Mayo Clinic Cancer Center

Shaji K. Kumar, MD, professor of medicine, Mayo Clinic, discusses stem cell mobilization multiple myeloma.

Although stem cell mobilization is successful in the majority of patients with multiple myeloma, the use of granulocyte colony-stimulating factor (G-CSF) used alone is associated with up to a 10% failure rate, Kumar explains. This rate increases for patients who receive prolonged treatment exposure with lenalidomide (Revlimid), alkylating agents, or daratumumab (Darzalex). 

​Additional techniques such as chemomobilization or mobilization using the use of plerixafor ​(Mozobil), a CXCR4-targeted agent, can be used ​in patients who fail G-CSF–alone mobilization, says Kumar. 

More cells can be collected with chemomobilization compared with G-CSF–alone, and the failure rate is lower, explains Kumar. However, the modality is associated with ​an increased risk of cytopenia, neutropenic fever that could lead to hospitalization, and longer time to mobilization. 

Plerixafor can be used as a risk-adapted strategy based on CD34 counts after G-CSF or on the number of CD34 cells that were gathered in the first collection, says Kumar. The failure rate with this method may be reduced to about 1% to 2% in patients with multiple myeloma.

Videos

Shaji K. Kumar, MD, discusses stem cell mobilization multiple myeloma.

Dr. Kumar on Stem Cell Mobilization in Multiple Myeloma 

Shaji K. Kumar, MD, professor of medicine, Mayo Clinic, discusses key takeaways from the phase 3 ENDURANCE trial in newly diagnosed multiple myeloma.

The results from the trial showed similar progression-free survival and overall survival (OS) with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) versus carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd) in this setting, says Kumar. The estimated 3-year OS rates were approximately 85% in both arms. Additionally, the overall response rates were comparable between arms. Notably, deeper responses such as the rate of very good partial response, was more common among patients in the KRd arm, says Kumar.

In terms of safety, a higher incidence of grade 3 or higher non-hematological adverse effects was seen in the KRd arm, particularly cardiac, pulmonary, and renal toxicities. However, patients in the VRd arm had a higher risk of peripheral neuropathy. Taken collectively, the results do not provide sufficient evidence that KRd should replace VRd as the current frontline standard of care in newly diagnosed patients with transplant-eligible myeloma. Trials evaluating the addition of monoclonal antibodies to VRd or replacing bortezomib are ongoing, concludes Kumar.

Shaji K. Kumar, MD, discusses key takeaways from the phase 3 ENDURANCE trial in newly diagnosed multiple myeloma.

Dr. Kumar on Takeaways From the ENDURANCE Trial in Multiple Myeloma

Shaji K. Kumar, MD, professor of medicine, Mayo Clinic, discusses the rate of treatment discontinuation in the phase 3 ENDURANCE (E1A11) trial in newly diagnosed multiple myeloma.

Patients with newly diagnosed multiple myeloma were randomized to received bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) or carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd).

Findings from the study showed that KRd did not improve progression-free survival compared with VRd in this patient population.

Early discontinuation of treatment was relatively common among patients treated in both arms of the ENDURANCE study, says Kumar. About 43% of patients completed the full 12 cycles of VRd and 61.6% of patients completed the full 9 cycles of KRd.

Treatment discontinuation can be attributed to adverse effects, emergence of alterative therapy like stem cell transplant, or patient withdrawal/refusal, says Kumar.

Although the trial was not intended to enroll patients who would eventually go on to receive transplant, around 28% of patients in both arms went on to transplant before or shortly after completing induction therapy, concludes Kumar.

Shaji K. Kumar, MD, discusses the rate of treatment discontinuation in the phase 3 ENDURANCE trial in newly diagnosed multiple myeloma.

Dr. Kumar on Treatment Discontinuation in the ENDURANCE Trial in Multiple Myeloma

Although targeted therapy developments have lagged behind in colorectal cancer (CRC), molecular subtyping of patients is pushing the field toward an era of targeted treatment, said Tanios S. Bekaii-Saab, MD, FACP.

"I hope we can continue along the track of other cancers where identifying these subgroups has transformed survival outcomes for some patients," said Bekaii-Saab, who is a medical oncologist at Mayo Clinic. "I am not scared of saying the word 'cure' for stage IV colon cancer anymore because we are getting close to that. In some patients, we are achieving it."

