Tony Berberabe

demonstrated positive clinical activity in an ongoing phase 1a trial (NCT03544905) at the European Society for Medical Oncology Targeted Anticancer Therapies Virtual Congress 2021 by lead investigator Xiao-Li Wei, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China.

“Objective tumor responses were observed in 5 patients, including 1 complete response (CR) in 1 patient with ovarian cancer and 4 partial responses (PRs), 1 each in patients with colorectal cancer, breast cancer, ovarian cancer, and gastric cancer,” Wei said, during a virtual presentation of the findings.

The study was composed of 2 stages—a dose-escalation phase and a dose-expansion phase. In the dose-escalation phase, patients received 1 mg, 5, mg, 10 mg, 20 mg, 40 mg, and 60 mg of the agent. Dose expansion occurred at 20 mg, 30 mg, and 40 mg. Patients with or without 

mutations were eligible for dose escalation, but only patients with 

mutations were eligible for dose expansion.

The trial’s primary end points were safety, tolerability, and maximum tolerated dose of the oral monotherapy. The secondary end points were preliminary efficacy and pharmacokinetics, objective response rate (ORR), progression-free survival, duration of response, disease control rate, and the clinical benefit rate.

Thirty-nine patients, about evenly divided between male and female, were enrolled between July 2018 and November 2020.

Their median age was 54 years, and 21 (53.8%) harbored a 

mutation. Twenty-one patients (53.8%) had an ECOG performance status of 1, and the majority (71.8%) of patients had received 2 or more lines of prior therapy. 

The most common treatment-related adverse effect (TRAE) was any-grade hyperglycemia, affecting 84.6% of patients. Grade 3 hyperglycemia affected 51.3% of patients.

“Hyperglycemia was manageable and reversible, effectively controlled by antihyperglycemic medication or insulin,” said Wei.

Subsequent any-grade TRAEs observed were decreased appetite (33.3%), nausea (33.3%), and diarrhea (28.2%), on-target effects that were expected, Wei noted. Peripheral and facial edema each affected 15.4% of patients, which clinicians should keep in mind, added Wei. She said that no grade 4 or 5 TRAEs were reported.

Investigators reported that 3 patients had experienced dose-limiting toxicity: grade 3 hyperglycemia at the 40-mg and 60-mg dose level, and grade 3 nausea at the 60-mg dose level. Ultimately, the 40-mg dose was deemed to be the recommended phase 2 dose. 

Overall, 17 of 33 patients whose tumors harbored 

mutations were identified, and the ORR in this subpopulation was 23.5%. There were 4 patients on treatment as of the data cutoff date of November 15, 2020, Wei said.

“The main reason for stopping treatment was disease progression [56.4%] or subject withdrawal [17.9%],” Wei said. In patients with disease control, the median treatment duration was 16.4 weeks and the longest treatment duration time was 51 weeks in 1 patient with ovarian cancer.

In the dose-escalation phase, investigators reported 1 CR, 4 PRs, and 11 patients with stable disease. At the 40-mg dose, the overall ORR was 25.0%, and in the 

A total of 4 PI3K inhibitors have been approved by the FDA: idelalisib (Zydelig), copanlisib (Aliqopa), and duvelisib (Copiktra), all in hematologic malignancies; and alpelisib (Piqray), approved for hormone receptor–positive, HER2-negative breast cancer.

Studies involving CYH33 as monotherapy and in combination with other antitumor agents are ongoing to further explore the safety and efficacy in larger populations, concluded Wei.

Wei X-L, Liu J-H, Zhao H, et al. 33O: A phase I study to evaluate safety, pharmacokinetics (PK), and preliminary efficacy of CYH33, a phosphatidylinositol 3-kinase α (PI3Kα) inhibitor, in patients (pts) with advanced solid tumours. 

. 2021;32(suppl 1):S14. doi:10.1016/annonc/j.annonc.2021.01.048

Articles

A PI3Kα inhibitor, CYH33, demonstrated positive clinical activity in an ongoing phase 1a trial  at the European Society for Medical Oncology Targeted Anticancer Therapies Virtual Congress 2021.









