from the original set of screened patients did not meet the PSMA expression criteria. The PSMA prescreening may explain why the rate of hepatic metastases—which is approximately 25% in most studies—is a little bit lower here. PSMA is not expressed at a particularly high rate in the poorly differentiated liver metastases or some of the poorly differentiated tumors. So, that may be a distinguishing factor in this study.

In all randomized patients, approximately 40% to 50% of patients had ≥1 prior taxane treatment, and 45% to 55% of patients had ≥1 prior androgen receptor pathway inhibitor.

VISION: Survival

Daniel P. Petrylak, MD:
When you look at survival with 177-Lu-PSMA-617 plus SoC in the VISION trial, the median OS was similar in the rPFS analysis set vs all randomized patients, with an approximately 4-month difference (15.3 months vs 14.6 months, respectively). There was an increase in median OS with the addition of 177-Lu-PSMA-617 to SoC compared with the median OS for SoC only in the rPFS analysis set vs all randomized patients (10.4 months vs 11.3 months). The HR for OS in all randomized patients was 0.62 (95% CI: 0.52-0.74; 1-sided P <.001), and the HR for the rPFS analysis set was 0.63 (95% CI: 0.51-0.79), with both being in favor of 177-Lu-PSMA-617 plus SoC.

The median rPFS was approximately 8.7 months for patients receiving 177-Lu-PSMA-617 and 3.5 months for patients receiving SoC in both analysis sets.

OS and rPFS were consistent across prespecified subgroups, including lactate dehydrogenase level, liver metastases, ECOG PS, age, race, and whether SoC included androgen receptor pathway inhibitors.

VISION: Other Efficacy Outcomes

Daniel P. Petrylak, MD:
In patients with measurable disease receiving 177-Lu-PSMA-617 plus SoC, the partial response rate was 41.8%, and the complete response rate was 9.2%. By contrast, for patients receiving SoC alone, the partial response rate was 3.1%, and none of the patients achieved a complete response.

If we look at PSA responses, 177-Lu-PSMA-617 plus SoC was superior, with 46% of patients having a ≥50% decrease vs 7.1% for SoC alone. That is not surprising, because sequential antiandrogens are generally not very effective. That is one of the critiques I would have of the VISION trial.

VISION: Safety

Daniel P. Petrylak, MD:
As one would expect, there were more treatment-related AEs in the 177-Lu-PSMA-617 plus SoC arm than the SoC-only arm. The rate of any-grade treatment-emergent AEs was 85.3% vs 28.8%, respectively, and the rate of grade 3-5 events was 28.4% vs 3.9%. The most common AEs were fatigue and bone marrow suppression, including leukopenia, lymphopenia, anemia, and thrombocytopenia. There were 5 deaths due to AEs (0.9%) in the 177-Lu-PSMA-617 combination arm and no AEs leading to death in the SoC-only arm.

When we are talking about long-term AEs, it is important to note that PSMA is expressed in salivary glands, so patients can develop dry mouth. In this study, the rate of dry mouth was 39.3% in the 177-Lu-PSMA-617 combination arm, and there were no events in the SoC arm. In my experience, dry mouth is permanent once it does happen, so that is an important factor to note.

VISION: Treatment Exposure and Subsequent Therapy

Daniel P. Petrylak, MD:
Patients receiving 177-Lu-PSMA-617 stayed on treatment longer and received more cycles of therapy. The total median exposure time in the 177-Lu-PSMA-617 combination arm was 7.82 months compared with 2.07 months in the SoC-only arm. The median number of cycles started was 5 in the 177-Lu-PSMA-617 combination arm vs 2 with SoC alone.

After completing their therapy, some patients went on to receive subsequent therapy. In total, 18% of patients in the 177-Lu-PSMA-617 combination arm received a subsequent taxane therapy compared with 21.8% in SoC-only arm. A small number of patients in the 177-Lu-PSMA-617 combination arm (2.9%) and the SoC-only arm (8.2%) went on to receive other radiopharmaceuticals, with most receiving radium-223.

VISION: Conclusions

Daniel P. Petrylak, MD:
The VISION trial showed that 177-Lu-PSMA-617 plus SoC improves both OS and rPFS compared with SoC alone. This combination regimen was well tolerated, but there was a higher rate of treatment-related AEs, including grade 5 events.

These patients remained on therapy longer, which is not surprising because they are responding. The investigators suggest that this is a new treatment option for patients with mCRPC who received prior taxane therapy.

These data are exciting, but one issue is going to be whether we can we get a PSMA PET scan to every institution. Access may be limited at community-based centers because they may not have a PSMA PET scan available. However, for patients with high expression of PSMA, this is a promising treatment approach.

The questions I have are: Can we administer subsequent chemotherapy after 177-Lu-PSMA-617? And will we see more marrow suppression by giving cabazitaxel in that scenario?

177-Lu-PSMA-617 is not a curative treatment, but it is improving the end survival, so this is an impressive result from that standpoint. I would use this treatment approach earlier in the course of treatment, probably before cabazitaxel. In a randomized trial with the same approach—comparing 177-Lu-PSMA-617 to cabazitaxel26—there was a better PSA progression rate with 177-Lu-PSMA-617 therapy compared with cabazitaxel. However, that study did not give information on subsequent therapy.

I would like to know the toxicity rates associated with using chemotherapy after 177-Lu-PSMA-617. We know that we can use chemotherapy safely after radium, for example. If there is no increase in the incidence or severity of toxicities associated with chemotherapy after 177-Lu-PSMA-617 therapy, I would tend to use 177-Lu-PSMA-617 before cabazitaxel. If there is an effect with increased incidence and/or severity, I probably would use it after cabazitaxel and then watch the patients carefully. But again, I think it largely depends on the fact that we need to use PSMA PET scans to help us determine what to do.