One of the most recent examples of the emergence of targeted therapy is the April 2020 FDA approval of the 

combination of encorafenib (Braftovi) and cetuximab (Erbitux)

 for the treatment of previously treated adult patients with metastatic CRC who harbor a 

The approval was based on findings from the phase 3 BEACON CRC study, in which the combination was evaluated with or without binimetinib (Mektovi) in this subgroup of patients. The study demonstrated improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) with the doublet and triplet regimens.

Targeting other aberrations found in patients with CRC, such as 

 fusions, could provide additional pathways toward personalizing treatment to specific subgroups of patients.

, Bekaii-Saab, who is also medical director of the Cancer Clinical Research Office, and vice chair and section chief of Medical Oncology in the Department of Internal Medicine at Mayo Clinic, discussed the growing role of targeted therapy in CRC.

: Could you discuss the emergent role of targeted therapy in CRC?

: For the longest time, most of our questions in CRC have revolved around [treatment selection]. Should we give FOLFOX or FOLFIRI? What about bevacizumab (Avastin) or cetuximab? Do we move to triplet regimens? Those were relevant questions.

For 2 or 3 decades, we had lagged behind in the era of biologic and immune-based therapy. Now, we are seeing a trickling in a lot of these targeted agents that are transforming how we treat and will continue to treat patients with CRC.

We know the story of microsatellite instability—high (MSI-H) and PD-L1 inhibitors, specifically pembrolizumab (Keytruda) and nivolumab (Opdivo) plus or minus a CTLA-4 [inhibitor]. That [approach] applies to about 4% of patients with CRC. 

 fusions are present in about 0.5% of colon cancers. We have 2 agents, entrectinib (Rozlytrek) and larotrectinib (Vitrakvi), to target that fusion, and [those agents] have [led to] many patients into remission.

Could you shed light on some of the targeted therapies that are available for patients with BRAF mutations?

 V600E mutations typically [have a poor prognosis] with an average survival of about 1 year compared with a survival of closer to 3 years in the general population of patients with colon cancer. 

-mutant CRC accounts for 8% of all patients with CRC; that is not an insignificant number.

Over the last few months, we have seen a combination of a BRAF inhibitor such as regorafenib (Stivarga) plus cetuximab with or without the MEK inhibitor binimetinib transform the way we care for those patients. The traditional wisdom had been that EGFR inhibitors like cetuximab do not have activity [in 

-mutant disease]. That makes sense because BRAF is in the RAS [pathway], so EGFR inhibition is not as relevant.

Unlike in melanoma, if we block RAF in colon cancer, we see less than a 5% response rate of responses that are barely durable. This is because of the loop mechanism that makes EGFR relevant again. Therefore, we have to block EGFR and BRAF.

The BEACON trial looked at whether we could combine cetuximab and encorafenib or the same combination with the addition of a MEK inhibitor, which is below the RAF pathway and perhaps controls for some of the escape mechanisms through 

. That was compared with standard chemotherapy of FOLFIRI and cetuximab.

The results of the BEACON study came back positive. Every end point was met, including OS, PFS, and ORR. Surprisingly, the toxicity with the 2-drug regimen was lower than expected, despite some relative overlap. The quality of life in patients was better with the doublet [compared with standard chemotherapy].

The BEACON study was done in the refractory setting, which means that patients had progressed on at least 1 and up to 2 lines of therapy. Interestingly, patients who received this regimen in the second-line setting did much better than those who received it in the third-line setting. Now, we are moving this [combination] to the first-line setting to see if we can achieve the same transformational activity.

If you look at the tail of the curve, about 20% to 30% of patients have not progressed and are alive after at least 1 year. That is remarkable for this patient population who traditionally do not do very well.

I believe this [combination] is perhaps transforming the [disease] biology for some patients. Unfortunately, [it has not been as effective] for all patients with this alteration. There is still a lot to learn.

Could you highlight the progress that has been made regarding HER2-targeted strategies?

 amplification, which is present in about 3% to 4% of patients. It is only relevant in 

 is mutated, it counteracts the meaningfulness of a 

-amplified tumor do not respond to EGFR inhibitors. That is important to note because we can spare those patients EGFR inhibitors. It turns out that 

-amplified patients have a better biology than the average patient. However, chemotherapy may not be effective [in these patients]. We knew from breast cancer and gastric cancer that HER2-targeting agents could change outcomes for patients. We've seen that happen with trastuzumab (Herceptin) plus lapatinib (Tykerb) or pertuzumab (Perjeta) at a 20% to 30% response rate and interesting PFS and OS. Those were certainly important studies that established added guidelines [for HER2-targeted therapy].

