Kristi Rosa

In a session at the 2022 LUGPA Annual Meeting, Emmanuel S. Antonarakis, MD, provided an in-depth analysis of everything urologists need to know about the current state of genomic/genetic testing in prostate cancer.

“Homologous repair mutations and mismatch mutations have therapeutic implications in the context of PARP inhibitors and PD-1 inhibitors, respectively,” said Emmanuel S.Antonarakis, MD. 

Antonarakis, who is the Clark Endowed Professor of Medicine in the Division of Hematology/Oncology and Transplantation at the University of Minnesota, Masonic Cancer Center, explained to attendees that all patients with prostate cancer, except for those with low-risk or very low-risk localized disease, should be tested for germline mutations, and somatic testing should be done in all patients with metastatic disease as there are therapeutic implications.

“Homologous repair mutations and mismatch mutations have therapeutic implications in the context of PARP inhibitors and PD-1 inhibitors, respectively,” said Antonarakis, who is the Clark Endowed Professor of Medicine in the Division of Hematology/Oncology and Transplantation at the University of Minnesota, Masonic Cancer Center. “[Additionally,] the identification of a germline mutation, but not a somatic mutation, has family counseling and genetic implications for first-degree relatives.”

Many commercial and in-house platforms are available to assay the germline and somatic DNA of patients with prostate cancer. The landscape has become complicated, according to Antonarakis, who added that this is a both “good and a bad thing.”

Options that target either a genetic alteration or a particular protein in prostate cancer have become available: olaparib (Lynparza) and rucaparib (Rubraca) for homologous recombination repair (HRR)–deficient or 

-mutated disease, pembrolizumab (Keytruda) for mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) cancers, and Lu 177 vipivotide tetraxetan (Pluvicto) for those with prostate-specific membrane antigen (PSMA)–positive, metastatic castration-resistant prostate cancer (mCRPC).

Germline mutation vs somatic mutation: what you need to know

A germline mutation is a genetic change in a parental germ cell that becomes incorporated into the DNA of every cell in the body of the offspring, Antonarakis said, adding that a variant contained in the germline can be passed from parent to their offspring; therefore, this kind of mutation is hereditary.

A somatic mutation is an alteration in DNA that occurs following conception, he added. These kinds of mutations can present in any cell of the body except the germ cells, and they are acquired; as such, they cannot be passed on to children.

Twenty-three percent of men with mCRPC harbor somatic DNA repair alterations, and the frequency of these alterations increases in metastatic disease vs localized disease. Moreover, 12% of men with metastatic disease have a germline DNA repair defect.

According to the National Comprehensive Cancer Network’s 2022 guidelines, germline genetic testing is recommended for patients with prostate cancer who have high-risk, very high-risk, regional, or metastatic disease, those with Ashkenazi Jewish ancestry, those with a family history of high-risk germline mutations like 

“At the somatic level, tumor genomic testing should be recommended for all patients with metastatic prostate cancer, but it should be strongly considered in those also with nodal metastatic disease,” Antonarakis said.

Importance of family history and cascade testing

Family history has become increasingly important. According to Antonarakis, it is important to ask about if there is a family history of prostate cancer, but also of breast cancer, ovarian cancer, and pancreatic cancer. At least 4 

-associated cancer types can increase the risk of a patient with prostate cancer having a germline mutation.

“If a patient is diagnosed with a germline mutation, this brings up the point of cascade testing, meaning that this patient has a 50% chance that his family members have the same mutation,” Antonarakis said. “This can lead to cascade genetic testing in other family members to look for the presence or absence of the same germline mutation. As such, there are family implications, if we find a germline mutation in a patient with prostate cancer.”

Getting acceptable samples for genetic/genomic testing

Two review articles recommend that a fresh metastatic tumor biopsy is the optimal choice of sample to use to identify HRR alterations using next-generation sequencing.

 “There are some differences [between the publications in terms of] what is the second and third best options,” Antonarakis said.

In one review article, the second and third choices were circulating tumor DNA (ctDNA) and archival biopsy/primary tumor tissue, respectively; in the other article, the archival biopsy/primary tumor tissue was thought to be the second-best option and ctDNA was the third best option.

“One important thing about ctDNA is the ability to get a positive or evaluable test depends on the prostate-specific antigen [PSA] level,” Antonarakis said. “ctDNA content increases with PSA level…In my practice, if a patient has metastatic disease with a PSA of less than 5 ng/mL, I think the yield of a ctDNA test will be low. For those with a PSA above 5 ng/mL, and especially those with a PSA above 20 ng/mL, the ctDNA yield is likely to be much higher, and therefore, giving rise to an evaluable test.”