Promising Efficacy, Manageable Safety Are Observed for CYH33 in Solid Tumors

Prostate-specific antigen (PSA) changes were observed 6 weeks after the administration of 

Lu-PSMA in men with metastatic castration-resistant prostate cancer (mCRPC), suggesting a prognostic value for long-term clinical benefit, according to a single center retrospective analysis presented at the Society of Nuclear Medicine and MolecularImaging 2020 Annual Meeting–Virtual Edition, held from July 11 to 14.

Lead author Andrei Gafi ta, MD, of the Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich in Germany, and colleagues wrote in their poster that the earlier response observed in this study could help clinicians decide if a change in treatment is required in the absence of a response. Further, the investigators noted that PSA responses at 6 weeks post treatment could indicate a long-term benefi t for overall survival (OS) and imaging-based progression- free survival (PFS). 

A total of 115 men had PSA levels measured at baseline, after 6 weeks of treatment, and at 12 weeks after

Lu-PSMA initiation. The percentage change from baseline at 6 and 12 weeks were categorized as a response, progression, and stable. Coprimary end points were OS and PFS. Secondary end points were PSA changes at 12 weeks and PSA flare-up, defined as an increase of at least 25% at 6 weeks followed by a decline below baseline levels at 12 weeks.

The investigators reported that median OS was 13.4 months (95% CI, 11.1-15.6) and the median PFS was 3.3 months (95% CI, 2.0-4.6). Overall, they noted that 50 patients (40%) experienced a PSA decline of greater than 30% at 6 weeks, whereas 30 patients (23%) had a PSA decline of greater than 50%. In the progression group, 3% of patients (1 of 36) had a PSA decline below baseline levels at 12 weeks, suggesting that minimal flare-up was experienced by patients.

Regarding changes to PSA, the investigators noted an association between PSA changes at 6 weeks and 12 weeks, and signifi cance between the percentage changes of those 2 time points (

 < .001). Ninety-four percent of 31 patients who exhibited progression at 6 weeks had PSA measurements at 12 weeks (

Gafita and colleagues reported that the PSA decline of 30% or greater at 6 weeks was associated with longer OS (median, 16.7 months) compared with both stable PSA (median, 11.8 months; 

 = .007) and PSA progression (median, 6.5 months; 

 < .001). PSA decline of 50% or greater at 6 weeks (median, 19.4 months) was not signifi cantly associated with longer OS compared with stable PSA (median, 12.6 months; 

 = .05), and in contrast to PSA progression (median, 6.5 months; 

The investigators observed that a PSA decline of 30% or greater at 6 weeks was associated with longer PFS (median, 7.1 months) compared with stable PSA (median, 2.0 months; 

 = .01) and PSA progression (median, 1.2 months; 

 <.001). A PSA decline of 50% or greater at 6 weeks was not statistically associated with longer PFS (median, 7.1 months) compared with stable PSA (median, 3.6 months; 

 = .30), in contrast to PSA progression (median, 1.2 months; 

The investigators reported that patients with a PSA response at 6 weeks also had a reduced risk of radiographic progression compared with those with stable PSA (HR, 0.60; 95% CI, 0.38-0.94; 

 = .02), whereas patients with PSA progression had a higher risk of radiographic progression compared with those showing stable PSA (HR, 3.18; 95% CI, 1.95-5.21; 

The investigators concluded that “PSA measurements as early as 6 weeks after 

LuPSMA initiation are associated with the clinical outcome and should be further investigated as a surrogate end point for clinical trials. Patient [treatment] decisions and…PSA flare-up during 

Gafi ta A, Heck M, Rauscher I, et al. Early prostate-specifi c antigen changes and clinical outcome following 177Lu-PSMA radionuclide treatment in patients with metastatic castration-resistant prostate cancer. 

d. 2020:61(suppl 1):591. doi:10.2967/jnumed.119.240242

Prostate-specific antigen changes were observed 6 weeks after the administration of 177Lu-PSMA in men with metastatic castration-resistant prostate cancer, suggesting a prognostic value for long-term clinical benefit, according to a single center retrospective analysis.