We presented data with the oral TKI tucatinib (Tukysa). That agent is more specific to targeting HER2 and is very well tolerated when added to trastuzumab. At the 2019 ESMO Congress, we presented data on 26 patients. We are [planning] to update those data to include 45 patients. To date, we've seen a 55% response rate—the highest response rate reported [in these patients]&mdash;as well as ease of administration and long PFS with tucatinib in patients with 

 amplifications. We see those trends continue.

Interestingly, once patients achieve a complete response in their symptoms, biochemical responses occur within 3 to 6 weeks. While tucatinib has not been compared head-to-head with other regimens, we are hopeful this will become another targeted strategy available to our patients.

Have we seen the same success with targeted agents for patients with KRAS mutations?

We have had an incredibly difficult time due to confirmation issues and an inability to find the key to [unlock treatment for patients with] 

, which is present in about 2% to 3% of patients with CRC. We see a higher rate in appendiceal cancer, which is a rare subset of colon cancer. In those patients, agents targeting 

 mutations seem to be immunomodulatory. As such, strategies that target 

 plus immunotherapy are being explored preclinically. That may bring immunotherapy into non—MSI-H tumors.

It is an exciting time in colon cancer. There are other [strategies] as well. We are starting to piecemeal colon cancer into subgroups.

What role do antibody-drug conjugates (ADCs) play in CRC?

Overall, there is a whole platform being developed for these agents that is based on a delivery of cytotoxic agents directly into tumor cells. Some of these targets are being developed in CRC with fam-trastuzumab deruxtecan-nxki (Enhertu). The agent looks promising in a number of cancers.

The principle [of ADCs] is a bit different because rather than targeting the receptor directly, the agent delivers a killing dose of cytotoxic therapy into the tumor. One may argue that the target itself is also affected by this because we are essentially preventing dimerization or other effects that [the target] typically has. In turn, there may be some direct-targeting effects.

Those agents are also interesting because they deliver these cytotoxic agents intratumorally, sparing the patient the toxicities associated with systemic chemotherapy. It is a promising way to target tumors.

Interestingly, these agents may fit [into sequencing] for patients who progress on trastuzumab and tucatinib, for example. Today, we don't have any evidence that targeting HER2 beyond HER2 failure works, but with these agents it makes sense. [When a patient progresses on another agent], we are specifically shutting down the receptor dimerization and receptor activity. When that fails, the receptor is still there. If we take advantage of this through this ADC-specific mechanism, we won't be as concerned with chasing down the activity of the receptor and instead, will use the target as a docking station to deliver the chemotherapy into the cancer cell.

Where do you see the future of targeted therapy headed?

At this point in time, I am excited about these targeted strategies. As we start moving the knowledge that we have acquired into the metastatic setting to see how we are transforming biology with 

-targeted strategies, immunotherapies, and now with emerging HER2-targeted strategies, we have to ask, "How do we bring those therapies into the adjuvant setting?" We already have studies [ongoing] with atezolizumab (Tecentriq) in MSI-H patients. We have planned studies [for patients with] 

-mutated colon cancer in earlier stages with the hope of inducing a more favorable biology and ultimately, curing more patients with early-stage colon cancer.

The last area of research that is being actively looked at in adjuvant colon cancer is the role of minimal residual disease (MRD) as measured by circulating free DNA (cfDNA) assays. Prognostically, we know that if a patient has some cfDNA, the likelihood of recurrence is higher. However, we do not know what that means in terms of predicting for [response to] chemotherapy or intensifying follow-up [treatment].

Overall, we are seeing great improvements in understanding subtypes of colon cancer, moving [effective agents] to the adjuvant setting, continuing to define oligometastatic disease and the role of locoregional therapies, and understanding risk stratification. In the next few years, we will move the needle in a very positive direction, in which we cure a lot of patients even with later-stage disease.

Editor's Note: This interview took place before the 2020 ASCO Virtual Scientific Program. 

A posthoc updated analysis of the phase 3 BEACON CRC trial

 was presented during the ASCO virtual platform.

Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. 

. 2019;381(17):1632-1643. doi:10.56/NEJMoa1908075

Articles

Tanios S. Bekaii-Saab, MD, FACP, discusses the growing role of targeted therapy in CRC. 

Bekaii-Saab Highlights Targeted Therapy Advances in CRC

David D. Thiel, MD, chair, Department of Urology, Mayo Clinic, discusses the measures that are being taken to protect patients and providers from the coronavirus disease 2019 (COVID-19).