Germline vs somatic: which to test for first?

A research group from Memorial Sloan Kettering Cancer Center set out to answer the question of what proportion of mutations found on tumor testing could be of germline origin. “There are certain gene mutations that, when found in the tumor, are virtually never germline mutations,” Antonarakis said. He added that when mutations like 

 are found in the tumor, they are virtually always somatic-only mutations.

“However, when you look at other genes like 

, a significant proportion of those mutations can reflect a germline mutation,” Antonarakis explained. “If someone begins with tumor-only testing and finds one of these mutations, you should strongly consider germline testing afterward to disambiguate a germline from a somatic mutation.”

Guidelines presented by the same authors also offer insight into when to proceed to germline testing after tumor-only testing. If a HRR gene mutation is found in the tumor, germline testing should be done afterward. If a 

 mutation is found, “you may be able to get away with omitting germline testing,” Antonarakis said.

He added that the caveat is if the patient meets NCCN guidelines, metastatic disease, node-positive disease, or high-risk localized disease, “they should undergo germline genetic testing anyway.”

 in the same cancer be treated? If the patient had mCRPC, a PARP inhibitor could be an option due to the 

mutation, as could pembrolizumab because of the mismatch-repair deficiency, according to Antonarakis. The patient did not respond to olaparib but did have a robust response of approximately 12 months when subsequently given pembrolizumab.

“The lesson here, which is the first caveat, is that a 

mutation in the context of MSI is usually a passenger mutation, not a driver mutation, and these patients in most cases, should probably be treated preferentially with a PD-1 inhibitor rather than a PARP inhibitor,” Antonarakis said.

The second caveat that Antonarakis mentioned in his presentation was the issue of 

alterations; these are mutations that come from the leukocytes from the white blood cells, which especially on a ctDNA assay, could appear to come from the tumor and could erroneously be classified as a tumor-derived mutation when it is a leukocyte mutation.

“These mutations increase with age and are present in about 10% of the prostate cancer population,” Antonarakis said. “Interestingly enough, these mutations can occur in the same genes for which PARP inhibitors are approved, such as 

. These mutations are difficult to resolve but can be identified by sequencing matched ctDNA and leukocyte DNA.”

Antonarakis shared a patient case who was found to have an 

 mutation but upon testing was noted to have a variant in the gene that may be derived from a non-tumor source like clonal hematopoiesis. “That 

 mutation—not a tumor-derived mutation. As such, this patient would not be expected to respond to a PARP inhibitor such as olaparib,” Antonarakis concluded.

1. Antonarakis ES. Genetic and genomic testing in prostate cancer. Presented at: 2022 LUGPA Annual Meeting; November 10-12, 2022; Chicago, IL. Accessed November 11, 2022

2. Antonarakis ES, Gomella LG, Petrylak DP, et al. When and how to use PARP inhibitors in prostate cancer: a systemic review of the literature with an update on on-going trials. 

. 2020;3(5):594-611. doi:10.1016/j.euo.2020.07.005

3. Abida W, Antonarakis ES. Management of advanced prostate cancer with germline or somatic homologous recombination deficiency. 2022. Accessed November 11, 2022. http://bit.ly/3TpGhZr

Articles

All patients with prostate cancer, except for those with low-risk or very low-risk localized disease, should be tested for germline mutations, and somatic testing should be done in all patients with metastatic disease as there are therapeutic implications, according to Emmanuel S. Antonarakis, MD.

Expert explains everything urologists need to know on genomic testing

In a presentation at the 2022 LUGPA Annual Meeting, Evan Y. Yu, MD, highlighted different sequencing strategies that can be utilized for patients with metastatic castration-resistant prostate cancer (mCRPC) and the data that support each approach.

"There is no definitive pathway. Patient individualization, comorbidities, and your clinical judgement needs to be applied to every single situation,” said Evan Y. Yu, MD.

Yu, a professor of Medicine and Oncology and clinical research director of Genitourinary Oncology at Fred Hutch Cancer Consortium, explained that for patients with mCRPC who experience disease progression on novel hormonal agents (NHAs) and androgen deprivation therapy (ADT), it is important to consider when the NHA was received and whether docetaxel has been administered, as these factors affect downstream options and sequencing.