Early Responses Observed With Lu-PSMA Administration May Provide Prognostic Outlook in mCRPC

The HER2 receptor represents a prototypical molecular abnormality that is detectable in several common solid tumors including breast, ovarian, endometrial, colon, non–small cell lung, prostate, and cervical cancer. HER2 is an established target in breast cancer, but success in other solid tumors, remains elusive. Anti-HER2 agents in breast cancer have helped inform further development of agents in other tumor types moving forward.

 At the recent 2020 American Society of Clinical Oncology Virtual Scientific Program (2020 ASCO), key research evaluating the use of anti-HER2 agents were highlighted across multiple solid tumors, including gastric or gastroesophageal junction (GEJ) adenocarcinoma, colorectal cancer (CRC), and non–small cell lung cancer (NSCLC).

Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable linker, and a cytotoxic topoisomerase I inhibitor.

In the DESTINY-Breast01 trial (NCT03248492), which evaluated patients with HER2-positive metastatic breast cancer who had previously been treated with ado-trastuzumab emtansine (T-DM1; Kadcyla), T-DXd demonstrated strong efficacy, with an objective response rate (ORR) of 60.9% and median progression-free survival (PFS) of 16.4 months.2 These data were simultaneously published in the 

Further analysis of the DESTINY-Breast01 trial was presented during 2020 ASCO. Investigators explored the association between 15 clinical predictor variables and efficacy using logistic regression models and Cox proportional hazard models. Efficacy was demonstrated in all clinical subgroups analyzed; subgroups had ORRs ranging from 46.4% to 74.5% and PFS values ranging from 12.3 to 18.1 months, similar to the results reported for the overall cohort. Variables associated with improved efficacy included hormone receptor–positive status, fewer previous treatments, pertuzumab (Perjeta) given in the first or second line, and normal renal and hepatic function.

Additional DESTINY trials were presented during 2020 ASCO, as well as stand-alone trials with other HER2-directed therapies that are summarized herein.

Gastric cancer is proving to be an important setting for the use of anti-HER2 therapies in general and for T-DXd specifically, demonstrated by positive results from the DESTINY-Gastric01 trial (NCT03329690). Results from the primary analyses in patients with HER2-positive status were presented. HER2-positive status was determined by an immunohistochemistry (IHC) score of 3+. In cases with a borderline IHC result (score of 2+), a positive in situ hybridization (ISH) result confirming 

gene amplification could also indicate HER2-positive status.

“Chemotherapy plus trastuzumab [Herceptin] is a standard treatment for HER2-positive gastric cancer,” Kohei Shitara, MD, staff physician in the Department of Experimental Therapeutics and Gastrointestinal Oncology, National Cancer Center Hospital East, in Kashiwa, Japan, said during a recorded presentation of the poster. “However, several phase 3 studies with other HER2- targeting agents have failed to show survival benefit. Therefore, there is still an unmet need for patients with HER2-positive gastric cancer.”

This phase 2 study enrolled 187 patients with HER2-expressing advanced gastric cancer (AGC) or GEJ adenocarcinoma at 66 sites: 48 in Japan and 18 in South Korea. Patients had progressed on 2 or more prior regimens. The primary cohort was randomized to receive 6.4 mg/kg of T-DXd every 3 weeks (n = 125) or physician’s choice of chemotherapy (n = 62; irinotecan or paclitaxel). The primary end point was ORR determined by independent central review using RECIST version 1.1, and secondary end points were overall survival (OS), duration of response, PFS, disease control rate (DCR), and safety.

Shitara said the study met its primary end point, with ORR for patients treated with T-DXd (51.3%) over patients in the physician’s choice arm (14.3%; 

<.0001). Median duration of response was 11.3 months (95% CI, 5.6-not estimable) for T-DXd versus 3.9 months (95% CI, 3.0-4.9) with physician’s choice.