It is important to protect all providers from COVID-19 exposure, particularly anesthesiologists who perform aerosolizing procedures such as intubation, says Thiel. Moreover, by separating COVID-19—positive patients from COVID-19–negative patients in the hospital, health care systems can reduce the risk of patient exposure to the virus.

Testing is a critical component of ensuring that COVID-19—positive patients can be distanced from COVID-19–negative patients. At Mayo Clinic, every patient who is scheduled for surgery receives a nasal swab to ensure that they don’t have the virus, says Thiel. These measures are particularly important for patients with cancer who are already immunocompromised but need to come into the clinic for treatment. Telehealth visits have helped reduce the volume of patients who come into the cancer center, but it is not appropriate for everyone.

Despite containment efforts, the virus is not likely to disappear, meaning that communities will have to learn to modify their behaviors to reduce the risk of further spread, concludes Thiel.

David D. Thiel, MD, chair, discusses the measures that are being taken to protect patients and providers from the coronavirus disease 2019 (COVID-19).

Dr. Thiel on Protecting Patients and Providers From COVID-19

Anastasios (Tassos) Dimou, MD, a medical oncologist at Mayo Clinic, shares advice from managing patients with non—small cell lung cancer (NSCLC) who experience disease progression following therapy.

For patients who progress on therapy, one approach is to rebiopsy, if possible, says Dimou; a tissue biopsy, a liquid biopsy, or both can be used, says Dimou. Several factors should be considered when choosing a patient’s next line of therapy.

First, one must identify whether they are experiencing oligoprogression; in this case, a local approach like radiation and staying the course with the same TKI might be considered.

Another question to contemplate is whether comprehensive retesting with a rebiopsy would identify mechanisms of resistance, and whether that mechanism of resistance is target oncogene dependent or independent, adds Dimou.

Additionally, the question of whether the patients is dealing with progression in the brain or with disease in the brain should also be taken into consideration; in this case, the use of a CNS-penetrant TKI might serve as an effective approach, concludes Dimou.

Anastasios (Tassos) Dimou, MD, shares advice from managing patients with non–small cell lung cancer who experience disease progression following therapy.

Dr. Dimou on Managing Disease Progression in NSCLC

Anastasios (Tassos) Dimou, MD, a medical oncologist at Mayo Clinic, shares advice from managing patients with non–small cell lung cancer (NSCLC) who experience disease progression following therapy.

For patients who progress on therapy, one approach is to rebiopsy, if possible, says Dimou; a tissue biopsy, a liquid biopsy, or both can be used, says Dimou. Several factors should be considered when choosing a patient’s next line of therapy.

First, one must identify whether they are experiencing oligoprogression; in this case, a local approach like radiation and staying the course with the same TKI might be considered.

Another question to contemplate is whether comprehensive retesting with a rebiopsy would identify mechanisms of resistance, and whether that mechanism of resistance is target oncogene dependent or independent, adds Dimou.

Additionally, the question of whether the patients is dealing with progression in the brain or with disease in the brain should also be taken into consideration; in this case, the use of a CNS-penetrant TKI might serve as an effective approach, concludes Dimou.

The FDA approval of rucaparib (Rubraca) in 

-mutant metastatic castration-resistant prostate cancer (mCRPC) marks the first designation for a biomarker-driven targeted therapy in the field, said Alan H. Bryce, MD, who added that the regulatory decision reinforces the importance of germline and somatic genetic testing for men with high-risk and metastatic disease.

“Until this approval, prostate cancer was 1 of the big 4 tumors without any biomarker-directed therapies. That has changed with rucaparib, which is an extremely effective and attractive treatment option for patients who harbor 

 mutations,” said Bryce. “In summary, germline testing should be done unequivocally for all patients with high-risk, very high-risk, or metastatic prostate cancer. Somatic testing, either by tissue biopsy or cell-free DNA (cfDNA) should be done at the time of progression when you’re looking to make a treatment decision about what to put the patient on next.”

 is based on data from the ongoing phase 2 TRITON2 trial (NCT02952534), in which interim results showed that treatment with rucaparib led to a 44% confirmed objective response rate (ORR) in 62 evaluable patients with 

-mutant mCRPC who had received prior androgen receptor (AR)—directed therapy and taxane-based chemotherapy.

 alterations, 51.1% experienced a prostate-specific antigen (PSA) response to the PARP inhibitor.

At the 2019 ESMO Congress, updated findings with an additional 7 months of follow-up showed that rucaparib led to a 43.9% confirmed ORR and a confirmed PSA response of 52.0% in patients with 

-mutant mCRPC. At 24 weeks, 60% of responses were still ongoing.