“Combination therapy for mCRPC has generally been unremarkable, [although we have seen] early hits for combining NHAs with PARP inhibitors,” said Yu, who is also the medical director of Clinical Research Services at Fred Hutch. “There are many options for patients who progress on a NHA, but [several factors go] into the equation [of what to do next] …There is no definitive pathway. Patient individualization, comorbidities, and your clinical judgement needs to be applied to every single situation.”

Pathway for Patient With mCRPC Who Receives Frontline NHA/ADT and Progresses

For patients with mCRPC who received NHAs like abiraterone acetate (Zytiga) or enzalutamide (Xtandi) in the first-line setting, Yu shared that the top second-line options are docetaxel or radium-223 dichloride (Xofigo) if the patient has bone metastases, does not have visceral metastases, and is symptomatic.

“If you have patients who have mismatch-repair alterations, hypermutation, or microsatellite instability, pembrolizumab [Keytruda] can be used here,” Yu noted. “If you have patients with DNA repair deficiency, like 

, olaparib [Lynparza] could be used. But, generally speaking, I go with docetaxel or radium-223. A novel hormonal therapy switch is just not preferred.”

A multicenter, randomized, open-label, phase 2 trial (NCT02125357) conducted in 6 cancer centers throughout British Columbia, Canada, was designed to determine the optimal sequencing of enzalutamide and abiraterone in patients with mCRPC.

 Those enrolled to group A (n = 101) received abiraterone followed by enzalutamide, and those in group B (n = 101) received the reverse sequence.

Data indicated that at a median follow-up of 22.8 months, the time to second prostate-specific antigen progression was longer in group A vs group B, at a median of 19.3 months (95% CI, 16.0-30.5) vs 15.2 months (95% CI, 11.9-19.8), respectively (HR, 0.66; 95% CI, 0.45-0.97; 

= .036). PSA responses to second-line treatment were observed in 36% and 4% of patients, respectively.

“With that being said and done, if you’re going to go with back-to-back hormone agents, in terms of sequencing, abiraterone followed by enzalutamide is most ideal,” Yu noted. “But back-to-back NHAs yield poor results.”

The use of radium-223 comes with several considerations, Yu said. The agent can be administered to those with bone metastases and symptoms, but it cannot be given to those with visceral metastases.

There are other stringent eligibility requirements for the agent regarding “hemoglobin, platelet count, and white blood cell count or ANC,” Yu added.

Previous treatment with docetaxel is known to increase the likelihood of challenges with neutropenia and/or thrombocytopenia. Radium-223 requires preauthorization and docetaxel does not. However, there is a higher likelihood of being able to administer all 6 doses of radium-223 in the pre-chemotherapy setting rather than the post-chemotherapy setting.

“For pragmatic reasons, I kind of like the idea of trying to use radium-223 before chemotherapy if you can do it and the patient meets the criteria,” he noted.

“Precision therapy [should be used for these patients] when possible, not back-to-back NHAs because it yields poor results. If you have to do it, it’s better to go with abiraterone and then enzalutamide rather than [the reverse],” Yu said. “Radium-223 can be administered before docetaxel; there’s a survival benefit either before or after docetaxel, but the patient has to [meet the requirements]. However, if your patient has rapidly progressing disease, a PSA that is shooting up really fast, you restage them and their disease is really exploding on the scans, docetaxel is your best shot at a response; it should be the most frequently relied upon pathway.”

Pathway for Patients With M0 CRPC Who Progress on Frontline NHAs/ADT

Considerations differ depending on how a patient enters into resistance to NHAs, Yu added. If a patient has M0 CRPC and receives an androgen receptor (AR) antagonist, the FDA-approved options are apalutamide (Erleada), enzalutamide, or darolutamide (Nubeqa).

“Although many of the options are the same, I think about things a little differently. Again, [I would go with] precision therapy, when possible. The difference here is, I would never do back-to-back hormonal therapies. I’ll never go to abiraterone in this situation just because the response rates are abysmal after an AR-targeted therapy,” Yu explained. “Again, radium-223 can be used here before docetaxel if the patient meets the [required criteria] but again, docetaxel is your best shot at response—especially if the patient is progressing rather rapidly.”

Pathway for Patients With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) Following Frontline NHA/ADT

For patients with mHSPC who received a NHA in the first-line setting, but not a triplet regimen, second-line treatment options are similar, according to Yu. Again, he will use precision therapy, when possible. Radium-223 is preferable before docetaxel in eligible patients, and docetaxel should be the most relied upon pathway to increase chances of response.