The investigators reported a significant improvement in median OS that favored the T-DXd arm (12.5 months) compared with 8.4 months for the physician’s choice arm (HR, 0.59; 95% CI, 0.39-0.88; 

= .0097) (TABLE 1).4 Additionally, the OS 

value crossed the prespecified boundary of .0202. OS rates at 6 and 12 months also favored T-DXd versus physician’s choice, at 80.3% versus 66.4% and 52.1% versus 28.9%, respectively.

Forty-eight percent of patients in the T-DXd arm received poststudy treatment, with 31.2% receiving a PD-1/PD-L1 inhibitor, versus 74.2% of patients in the physician’s choice arm, with 45.2% receiving a PD-1/PD-L1 inhibitor.

“Interestingly, more patients were on treatment at the time of data cutoff in the T-DXd arm than in the physician’s choice arm [22.4% vs 4.8%],” Shitara said.

Median PFS was 5.6 months (95% CI, 4.3-6.9) with T-DXd versus 3.5 months (95% CI, 2.0-4.3) with physician’s choice (HR, 0.47; 95% CI, 0.31- 0.71; 

= .0003). In subgroup analyses, ORRs also favored T-DXd and were consistent within each treatment arm across subgroups.

Regarding safety, the most common grade 3 or greater treatment-emergent adverse effects (TEAEs) were decreased neutrophil count, observed in 51.2% of patients who received T-DXd and 24.2% of patients who received physician’s choice, followed by anemia (37.6% vs 22.6%), decreased white blood cell count (20.8% vs 11.3%), and decreased appetite (16.8% vs 12.9%). Among patients in the T-DXd arm, 9.6% developed interstitial lung disease (ILD)/pneumonitis, with a median time to onset of 84.5 days (range, 36-638 days). Most cases were grade 1 or 2 in severity, although there were 2 patients with grade 3 and 1 patient with grade 4.

“In summary, T-DXd demonstrated statistically significant and clinically meaningful improvements in objective response rate and overall survival compared with the standard chemotherapy in patients with HER2-positive gastric cancer, with separation [of the Kaplan-Meier curves] and [with] intestinal lung disease as notable toxicity,” Shitara said. “Based on these findings, T-DXd may be an effective treatment option for patients with advanced HER2-positive gastric/GEJ adenocarcinoma who have progressed after trastuzumab.”

Further research in the gastric setting is examining combination therapies. The following phase 1 and 2 trials often combine anti-HER2 agents with immunotherapies.

Significant tumor shrinkage was observed in the phase 1b/2 PANTHERA trial (NCT02901301) of the triplet combination of pembrolizumab (Keytruda), trastuzumab, and chemotherapy as first-line therapy for HER2-positive AGC.

Investigators from Yonsei Cancer Center of Yonsei University College of Medicine in Seoul, South Korea, reported tumor shrinkage of 95.3%, a median depth of response of 54.6%, and an ORR of 76.7% (TABLE 2).5 Further analysis revealed that the ORR consisted of 16.3% complete responses (CRs) and 60.5% partial responses (PRs), and the DCR was 97.7%. Median PFS was 8.6 months (95% CI, 7.2-22.0), and median OS was 18.4 months (95% CI, 17.9-not available).

Results of the open-label, phase 1b Ni-HIGH study to determine the safety and tolerability of adding an anti–PD-1 antibody to trastuzumab in patients with HER2-positive AGC were also presented at 2020 ASCO. The trial consisted of a safety portion and an expansion portion.

 Eligible patients had histopathologically confirmed HER2-positive AGC and measurable lesions.

In the safety portion, patients were randomized to receive nivolumab (Opdivo; 360 mg), trastuzumab (course 1, 8 mg/kg; course ≥2, 6 mg/kg), and oxaliplatin (130 mg/m2) once every 3 weeks plus either S-1 (a prodrug of 5-fluorouracil at 40 mg/m2 twice per day) or capecitabine (1000 mg/m2 twice per day) for 14 days of every 3-week cycle until disease progression or unacceptable toxicity.

Both the S-1– and capecitabine-containing regimens were shown to be well tolerated. The investigators reported that this ongoing study demonstrates favorable efficacy for these combinations.