The adverse effects (AEs) of the PARP inhibitor were consistent with the drug’s use in breast cancer and ovarian cancer, said Bryce. In the trial, the most common all-grade treatment-related AEs occurring in more than 20% of patients included asthenia/fatigue (55.3%), nausea (49.5%), anemia/decreased hemoglobin (37.9%), decreased appetite (27.9%), transient increased aspartate transaminase/alanine aminotransferase (24.7%), constipation (24.7%), vomiting (22.1%), and diarrhea (21.1%).

The approval is contingent on the results of a confirmatory trial. The phase 3 TRITON3 trial (NCT02975934), in which patients with homologous recombination deficient mCRPC who have received 1 prior AR-directed therapy will be randomized to rucaparib or physician’s choice of abiraterone acetate (Zytiga), enzalutamide (Xtandi), or docetaxel.

, Bryce, assistant professor of medicine and medical director of the Genomic Oncology Clinic, Mayo Clinic, discussed the recent regulatory approval of rucaparib in mCRPC and explained how the approval has underscored the importance of genetic testing in the field.

: How will the accelerated approval impact the treatment paradigm for patients with BRCA1/2-mutant mCRPC?

: This is an important moment in prostate cancer in that we finally have the first approval for a biomarker-selected targeted therapy. We’ve known for some time that 

 mutations in prostate cancer are predictors for efficacy to PARP inhibitors. Multiple studies have shown that. Now, we have [data from the TRITON2 trial] which led to the FDA approval of the PARP inhibitor rucaparib for use in patients with 

Could you expand on the data from the TRITON2 trial, which served as the basis for the drug’s approval?

The accelerated approval was based on ORR in patients [with soft tissue disease] who had measurable disease by RECIST criteria. Only a proportion of patients with prostate cancer have measurable soft tissue disease. Approximately half of patients will have bone-only disease, which is not assessable by RECIST criteria. The approval was based on the patients who had some degree of soft tissue disease, whether lymph node or visceral disease.

In patients with RECIST measurable soft tissue disease, rucaparib led to an ORR of 44% by RECIST criteria, which is fantastic. It’s better than we expect to see with chemotherapy in the same setting. It’s a meaningful outcome. Patients’ soft tissue tumors shrank. In the overall population, we saw a PSA response rate of over 50%.

Regarding safety, what does the toxicity profile for the agent look like?

We know a lot about the toxicities of PARP inhibitors because of their extensive use in breast cancer and ovarian cancer. The only variable in prostate cancer is that these are male patients. Despite this, we didn’t see a difference [in toxicity]. The toxicity profile is the same as what oncologists are accustomed to from treating patients with breast cancer and ovarian cancer. Additionally, this is a slightly older patient population who have potentially had pelvic radiation and other myelosuppressive treatments over time.

[Even so], the main toxicity is anemia. Prolonged use of a PARP inhibitor can certainly cause some myelosuppression. You can see the blood counts drop. Other than that, there is some potential for gastrointestinal toxicity, nausea, diarrhea, and some fatigue. However, it’s fairly well tolerated and consistent with what the oncologist already knows from their use in patients with breast cancer and ovarian cancer.

The approval is contingent on results from the TRITON3 trial in patients who have not received prior chemotherapy. Could rucaparib be moved to earlier lines of therapy?

TRITON2 was a phase 2, single-arm study in patients who had already received chemotherapy. TRITON3 is the phase 3, randomized study in patients who have not received prior docetaxel but have had at least 1 of the AR inhibitor, abiraterone or enzalutamide. The TRITON2 population [enrolled patients with] later-stage disease. TRITON3 is going to [evaluate rucaparib] earlier in the disease course.

We expect to see the [same] drug development with rucaparib as we see with every other cancer drug in which it starts in the late-stage setting and is marched forward in the treatment paradigm. TRITON3 is moving [rucaparib] further forward.

Trials have already launched [with rucaparib] in the first-line CRPC setting. For example, rucaparib in combination with abiraterone or other AR inhibitors. We have already seen studies launch with combinations of PARP and AR inhibitors, such as abiraterone or enzalutamide in the first-line CRPC setting. Other smaller studies are evaluating [rucaparib] in the neoadjuvant or metastatic hormone-sensitive settings as well. You can expect to see PARP inhibitors try to cross the full spectrum of metastatic prostate cancer.

How will the approval impact the use of genetic testing in prostate cancer?

The National Comprehensive Cancer Network already recommends germline testing in every patient with high-risk, very high-risk, or metastatic prostate cancer. With germline testing, we test a patient’s inherited genetic profile and [determine what] they are passing onto their children and what is associated with any relatives.