However, a novel hormonal therapy switch is more acceptable for these patients if they started with abiraterone rather than apalutamide or enzalutamide; those who received abiraterone can switch to another AR-targeted therapy.

“The reason to switch them is if you think about how patients progress, they have hormone-sensitive disease and now they are starting to progress to castration resistance. They are coming in every 3 to 4 months for their leuprorelin shots, for example, and you are checking their PSA,” Yu explained. “The vast majority of these patients are going to progress asymptomatically, and a lot of them do not want to move onto chemotherapy or intravenous therapies. As such, I do this switch a little bit more often from abiraterone to enzalutamide.”

Pathway for Patients With mHSPC Who Progress on ADT, Docetaxel With or Without NHA

For patients with mHSPC who have high-volume de novo metastases and received ADT and either abiraterone/docetaxel or ADT and darolutamide/docetaxel, the following options can be considered:

Docetaxel retreatment if the patient had an outstanding response during the initial 6 cycles of treatment and their time to castration-resistant disease was over 2 years

Cabazitaxel (Jevtana) for those without an outstanding response to docetaxel or who experienced many adverse effects previously

Radium-223 for those with bone metastases, no visceral metastases, and symptoms

“What I would rely on here is either cabazitaxel or Lutetium,” Yu said. “I might lean a little bit more toward Lutetium, just because there is the TheraP study [NCT03392428], which showed a superior PSA decline rate, composite progression-free survival (PFS), and [toxicity] profile with Lutetium over cabazitaxel. NHA switch should be strongly discouraged, given the other good available options.”

Combination Regimens of NHAs and PARP Show Early Promise

A combination comprised of niraparib (Zejula) plus abiraterone and prednisone (AAP) is under exploration as a frontline treatment for patients with mCRPC with and without homologous recombination repair (HRR) gene alterations, as part of the phase 3 biomarker-selected MAGNITUDE trial (NCT03748641).

To participate, patients needed to have an ECOG performance status of 0 or 1 and a BPI-SF worst pain score of up to 3. Patients were split into 2 cohorts, those positive for HRR gene alterations, and those who were negative. Within those cohorts, patients were randomly assigned 1:1 to receive niraparib plus AAP or placebo plus AAP. rPFS by central review served as the primary end point of the research.

 mutations, the combination of niraparib and AAP resulted in a significant 47%. Here, the median radiographic PFS (rPFS) by central review in the investigative and control arms was 16.6 months vs 10.9 months, respectively (HR, 0.53; 95% CI, 0.36-0.79; 

= .0014). In all patients positive for HRR, niraparib plus AAP reduced the risk of progression or death by 27%. The median rPFS by central review was 16.5 months in the investigative arm vs 13.7 months in the control arm (HR, 0.73; 95% CI, 0.56-0.96; 

“That showed a PFS benefit for the biomarker-selected population – not overall, and not for the negative population,” Yu noted.

In the phase 3 PROpel trial (NCT03732820), the combination of olaparib at 300 mg and abiraterone at 1000 mg (n = 399) was compared with placebo and abiraterone (n = 397) at the same dose in the frontline treatment of patients with mCRPC.

 Investigator-assessed rPFS served as the primary end point of the trial.

Data showed that the combination of olaparib and abiraterone significantly improved investigator-assessed rPFS over abiraterone alone, with a median of 24.8 months vs 16.6 months, respectively (HR, 0.66; 95% CI, 0.54-0.81; 

< .0001); this translated to a 34% reduction in the risk of disease progression or death and a median rPFS improvement of 8.2 months with the olaparib combination. The 12-month rPFS rates in the investigative and control arms were 71.8% and 63.4%, respectively; at 24 months, these rates were 51.4% and 33.6%, respectively.

“The subgroup analyses also look positive for both the biomarker positive and negative populations, which is very interesting,” Yu noted.

Lastly, as part of the phase 3 TRITON3 trial (NCT02975934), investigators are examining the safety and efficacy of rucaparib (Rubraca) monotherapy vs physician’s choice of docetaxel, abiraterone acetate, or enzalutamide in patients with mCRPC with mutations in 

In a recently issued press release, it was reported that single-agent rucaparib significantly improved rPFS by independent radiology review compared with physician’s choice of treatment. Notably, benefit was observed in both primary efficacy analyses of patients with chemotherapy-naïve metastatic disease: in those whose tumors harbored 

 mutations and the overall intention-to-treat (ITT) population.