Another trial evaluated pembrolizumab with trastuzumab, fluoropyrimidine, and platinum chemotherapy in HER2-positive metastatic esophagogastric cancer using plasma and tumor-based biomarker analysis.

The objectives were to evaluate circulating tumor DNA (ctDNA) as a possible early predictor of therapeutic response and resistance and to identify genomic mutations leading to resistance. Tumor biopsies and serial blood samples were collected from patients. To be eligible for this first-line regimen, patients had to have a diagnosis of stage IV, HER2-positive metastatic esophagogastric cancer.

Tumor-matched ctDNA was detected at baseline in 84% of patients. Median PFS was longer in patients who cleared ctDNA at 9 weeks (12.3 months; 95% CI, 7.44-not available) than in those who did not (3.9 months; 95% CI, 2.01-not available). Activating 

alterations were found in 10 patients upon progression.

Loss of HER2 overexpression/amplification was noted in 44% of patients with postprogression samples, as determined by IHC or fluorescence ISH. The reappearance of ctDNA preceded radiographic progression in 56% of patients with serial ctDNA. The investigators concluded that reappearance of ctDNA may serve as an early predictor of progression.

The open-label, phase 2 DESTINY-CRC01 study (NCT03384940) evaluated T-DXd in patients with HER2-expressing, unresectable, and/or metastatic CRC. Eligible patients had progressed on 2 or more lines of therapy and had wild-type 

“Importantly, patients who received prior anti-HER2 therapies were allowed to enroll, [whereas] patients with a history of or suspected interstitial lung disease were excluded,” lead investigator Salvatore Siena, MD, a professor of medical oncology at Università degli Studi di Milano in Italy, said during a recorded presentation of the data.

Three cohorts were evaluated. Cohort A comprised 53 patients with HER2-positive tumors, defined as IHC 3+ or IHC 2+/ISH positive. Siena said that futility monitoring was conducted after at least 20 patients in cohort A had undergone 12 weeks of follow-up to inform the opening of cohorts B and C, which both had low HER2 expression. Cohort B comprised 7 patients whose tumors were HER2 IHC 2+ and ISH negative. Cohort C contained 18 patients who had HER2 IHC 1+ tumors.

The primary end point was confirmed ORR by independent central review in cohort A. In the overall study population, the median age was 58.5 years. The median sum of target lesions was 8.4 cm in cohort A and 8.8 cm for all patients. The primary tumor site was the left intestine in almost 90% of patients, both in cohort A (88.7%) and in the overall study population (89.7%). About 80% of patients had microsatellite-stable tumors; the remainder had unknown status.

Regarding previous treatments, 100% of patients in cohort A had received either panitumumab (Vectibix) or cetuximab (Erbitux), which are both anti-EGFR antibodies. About 30% of patients in cohort A had received anti-HER2 agents, such as pertuzumab, trastuzumab, T-DM1, lapatinib (Tykerb), or tucatinib (Tukysa).

The ORR in cohort A was 45.3% (24 of 53 patients) and consisted of 1 CR and 23 PRs. An additional 20 patients in cohort A had stable disease, resulting in a DCR of 83%.

“Interestingly, median duration of response was not reached,” Siena said. “There were no confirmed responses in cohorts B and C.”

The median treatment duration was 4.8 months (range, 1-11) in cohort A and 3.5 months (range, 1-11) in all patients.

Drug-related TEAEs of grade 3 or higher occurred in 50.9% of patients in cohort A and 48.7% of all patients. Serious drug-related TEAEs were reported in 22.6% of patients in cohort A and 17.9% of all patients. There were 2 deaths related to the study drug, including 1 death of pneumonitis and 1 caused by ILD; both occurred in cohort A.

“[ILD] was an adverse effect of special interest,” Siena said. “Among 78 patients treated with T-DXd, ILD occurred in 5 patients, with a median time to onset of 80 days, ranging from 22 to 132 days.” He added that ILD is an important risk that requires careful monitoring and proper intervention.