Somatic mutations are the private mutations in the cancer cells themselves. PARP inhibitors have utility in patients with germline or somatic mutations. In the setting of any high-risk, very high-risk, or metastatic prostate cancer, patients should have germline testing to inform themselves and their family. Secondly, in the context of treatment decisions, somatic testing needs to be done on top of germline testing. It’s really not one or the other. At least half of patients will only have mutations in their tumor and not in their germline.

Tissue testing should be done on the most recent tissue possible. It’s a common scenario in prostate cancer that men will have had their prostatectomy or radiation 10 years prior, for example. If you test that old biopsy tissue or prostatectomy tissue, the DNA might be degraded, so you might not be able to get a good result.

Secondly, the tumor will evolve over time. Over those 10 years, the genetic signature of that tumor will change. It will be different today than it was at the time of initial diagnosis. It’s really important for treating clinicians to remember to test the current tumor to determine how to treat the patient, the gold standard being a repeat biopsy with a piece of tissue from any tumor. You don’t have to biopsy each tumor site—just 1 is ok.

If for whatever reason, a biopsy is not feasible or perhaps the risk is too high, the clinician can get a cfDNA blood test that will screen for the mutation in the circulating DNA in the blood. That was a major part of the TRITON studies, as well as other PARP inhibitor studies in other disease settings.

The correlation between cfDNA and tissue is extremely high. A cfDNA test is a good test to determine which patients will respond to PARP inhibitors. A positive cfDNA test for 

predicts for response to rucaparib in this setting. A positive test is a real result; a negative test result isn’t necessarily real. A negative test can mean that there’s just not enough cfDNA in the blood. [The amount of cfDNA could] fall below the level of detection.

Get the test as the cancer is advancing. You need growing tumor that is shedding DNA. You don’t want [to order] a cfDNA test when the PSA is 0 and the disease is responding to therapy.

As the clinician [exhausts] multiple therapies, they should be repeating that somatic testing. Every time we treat a patient with a new drug, the tumor is going to evolve in response to that treatment, so the patient might not have a 

 mutation at initial diagnosis. They might not have [a 

 mutation] when we’re treating hormone-sensitive disease or first-line castration-resistant disease, but they might [develop a 

 mutation] in the second- or third-line castration-resistant setting, so it’s important to retest.

Are there any unanswered questions with rucaparib that future research efforts should address?

Outstanding questions include the use of PARP inhibitors in other DNA damage response mutations apart from 

. We know PARP inhibitors work in patients with 

? There’s a long tail of the curve of uncommon mutations that still fall on this pathway. Several publications are coming out, specifically looking at this. I really don’t think there is a role for PARP inhibitors in patients with 

mutations right now. Those data are fairly unimpressive. A small proportion [of patients with 

 mutations] will respond to these agents, but the vast majority don’t seem to benefit much at all.

We’re seeing responses in other mutations, such as 

. However, they’re such uncommon mutations that it’s going to be hard to build a big enough data set moving forward. The field is going to have to put quite a bit of thought into how we develop a meaningful set of criteria around these rare mutations. There is more to come on that. It’s probably going to require meta-analyses from multiple studies and perhaps prospective registrational studies in order to gather enough data to answer those questions.

Clovis Oncology highlights Rubraca (rucaparib) updated data from the ongoing TRITON2 clinical trial in patients with mCRPC and exploratory and integrated analyses in recurrent ovarian cancer at the ESMO Congress 2019 [news release]. Clovis Oncology: Boulder, CO; September 29, 2019. bit.ly/2u4iEPS. Accessed May 19, 2020.

Abida W, Bryce AH, Vogelzang NJ, et al. Preliminary results from TRITON2: a phase 2 study of rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. 

. 2018;29(suppl_8):viii271-viii302. doi:10.1093/annonc/mdy28

A Study of Rucaparib Versus Physician’s Choice of Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON3). https://bit.ly/2zf65Et. Updated March 31, 2020. Accessed May 19, 2020.

Alan H. Bryce, MD, discusses the recent regulatory approval of rucaparib in metastatic castration-resistant prostate cancer and explains how the approval has underscored the importance of genetic testing in the field.

Rucaparib Prostate Cancer Approval Sets Stage for Further Research

-mutant metastatic castration-resistant prostate cancer (mCRPC) marks the first designation for a biomarker-driven targeted therapy in the field, said Alan H. Bryce, MD, who added that the regulatory decision reinforces the importance of germline and somatic genetic testing for men with high-risk and metastatic disease.