-positive subgroup, the median rPFS in the rucaparib arm was 11.2 months vs 6.4 months in the control arm. In the ITT population, the median rPFS was 10.2 months with single-agent rucaparib vs 6.4 months with physician’s choice of treatment.

That being said, we haven’t seen the breakdown of biomarker positive vs negative,” Yu noted. “Growing data support these kinds of combinations of PARP inhibitors and abiraterone or enzalutamide, even potentially in the DNA repair–proficient population. Overall survival data are not mature yet, so we have to wait and see.”

Yu E. Metastatic castration-resistant prostate cancer: combining and sequencing. Presented at: 2022 LUGPA Annual Meeting; November 10-12, 2022; Chicago, IL. Accessed November 11, 2022

Khalaf DJ, Annala M, Taavitsainen S, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. 

. 2019;20(12):1730-1739. doi:10.1016/S1470-2045(19)30688-6

Chi KN, Rathkopf DE, Smith MR, et al. Phase 3 MAGNITUDE study: first results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. 

. 2022;40(suppl 6):12. doi:10/1200/JCO.2022.40.6_suppl.012

Saad F, Armstrong AJ, Theiry-Fuillemin A, et al. PROpel: phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). 

. 2022;40(suppl 6):011. doi:10.1200/JCO.2022.40.6_suppl.011

TRITON3 phase 3 trial of Rubraca (rucaparib) achieves primary endpoint in men with metastatic castration-resistant prostate cancer with BRCA or ATM mutations. News release. Clovis Oncology, Inc. October 3, 2022. Accessed November 11, 2022. http://bit.ly/3hphW8z

For patients with mCRPC who experience disease progression on novel hormonal agents (NHAs) and androgen deprivation therapy, it is important to consider when the NHA was received and whether docetaxel has been administered, explains Evan Y. Yu, MD. 

Expert explains sequencing strategies in patients with mCRPC

“ADT intensification for patients with mCSPC is the standard of care; ADT alone is not enough," said Alicia Morgans, MD, MPH.

A critical component of the treatment paradigm in metastatic castration-sensitive prostate cancer (mCSPC) is deciding between doublet and triplet regimens, as the treatment standard has moved beyond androgen deprivation therapy (ADT)—alone or with docetaxel—for most patients, Alicia Morgans, MD, MPH, explained in a presentation at the 2022 LUGPA Annual Meeting.

Morgans, who is the medical director of the Survivorship Program at Dana-Farber Cancer Institute and an associate professor at Harvard Medical School, said that the National Comprehensive Cancer Network guidelines have been updated, and it is recognized that ADT in combination with docetaxel is no longer recommended: “ADT alone is really not preferred here; it’s going to be a combination of a doublet or a triplet.”

Morgans further explained that the first factor to consider when selecting the optimal approach for each patient is whether they have high- or low-volume disease.

“For high-volume patients, I always think about if the patient is fit for chemotherapy. [If they are,] I can give them that triplet therapy of ADT, docetaxel, and an androgen receptor (AR)–targeting agent. If they are not fit, then we might just do ADT and an AR-signaling inhibitor,” Morgans said. “If the patient has low-volume disease, we usually err on the side of ADT and an AR-signaling inhibitor and we have to decide about radiating the prostate. This is the decision tree that I think through.”

“The overall survival [OS] benefit [with a combination of ADT and an AR-targeted agent over ADT alone] was confirmed in multiple long-term analyses,” Morgans said.

Long-term data from the phase 3 LATITUDE trial (NCT01715285), which evaluated abiraterone acetate (Zytiga) plus prednisone and ADT (n = 597) vs ADT alone (n = 602) in patients with newly diagnosed, high-risk mCSPC, revealed a significant improvement in overall survival (OS) with the combination.

 The median OS in the abiraterone arm was 53.3 months (95% CI, 48.2–not reached) vs 36.5 months (95% CI, 33.5-40.0) in the placebo arm (HR, 0.66; 95% CI, 0.56-0.78; 

The OS benefit of adding abiraterone and prednisolone to ADT (n = 501) over ADT alone (n = 502) in patients with metastatic hormone-sensitive disease was also demonstrated in the phase 3 STAMPEDE trial (NCT00268476) and confirmed with long-term data

 The median OS favored the abiraterone combination (HR, 0.60; 95% CI, 0.50-0.71; 

“We know that ADT and abiraterone is going to provide a better survival advantage vs ADT alone,” Morgans said. “We certainly saw this with our other agents, apalutamide [Erleada] and enzalutamide [Xtandi], [as well].”