Interim results of DESTINY-Lung01 (NCT03505710) revealed a high response rate that was durable in 42 patients with 

- mutated NSCLC who were treated with T-DXd.9 Findings were presented in a prerecording by Egbert Smit, MD, PhD, professor of pulmonary medicine (pulmonary oncology) at the Netherlands Cancer Institute and in the Department of Pulmonary Diseases of Vrije Universiteit Medical Centre in Amsterdam, the Netherlands.

Eligible patients had unresectable, metastatic NSCLC that was relapsed or refractory to standard treatments. The primary end point was confirmed ORR by independent central review.

Cohort 1 enrolled patients with HER2-expressing tumors, defined as IHC 2+ or 3+. Cohort 2 consisted of patients whose tumors harbored an activating 

mutation. All patients were treated with T-DXd (6.4 mg/kg) every 3 weeks. The authors presented results for cohort 2 in this report.

The median age of patients at baseline was 63.0 years, and the majority (64.3%) were women. ECOG performance status was 0 (23.8%) or 1 (76.2%). Central nervous system metastases were present in 45.2%. Median prior lines of treatment was 2 and included platinum-based therapy (90.5%), a PD-1/PD-L1 inhibitor (54.8%), and docetaxel (19.0%).

The investigators reported that 45.2% of patients in cohort 2 remained on treatment at the data cutoff in November 2019. The other 54.8% discontinued treatment, with the primary reasons being progressive disease (21.4%) and adverse events (AEs; 21.4%).

The confirmed ORR by independent review was 61.9% (95% CI, 45.6%-76.4%). One patient (2.4%) had a CR, 59% had PRs, and 28.6% had stable disease as their best outcome.

Median PFS was 14.0 months (95% CI, 6.4- 14.0), and median OS was not reached (95% CI, 11.8-not evaluable).

- mutated NSCLC was generally consistent with what was previously reported, said Smit. Low-grade gastrointestinal and hematological AEs were most commonly observed. TEAEs that occurred in more than 15% of patients were mainly nausea, alopecia, anemia, decreased appetite, decreased neutrophil count, and vomiting. The majority of the TEAEs were either grade 1 or 2.

“Of note, the median duration of exposure of patients to the study drug was 7.8 months,” Smit said. The most common TEAEs associated with dose reduction were fatigue and nausea. The most common TEAEs associated with dose interruption were decreased neutrophil count and lung infection. Five patients with TEAEs died, but investigators noted that none of the deaths were considered to be related to the treatment.

“In this analysis, there were 5 patients [who] experienced grade 2 interstitial lung disease, but there were no patients [who] had interstitial lung disease of higher grades,” said Smit.

“However, ILD remains an important identified risk for patients treated with T-DXd and requires careful monitoring and management,” Smit said. “The study was expanded with an additional 50 patients to better characterize the risk-benefit ratio of T-DXd in patients with 

-mutated non–small cell lung cancer,” Smit concluded.

1. Wang J, Xu B. Targeted therapeutic options and future perspectives for HER2-positive breast cancer. 

. 2019;4:34. doi:10.1038/s41392-019-0069-2

2. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. 

. 2020;382(7):610‐621. doi:10.1056/NEJMoa1914510

3. Modi S, Andre F, Krop IE. Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis. 

38: 2020 (suppl 15):1036. doi:10.1200/JCO.2020.38.15_suppl.1036

4. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS- 8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: a randomized, phase II, multicenter, open-label study (DESTINY-Gastric01). 

. 2020;38: (suppl 15): 4513. doi:10.1200/JCO.2020.38.15_suppl.4513

5. Rha SY, Lee CK, Kim HS, et al. Targeting HER2 in combination with anti-PD-1 and chemotherapy confers a significant tumor shrinkage of gastric cancer: A multi-institutional phase Ib/II trial of first-line triplet regimen (pembrolizumab, trastuzumab, chemotherapy) for HER2-positive advanced gastric cancer (AGC). 

2020;38(suppl 15):3081. doi:10.1200/ JCO.2020.38.15_suppl.3081

6. Takahari D, Shoji H, Minashi K, et al. A phase Ib study of nivolumab plus trastuzumab with S-1/capecitabine plus oxaliplatin for HER2-positive advanced gastric cancer (Ni-HIGH study): safety evaluation. 