Elizabeth R. Plimack, MD, MS:
I was compelled by the analysis you just gave of the toxicity. In this trial, the fact that 39% of patients experienced permanent dry mouth is notable. In addition, the bone marrow suppression associated with treatment seemed significant, as well. So, I like your idea of positioning it after cabazitaxel, because the risk of irreversible toxicity seems a little higher with 177-Lu-PSMA-617.

Daniel P. Petrylak, MD:
There have been discussions in the field that 177-Lu-PSMA-617 is going to possibly limit the use of radium-223. Having an agent that does not specifically target bone is going to be important. Radium-223 is not associated with PSA declines or soft tissue responses, obviously, because it is a bone-targeted agent. 177-Lu-PSMA-617 will change the treatment landscape, but we still need to determine the optimal time to use it in the treatment of patients with mCRPC.

We also are seeing trials that are being designed to use 177-Lu-PSMA-617 up front in castration-sensitive disease, but the 39% rate of dry mouth in a patient with an expected lifespan of 5-7 years is a significant issue. It will be interesting to see where 177-Lu-PSMA-617 fits into our current treatment landscape as we learn more.

EORTC GUCG 1333/PEACE-3 Skeletal Safety Analysis: Study Design

Daniel P. Petrylak, MD:
There have been studies combining radium-223 with other agents that will lower PSA and cause soft tissue responses. There have been trials with radium-223 plus abiraterone, such as the ER-233 study, which showed no improvement in symptomatic skeletal event–free survival and higher rates of bone fracture with the addition of radium-223 to abiraterone in patients with early-stage mCRPC.27 In the PEACE-3 trial, investigators combined radium-223 with enzalutamide and compared this combination with enzalutamide alone.

The PEACE-3 trial is a randomized, multicenter, open-label phase III trial that enrolled patients (N = 267) with bone-predominant mCRPC with >2 bone metastases who are asymptomatic or mildly symptomatic with no brain or visceral metastases.28-29

The primary endpoint for the PEACE-3 trial was rPFS, and the secondary endpoints were OS, disease-specific survival, skeletal-related events, and time to initiation of next systemic therapy.

EORTC GUCG 1333/PEACE-3 Skeletal Safety Analysis: Use of BPAs

Daniel P. Petrylak, MD:
The question in this analysis presented at ASCO 2021 was: How does the use of a bone protective agent (BPA) such as denosumab or bisphosphonate affect the rate of fractures and the overall compliance with the study?

A safety letter was sent in March 2018 based on data on the use of abiraterone and radium-223 in combination that showed a high rate of bone fractures, with a reduction in fractures for patients who received BPAs. Before the safety letter was released, 45% of randomized patients did not use a BPA in the PEACE-3 trial; after the letter, only 2.9% did not use a BPA. The use of BPAs after bone fracture was 7% before the letter and 0.7% after the letter. Before the letter, 16% of randomized patients used BPAs at registration and continued their use throughout treatment; after the letter, this number went up to 88%. So, again, the urgent safety letter made a difference in how these patients were treated.

EORTC GUCG 1333/PEACE-3 Skeletal Safety Analysis: Cumulative Incidence of Bone Fractures

Daniel P. Petrylak, MD:
When you look at the cumulative incidence of bone fractures across the board, there is an important difference. For patients receiving enzalutamide plus radium-223, the rate of bone fracture was 25.7% without BPA use vs 2.7% with BPA use at 9 months. At this time point, the rate of fracture with enzalutamide also decreased from 9.4% to 1.3% with the addition of BPAs. That pattern is consistently seen from 9-21 months on the study.

EORTC GUCG 1333/PEACE-3 Skeletal Safety Analysis: Conclusions

Daniel P. Petrylak, MD:
This safety analysis confirms that the risk of fracture was controlled in both treatment arms in patients with mCRPC who were receiving BPAs. So, these data highlight the importance of giving a BPA to patients with metastatic prostate cancer to prevent skeletal complications.

Elizabeth R. Plimack, MD, MS:
I think this is very important, because we think of BPAs as a supportive measure. I tend to be conservative with them based on the risk of osteonecrosis of the jaw and other issues, such as hypocalcemia. However, there was such a high rate of fracture in patients who received enzalutamide or enzalutamide plus radium-223 who did not receive a BPA. Dr. Petrylak, do you think we can extrapolate this to anyone with mCRPC receiving any therapy, or do you think this is something specific to enzalutamide and enzalutamide plus radium-223?

Daniel P. Petrylak, MD:
I think these data should be extrapolated. There has been some suggestion that giving denosumab or any BPA with radium-223 may provide better survival than giving radium-223 alone. So, clearly, there may be an interaction.

Most patients receiving radium-223 also receive denosumab, and I recommend monthly treatment if they have no dental issues. In the PEACE-3 trial, the enzalutamide alone arm suggests that you should give a BPA in that setting, as well, because of the 16% fracture risk without BPAs.

The question is: How much BPA do we need to give? The indication is to give denosumab monthly, but when should we stop giving it monthly and switch to an every-3-month maintenance approach? At this time, there is no good answer to that question. I give monthly denosumab to my patients receiving radium-223 if they can tolerate it, but the risk of osteonecrosis begins to develop as you get further along the course of treatment.

Elizabeth R. Plimack, MD, MS:
I think those are good guidelines. While on radium-223, everyone treated for mCRPC should be getting a BPA. Also, we need clinical trials to look at whether we can reduce the frequency of BPA dosing and balance the risk of fracture with the risk of osteonecrosis of the jaw.

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