Final data from the phase 3 TITAN trial (NCT02489318) showed that at a median follow-up of 44.0 months, apalutamide plus ADT (n = 525) resulted in a significant 35% reduction in the risk of death vs placebo plus ADT (n = 527).

 The median OS in the investigative and control arms was not reached (NR; 95% CI, NR-NR) vs 52.2 months (95% CI, 41.9-NR), respectively (HR, 0.65; 95% CI, 0.53-0.79; 

The addition of enzalutamide to ADT was also found to prolong OS over placebo plus ADT in this population.

 Data from the phase 3 ARCHES trial (NCT02677896) showed that at a median follow-up of 44.6 months, enzalutamide/ADT (n = 574) reduced the risk of death by 34% vs placebo/ADT (n = 576; HR, 0.66; 95% CI, 0.53-0.81; 

< .001). Moreover, updated data from the phase 3 ENZAMET trial (NCT02446405) showed that at a median follow-up of 68 months, the median OS with enzalutamide plus testosterone suppression (n = 563) was NR (95% CI, NR-NR) vs 73.2 months (95% CI, 64.7-NR) with a conventional nonsteroidal antiandrogen and testosterone suppression (n = 562; HR, 0.70; 95% CI, 0.58-0.84; 

“So, what about triplet therapy? This is, importantly, going to be our combination that might be a little bit more toxic up front, but does seem to provide a bit of a bigger bang for our buck,” Morgans said.

When the Advanced Prostate Cancer Consensus Conference panel met in 2021, they were moving in the direction of ADT, docetaxel, and an AR pathway inhibitor for patients with high-volume disease, according to Morgans.

“Although [their vote] was split a bit, with providers at that time saying that ADT and an AR-targeting agent was really 1 of the preferred ways to go. Importantly, the vote happened after data from PEACE-1 [NCT01957436] came out, but before data from ARASENS [NCT02799602] came out. [I’m going to…] dig into these studies to familiarize everyone with why I think triplet therapy is something we should consider for a lot of our patients—especially if they have high-volume, de novo metastatic disease and fit for chemotherapy.”

The phase 3 PEACE-1 trial had a 2x2 factorial design and enrolled patients with de novo mCSPC with distant metastatic disease. There was an on-study requirement of continuous ADT, and those who received ADT up to 3 months were allowed to participate.

 Study participants were randomly assigned 1:1:1:1 to receive standard of care (SOC) comprised of docetaxel and ADT (n = 296), SOC plus abiraterone (n = 292), SOC plus radiation (n = 293), or SOC plus radiation plus abiraterone (n = 292). Radiographic progression-free survival (rPFS) and OS served as the primary end points.

Data showed that the addition of abiraterone to ADT and docetaxel resulted in a significant improvement in median rPFS over SOC alone, at 4.46 years (interquartile range [IQR], 1.9-NR) vs 2.03 years (IQR, 1.09-NR), respectively (HR, 0.50; 95% CI, 0.34-0.71; 

In the overall population, the groups who received SOC plus abiraterone also experienced improved OS over the groups who did not receive abiraterone, with a median OS of 5.7 years vs 4.7 years, respectively (HR, 0.82; 95.1% CI, 0.69-0.98; 

= .030). Within the population of patients who received ADT plus docetaxel, the group that received SOC plus abiraterone had a median OS of NR vs 4.4 years in the groups that received SOC without abiraterone (HR, 0.75; 95.1% CI, 0.59-0.95; 

“Importantly, you can see these hazard ratios are really strong, demonstrating that survival benefit,” Morgans noted. “I do want to emphasize again, this is a de novo mHSPC patient population, so we think this is a more aggressive phenotype.”

“ARASENS really suggests a similar advantage to this type of approach with a triplet,” Morgans said.

The international phase 3 ARASENS trial enrolled patients with newly diagnosed metastatic disease who had an ECOG performance status of 0 or 1.

 “A majority of patients enrolled did have high-volume disease, from what we can figure out from the baseline characteristics [shared] although this was not determined prior to enrollment, at least in the data that have been released,” Morgans added. “A majority [also] appear to have de novo metastatic disease.”