2020;38(suppl 15):4525. doi:10.1200/JCO.2020.38.15_suppl.4525

7. Maron SB, Chatila WK, Millang BM, et al. Pembrolizumab with trastuzumab and chemotherapy (PTC) in HER2-positive metastatic esophagogastric cancer (mEG): plasma and tumor-based biomarker analysis. 

38;2020(suppl 15):4559. doi:10.1200/JCO.2020.38.15_suppl.4559

8. Siena S, Di Bartolomeo M, Raghav KPS, et al. A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01. 

2020;38(suppl 15):4000. doi:10.1200/ JCO.2020.38.15_suppl.4000

9. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. 

2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504

At the recent 2020 American Society of Clinical Oncology Virtual Scientific Program, key research evaluating the use of anti-HER2 agents were highlighted across multiple solid tumors, including gastric or gastroesophageal junction adenocarcinoma, colorectal cancer, and non–small cell lung cancer.

Anti-HER2 Agents Explored Further in Gastric, Colorectal, and NSCLC Settings

New guidelines issued jointly by the American Urological Association (AUA), American Society for Radiation Oncology (ASTRO), and Society of Urologic Oncology (SUO) focus on men withadvanced stage disease and now include new treatments, including the use of PARP inhibitors in the metastatic castration-resistant (mCRCP) setting. The guidelines were co-presented by William T. Lowrance, MD, MPH, and Michael S. Cookson, MD, MMHC, during the 2020 American Urological Association Virtual Experience.

“Men with advanced prostate cancer have exhausted local therapies and are now moving on to systemic options,” said Lowrance, who is an associate professor in the Division of Urology at the University of Utah School of Medicine and an investigator at the Huntsman Cancer Institute. “Specifically, these guidelines focus on men who experience biochemical recurrence, metastatic hormone-sensitive prostate cancer [mHSPC], non-metastatic castration-resistant prostate cancer [nmCRPC], or metastatic castration-resistant prostate cancer.”

The guidelines panel, made up of members from the 3 organizations, emphasized important principles in the early evaluation and counseling for these patients.

“In patients with suspicion of advanced prostate cancer and no prior histologic confirmation, clinicians should obtain a tissue diagnosis from the primary tumor or metastatic site,” Lowrance said. The guidelines recommend that counseling for patients with advanced prostate cancer should be based on the life expectancy, comorbidities, patient treatment preferences, and tumor characteristics. In addition, pain control and palliative care should be offered whenever possible.

In men who experience biochemical recurrence without metastatic disease, prostate-specific antigen (PSA) recurrence almost always precedes clinical detection of metastasis, Lowrance said. Therefore, clinicians should perform serial PSA measurements, clinical evaluation, and staging evaluations using standard-of-care imaging, including bone scans.

“Clinicians may use novel PET-CT scans in patients with PSA recurrence after failure of local therapy as an alternative to conventional imaging or in the setting of negative conventional imaging,” Lowrance said.

In this setting, a rising PSA after failure of local therapy and no metastatic disease demonstrated by conventional imaging, clinicians should offer observation or enrollment on to a clinical trial. Androgen deprivation therapy (ADT) should not be routinely initiated in this population. If ADT is initiated in the absence of metastatic disease, intermittent therapy may be offered in lieu of a continuous schedule.

In the setting of mHSPC, the guidelines recommend that patients receive genetic counseling and germline testing, regardless of age and family history. For treatment, the guidelines recommend that clinicians offer either chemotherapy (docetaxel) or continued ADT in combination with androgen pathway–directed therapy, including abiraterone plus prednisone, apalutamide (Erleada), or enzalutamide. The panel gave this treatment option a strong recommendation, with grade A evidence level data to support it. Another treatment option, but with a grade B evidence level, is to offer ADT with either luteinizing hormone–releasing hormone (LHRH) agonists or antagonists or surgical castration.