“Until this approval, prostate cancer was 1 of the big 4 tumors without any biomarker-directed therapies. That has changed with rucaparib, which is an extremely effective and attractive treatment option for patients who harbor 

 mutations,” said Bryce. “In summary, germline testing should be done unequivocally for all patients with high-risk, very high-risk, or metastatic prostate cancer. Somatic testing, either by tissue biopsy or cell-free DNA (cfDNA) should be done at the time of progression when you’re looking to make a treatment decision about what to put the patient on next.”



-mutant mCRPC who had received prior androgen receptor (AR)–directed therapy and taxane-based chemotherapy.

 alterations, 51.1% experienced a prostate-specific antigen (PSA) response to the PARP inhibitor.

At the 2019 ESMO Congress, updated findings with an additional 7 months of follow-up showed that rucaparib led to a 43.9% confirmed ORR and a confirmed PSA response of 52.0% in patients with 



The adverse effects (AEs) of the PARP inhibitor were consistent with the drug’s use in breast cancer and ovarian cancer, said Bryce. In the trial, the most common all-grade treatment-related AEs occurring in more than 20% of patients included asthenia/fatigue (55.3%), nausea (49.5%), anemia/decreased hemoglobin (37.9%), decreased appetite (27.9%), transient increased aspartate transaminase/alanine aminotransferase (24.7%), constipation (24.7%), vomiting (22.1%), and diarrhea (21.1%).

The approval is contingent on the results of a confirmatory trial. The phase 3 TRITON3 trial (NCT02975934), in which patients with homologous recombination deficient mCRPC who have received 1 prior AR-directed therapy will be randomized to rucaparib or physician’s choice of abiraterone acetate (Zytiga), enzalutamide (Xtandi), or docetaxel.

, Bryce, assistant professor of medicine and medical director of the Genomic Oncology Clinic, Mayo Clinic, discussed the recent regulatory approval of rucaparib in mCRPC and explained how the approval has underscored the importance of genetic testing in the field.





The accelerated approval was based on ORR in patients [with soft tissue disease] who had measurable disease by RECIST criteria. Only a proportion of patients with prostate cancer have measurable soft tissue disease. Approximately half of patients will have bone-only disease, which is not assessable by RECIST criteria. The approval was based on the patients who had some degree of soft tissue disease, whether lymph node or visceral disease.

In patients with RECIST measurable soft tissue disease, rucaparib led to an ORR of 44% by RECIST criteria, which is fantastic. It’s better than we expect to see with chemotherapy in the same setting. It’s a meaningful outcome. Patients’ soft tissue tumors shrank. In the overall population, we saw a PSA response rate of over 50%.





We know a lot about the toxicities of PARP inhibitors because of their extensive use in breast cancer and ovarian cancer. The only variable in prostate cancer is that these are male patients. Despite this, we didn’t see a difference [in toxicity]. The toxicity profile is the same as what oncologists are accustomed to from treating patients with breast cancer and ovarian cancer. Additionally, this is a slightly older patient population who have potentially had pelvic radiation and other myelosuppressive treatments over time.

[Even so], the main toxicity is anemia. Prolonged use of a PARP inhibitor can certainly cause some myelosuppression. You can see the blood counts drop. Other than that, there is some potential for gastrointestinal toxicity, nausea, diarrhea, and some fatigue. However, it’s fairly well tolerated and consistent with what the oncologist already knows from their use in patients with breast cancer and ovarian cancer.





TRITON2 was a phase 2, single-arm study in patients who had already received chemotherapy. TRITON3 is the phase 3, randomized study in patients who have not received prior docetaxel but have had at least 1 of the AR inhibitor, abiraterone or enzalutamide. The TRITON2 population [enrolled patients with] later-stage disease. TRITON3 is going to [evaluate rucaparib] earlier in the disease course.

We expect to see the [same] drug development with rucaparib as we see with every other cancer drug in which it starts in the late-stage setting and is marched forward in the treatment paradigm. TRITON3 is moving [rucaparib] further forward.

Trials have already launched [with rucaparib] in the first-line CRPC setting. For example, rucaparib in combination with abiraterone or other AR inhibitors. We have already seen studies launch with combinations of PARP and AR inhibitors, such as abiraterone or enzalutamide in the first-line CRPC setting. Other smaller studies are evaluating [rucaparib] in the neoadjuvant or metastatic hormone-sensitive settings as well. You can expect to see PARP inhibitors try to cross the full spectrum of metastatic prostate cancer.