Patients were randomly assigned 1:1 to receive ADT plus docetaxel for 6 cycles and darolutamide at 600 mg twice daily (n = 651) vs ADT plus docetaxel for 6 cycles plus placebo (n = 655). The primary end point of the trial was OS, and key secondary end points comprise time to metastatic castration-resistant disease, time to initiation of subsequent anticancer treatment, time to symptomatic skeletal-related (SSE) event-free survival, time to first SSE, and time to pain progression.

At a data cutoff date of October 25, 2021, the darolutamide regimen significantly reduced risk of death by 32.5% vs the control regimen. The median OS in the investigative arm was not evaluable (NE) vs 48.9 months (95% CI, 44.4-NE) in the control arm (HR, 0.68; 95% CI, 0.57-0.80; 

< .001). Time to castration-resistant disease was longer in the darolutamide arm vs the placebo arm (HR for disease progression, 0.36; 95% CI, 0.30-0.42; 

< .001). The darolutamide regimen also had prolonged time to pain progression vs the placebo regimen (HR for disease progression, 0.79; 95% CI, 0.66-0.95; 

“Here, again, we consistently see that differentiation and benefit of adding an AR-targeted agent onto an ADT/docetaxel backbone; there’s a clear and early separation of curves, demonstrating OS benefit [in the investigative arm],” Morgans said.

“ADT intensification for patients with mCSPC is the SOC; ADT alone is not enough. For treatment of patients with de novo, high-volume disease who are fit for docetaxel, I think this is the opportunity to use a triplet of ADT, docetaxel for 6 cycles, and either abiraterone, darolutamide, or enzalutamide as our partner, and we [should] continue that for maintenance. If a patient is unfit for docetaxel, they should receive ADT plus an AR-targeting agent,” Morgans concluded. “For patients with low-volume disease, there is not sufficient evidence to really push a docetaxel triplet, although we can offer it to really motivated patients. ADT and AR-targeted agent plus radiation to the prostate is really what I would recommend in that setting.”

Morgans A. mCSPC: doublets vs triplets. Presented at: 2022 LUGPA Annual Meeting; November 10-12, 2022; Chicago, IL. Accessed November 11, 2022

Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. 

. 2019;20(5):686-700. doi:10.1016/S1470-2045(19)30082-8

James N, Rush H, Clarke N, et al. Abiraterone acetate plus prednisolone for hormone-naïve prostate cancer (PCa): long-term results from metastatic (M1) patients in the STAMPEDE randomised trial (NCT00268476). 

. 2020;31(suppl 4):S509. doi:10.1016/j.annonc.2020.08.871

Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. 

. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488

Armstrong AJ, Azad AA, Iguchi T, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. 

. 2022;40(15):1616-1622. doi:10.1200/JCO.22.00193

Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). 

. 2022;40(suppl 17):LBA5004. doi:10.1200/JCO.2022.40.17_suppl.LBA5004

Fizazi K, Maldonado X, Foulon S, et al. A phase 3 trial with a 2x2 factorial design of abiraterone acetate plus prednisone and/or local radiotherapy in men with 

 metastatic castration-sensitive prostate cancer (mCSPC): first results of PEACE-1. 

. 2021;39(suppl 15):500. doi:10.1200/JCO.2021.39.15_suppl.5000

Fizazi K, Galceran JC, Foulon S, et al. LBA5 a phase III trial with a 2x2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: overall survival with abiraterone acetate plus prednisone in PEACE-1. 

. 2021;32(suppl 5):S1299. doi:10.1016/j.annonc.2021.08.2099

Smith MR, Hussain MHA, Saad F, et al. Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone sensitive prostate cancer in the phase 3 ARASENS trial. 

. 2022;40(suppl 6):13. doi:10.1200/JCO.2022.40.6_suppl.013

Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. 

. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115

ADT intensification through doublet and triplet regimens has become standard for most patients with metastatic castration-sensitive prostate cancer, Alicia Morgans, MD, MPH, explained in a presentation at the 2022 LUGPA Annual Meeting. 

Dr. Alicia Morgans details decision between doublets and triplets in mCSPC

The FDA has updated the label for mitomycin-containing reverse thermal gel (Jelmyto) in low-grade upper-tract urothelial cancer (LG-UTUC) by extending the in-use period for pyelocalyceal solution admixture from 8 hours to 96 hours (4 days) following reconstitution of the product, according to UroGen, the developer of the treatment.

“This extension expands access to Jelmyto and gives our customers greater flexibility in choosing when to mix and schedule instillations. It also prepares us for managing future growth based on increased patient volume.” Jeff Bova, chief commercial officer, UroGen, stated in a press release.