Evidence for these recommendations were based on findings from the CHAARTED (NCT00309985), STAMPEDE (NCT00268476), LATITUDE (NCT01715285), TITAN (NCT02489318), ARCHES (NCT02677896), and ENZAMET (NCT02446405) studies (

Recommendations in the Non-Metastatic Setting

Until recently, there were no agents available to treat men with nmCRPC, said Cookson, professor and chairman of the Department of Urology at the University of Oklahoma College of Medicine in Oklahoma City. Based on a new end point, metastases-free survival (MFS), 3 new androgen receptor antagonists—apalutamide, enzalutamide, darolutamide (Nubeqa)—have gained FDA approval based on phase 3 clinical trials SPARTAN (NCT01946204), PROSPER (NCT02003924), and ARAMIS (NCT02200614), respectively.

“Importantly, all men in this nonmetastatic CRPC group were at high risk for developing metastatic disease, with PSA doubling times of less than 10 months,” Cookson said. He also noted that the PROSPER study, whose survival data was subsequently published after the guidelines were finalized, demonstrated the benefit of enzalutamide in nmCRPC, with an overall survival of 67 months and a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.61-0.89; 

In the mCRPC setting, the use of a PARP inhibitor for men with metastatic castration-resistant prostate cancer (mCRPC) who have a deleterious or suspected deleterious germline or somatic homologous recombination repair mutation following prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga), and/or a taxane-based chemotherapy (docetaxel) is now recommended. The recommendation has the potential to benefit nearly 20% of patients with mCRPC. It is estimated that 23% of these prostate cancer tumors harbor alterations to DNA damage response and repair (DDR) genes, with 8% having DDR germline mutations.

In the mCRPC setting, Cookson noted that DNA repair gene alterations are common and that among DDR alterations, 

 genes were the most frequently altered (12.7%).

Cookson spoke about data from the phase 3 PROfound trial that looked at men with mCRPC and homologous recombination repair mutations who had previously failed enzalutamide, abiraterone, or docetaxel-based chemotherapy.. Enzalutamide, abiraterone, or docetaxel-based chemotherapy had failed in these patients.

 The investigators observed a median PFS of 7.4 months in those who were treated with olaparib (Lynparza) versus 3.6 months for the control of physician’s choice or enzalutamide or abiraterone. Results from the trial led to the approval of olaparib for adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone.

 Cookson said rucaparib (Rubraca) is also approved following ADT and chemotherapy.

In patients who cannot use a PARP inhibitor, platinum-based chemotherapy may be offered, according to the guidelines. Further, in patients with mCRPC whose tumors have mismatch repair–deficient or microsatellite instability–high status, clinicians should offer pembrolizumab (Keytruda).

These guidelines are a welcome addition as prostate cancer is the most commonly diagnosed solid tumor malignancy in men in the United States and remains the second leading cause of cancer deaths for this population, said Lowrance.

1. Lowrance W, Breau R, Chou R, et al. Advanced prostate cancer: AUA/ASTRO/SUO guideline. Accessed June 26, 2020. 

https://www.auanet.org/guidelines/advanced-prostate-cancer

2. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. 

. 2018;36(11):1080-1087. doi:10.1200/JCO.2017.75.3657

3. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. 

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4. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. 

. 2017;377(4):352-360. doi:10.1056/NEJMoa1704174

5. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. 

. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307

6. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase iii study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. 

. 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799

7. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. 

. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835

8. FDA approves apalutamide for non-metastatic castration-resistant prostate cancer. News release. FDA. February 14, 2018. Accessed June 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-apalutamide-non-metastatic-castration-resistant-prostate-cancer

9. FDA approves enzalutamide for castration-resistant prostate cancer. News release. FDA. July 13, 2018. Accessed June 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-castration-resistant-prostate-cancer

10.FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. News release. FDA. July 30, 2019. Accessed June 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer

11. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. 

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13. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. 

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14. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. News release. FDA. May 19, 2020. Accessed June 28, 2020. 

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer

15. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. News release. FDA. May 15, 2020. Accessed June 28, 2020. 

https://www.fda.gov/drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate

"Men with advanced prostate cancer have exhausted local therapies and are now moving on to systemic options."

Tony Berberabe | Authors

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