The National Comprehensive Cancer Network already recommends germline testing in every patient with high-risk, very high-risk, or metastatic prostate cancer. With germline testing, we test a patient’s inherited genetic profile and [determine what] they are passing onto their children and what is associated with any relatives.

Somatic mutations are the private mutations in the cancer cells themselves. PARP inhibitors have utility in patients with germline or somatic mutations. In the setting of any high-risk, very high-risk, or metastatic prostate cancer, patients should have germline testing to inform themselves and their family. Secondly, in the context of treatment decisions, somatic testing needs to be done on top of germline testing. It’s really not one or the other. At least half of patients will only have mutations in their tumor and not in their germline.

Tissue testing should be done on the most recent tissue possible. It’s a common scenario in prostate cancer that men will have had their prostatectomy or radiation 10 years prior, for example. If you test that old biopsy tissue or prostatectomy tissue, the DNA might be degraded, so you might not be able to get a good result.

Secondly, the tumor will evolve over time. Over those 10 years, the genetic signature of that tumor will change. It will be different today than it was at the time of initial diagnosis. It’s really important for treating clinicians to remember to test the current tumor to determine how to treat the patient, the gold standard being a repeat biopsy with a piece of tissue from any tumor. You don’t have to biopsy each tumor site—just 1 is ok.

If for whatever reason, a biopsy is not feasible or perhaps the risk is too high, the clinician can get a cfDNA blood test that will screen for the mutation in the circulating DNA in the blood. That was a major part of the TRITON studies, as well as other PARP inhibitor studies in other disease settings.

The correlation between cfDNA and tissue is extremely high. A cfDNA test is a good test to determine which patients will respond to PARP inhibitors. A positive cfDNA test for 

predicts for response to rucaparib in this setting. A positive test is a real result; a negative test result isn’t necessarily real. A negative test can mean that there’s just not enough cfDNA in the blood. [The amount of cfDNA could] fall below the level of detection.

Get the test as the cancer is advancing. You need growing tumor that is shedding DNA. You don’t want [to order] a cfDNA test when the PSA is 0 and the disease is responding to therapy.

As the clinician [exhausts] multiple therapies, they should be repeating that somatic testing. Every time we treat a patient with a new drug, the tumor is going to evolve in response to that treatment, so the patient might not have a 

 mutation] in the second- or third-line castration-resistant setting, so it’s important to retest.





Outstanding questions include the use of PARP inhibitors in other DNA damage response mutations apart from 

 mutations] will respond to these agents, but the vast majority don’t seem to benefit much at all.

We’re seeing responses in other mutations, such as 

Alan H. Bryce, MD, assistant professor of medicine and medical director of the Genomic Oncology Clinic, Mayo Clinic, discusses the accelerated approval of rucaparib (Rubraca) for the treatment of adult patients with 

 mutation (germline and/or somatic)—associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor–directed therapy and a taxane-based chemotherapy.

The accelerated approval is based on findings from the ongoing phase 2 TRITON2 trial (NCT02952534), in which the PARP inhibitor demonstrated a 44% confirmed objective response rate (ORR) in 62 evaluable patients with 

The results of the TRITON2 trial confirm historical data showing the efficacy of PARP inhibitors in 

-mutant prostate cancer, says Bryce. The regulatory decision marks the first approval for a biomarker-driven targeted therapy in prostate cancer, says Bryce. With this approval, patients with 

-mutant mCRPC now have access to an extremely effective and attractive treatment option, concludes Bryce.

Alan H. Bryce, MD, discusses the accelerated approval of rucaparib (Rubraca) for the treatment of adult patients with BRCA mutation (germline and/or somatic)–associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor–directed therapy and a taxane-based chemotherapy.

Mayo Clinic Cancer Center

Dr. Kumar on Stem Cell Mobilization in Multiple Myeloma

Dr. Kumar on Takeaways From the ENDURANCE Trial in Multiple Myeloma

Dr. Kumar on Treatment Discontinuation in the ENDURANCE Trial in Multiple Myeloma

Bekaii-Saab Highlights Targeted Therapy Advances in CRC

Dr. Thiel on Protecting Patients and Providers From COVID-19

Dr. Dimou on Managing Disease Progression in NSCLC

Dr. Dimou on Managing Disease Progression in NSCLC

Rucaparib Prostate Cancer Approval Sets Stage for Further Research

Rucaparib Prostate Cancer Approval Sets Stage for Further Research

Dr. Bryce on the FDA Approval of Rucaparib in BRCA-Mutant mCRPC