“This label change for Jelmyto gives physicians and patients the option to treat in the morning, whereas, in most cases, the afternoon was the only option before the change,” Rian Dickstein, MD, chairman of Urology, University of Maryland Baltimore Washington Medical Center, added in the press release. “Previously, centers with mixing partners had to have Jelmyto mixed and sent by courier in the morning, now this extension provides added convenience of opening up additional scheduling options, which is very important as it enables us to more efficiently manage patient care.”

The FDA approved mitomycin gel for LG-UTUC in April 2020, based on findings from thephase 3 OLYMPUS trial (NCT02793128).

 Long-term data from OLYMPUS presented at the 2021 AUA Annual Meeting showed that mitomycin gelinduced a durable recurrence-free survival benefit in patients with LG-UTUC.

As of March 4, 2021, the median duration of response (DOR) achieved with mitomycin gel induction therapy was 28.1 months (95% CI, 14.6-37.1) in 15 evaluable patients. Eighty percent of patients (n = 12) experienced a durable response, defined as having no evidence of recurrence or not having to undergo radical nephroureterectomy.

Twenty percent of patients (n = 3) did not experience a durable response because of disease recurrence (13%; n = 2). One patient needed to undergo radical nephroureterectomy (7%); however, notably, this was performed because of ureteral stricture rather than disease recurrence.

Patients who experienced recurrence underwent endoscopic ablation. None of the patients with disease recurrence progressed to high-grade disease. At the time of the last follow-up, the disease-specific survival rate was 100%.

The open-label, single-arm, phase 3 OLYMPUS trial enrolled a total of 71 patients with LG-UTUC who had never undergone treatment or who had recurrent low-grade, noninvasive disease with at least 1 measurable papillary tumor.

Study participants received mitomycin gel once a week for the duration of 6 weeks followed by a 4- to 6-week grace period. In this period, patients were assessed for the primary efficacy end point of CR rate at their primary disease evaluation (PDE) visit. If patients experienced a CR to treatment, they went on to receive the gel monthly for up to 11 additional months.

Patients were determined to have a complete response (CR) if ureteroscopy and cytology were entirely normal. If there were any abnormalities, patients underwent a biopsy by which this was determined to be either recurrence or a CR.

A key secondary end point of the trial was durable response at the 12-month follow-up visit, and other end points included durability of response with mitomycin gel at 3, 6, and 9 months following the PDE visit. As part of the long-term follow-up, investigators examined duration of response, disease recurrence, disease progression, and death.

The primary analysis of the trial was done on the intention-to-treat (ITT) population, which comprised patients who were given 1 or more instillation of the gel. Secondary analyses were conducted in patients who achieved a CR at the time of their PDE visit, and long-term follow-up analyses looked at those who had a CR at 12 months following their PDE visit.

Of the 71 patients enrolled to the study (ITT population), 10 discontinued mitomycin gel (9 because of adverse effects [AEs] and 1 because of withdrawn consent), and 19 did not achieve a CR by their PDE visit. A total of 42 patients in the ITT population experienced a CR to treatment at the time of their PDE visit, which translated to a CR rate of 59.2% (95% CI, 46.8%-70.7%). Of these patients, 1 withdrew consent, 10 discontinued treatment, and 8 experienced disease recurrence.

Twenty-three patients maintained their CR at 12 months, translating to a CR rate of 56.1% (95% CI, 39.7%-71.5%). Five of these patients were at sites where follow-up protocol was not yet initiated, 2 did not have data available, and 1 was lost to follow-up. The data presented at the 2021 AUA Annual Meeting were for the remaining 15 evaluable patients.

1. FDA Authorizes an Extension of the In-Use Period for UroGen Pharma’s JELMYTO® Admixture to 96 Hours Following Reconstitution. Published online September 29, 2022. Accessed September 29, 2022. https://bwnews.pr/3UOGbfL

2. FDA approves first therapy for treatment of low-grade upper tract urothelial cancer. News release. FDA. April 15, 2020. Accessed September 13, 2021. https://bit.ly/3liG6jn.

3. Kleinman N, Pierorazio P, Raman JD, et al. Long-term recurrence-free survival following UGN-101 treatment for low-grade upper tract urothelial carcinoma. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-10

The FDA has updated the label for mitomycin-containing reverse thermal gel (Jelmyto) in low-grade upper-tract urothelial cancer by extending the in-use period for pyelocalyceal solution admixture.

Kristi Rosa

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