Always leave 'em wanting more. That's a good approach for first dates and show biz, but maybe not the best for drug development. Relay Therapeutics doesn't care.

Instead, the protein motion pioneer is once again following its internal model-informed drug development (MIDD) analytics, optics be damned. This is not the same linear process of drug development investors are accustomed to. Similar to the ol' dosing switcheroo for the pivotal ReDiscover-2 study in later-line patients (2L+), the company is making another switch just before its first planned pivotal study in earlier-line patients (1L).

Whereas the April 2026 zovegalisib triplet data readout included fulvestrant, the company wants to switch that out for an aromatase inhibitor. It has never publicly shared data for an agent in that class. Nor does Relay Therapeutics have data in actual 1L patients, as the recent data readout evaluated triplets in 3L patients – the most advanced patient population for a zovegalisib data readout to date.

In other words, investors will see no data for the first zovegalisib triplet with an aromatase inhibitor in the 1L setting until the planned pivotal study wraps up in 2031. How strong is your conviction in the company's approach – and how do you know if you're just wishing for a specific outcome because you own a position?

Investors can find comfort knowing the data are relatively strong, the science is sound, and the commercial strategy is rock solid. It's important that all three are in agreement, which is often overlooked in biotech investing. Sound science doesn't always lead to favorable data. Good data without sound science creates uncertainty, while failing to optimize the commercial opportunity can sink previously strong data or even the best science.

Although the proposed pivotal study design is aggressive – once again going head-to-head against the standard of care (all three simultaneously, actually) – it throws elbows within a competitive landscape that suddenly finds itself years behind what appears to be a homerun combination of zovegalisib plus atirmociclib.

Zovegalisib Triplet Optimization, Explained

Before we jump into the data, competitive landscape, or commercial opportunity, let's straighten out a few likely points of confusion.

Patient populations

As described in the March 2026 research note, Relay Therapeutics is using the phase 1/2 ReDiscover study as a real-world sandbox for zovegalisib. The study was used to optimize dosing for zovegalisib doublets in later-line patient populations (2L+) ahead of the pivotal ReDiscover-2 study.

It is also being used to optimize dosing for zovegalisib triplets intended for use in multiple first-line patient populations (1L). Investors will get updated data from this sandbox study for multiple zovegalisib triplets in late 2026 and beyond.

However, most patients enrolled in the phase 1/2 ReDiscover study are more advanced than the intended patient population. The April 2026 data readout tested a zovegalisib triplet in 62 patients, including 3% who were 1L, 45% who were 2L, 31% who were 3L, and 21% who were 4L or later.

That means the median patient for this initial zovegalisib triplet was receiving her 3L of treatment. By contrast, the median patient in zovegalisib doublet data readouts to date received her 2L of treatment. What… the hell is the point of that?

First, it's simply easier to enroll later-line patients in non-pivotal clinical trials. Earlier-line patients have better prognosis and outlooks, which makes them less likely to roll the dice on experimental therapies. Second, the study was already established with geographically-distributed trial sites, so it was quicker to acquire data.

Third and perhaps most importantly, HR+/HER2- breast cancer is relatively common, well understood, and has a well-established commercial landscape. That minimizes uncertainty. Relay Therapeutics is simply trying to solve the existing problems everyone knows exist but haven't had molecules selective enough to address.

Optimizing dosing for triplets

The recent data readout was for a triple-combination of:

• zovegalisib (pan-mutant PI3K-alpha inhibitor)
• atirmociclib (CDK4 inhibitor)
• fulvestrant (selective estrogen receptor degrader)

The company used fixed doses of fulvestrant, but evaluated three different twice-daily doses of each zovegalisib (100 mg, 150 mg, and 200 mg) and atirmociclib (100 mg, 200 mg, and 300 mg).

As a CDK4 inhibitor, atirmociclib inhibits specific parts of the cell growth cycle. Slower cell growth means fewer cells to target, which means atirmociclib increases the exposure of zovegalisib by almost 150% compared to doublets with fulvestrant alone. So, a lower dose of zovegalisib goes further, with better tolerability to boot.

This is also why fulvestrant was used for the initial dosing optimization – it kept one variable constant. The company has a meaningful volume of data for zovegalisib doublets that include fulvestrant, so optimizing triplet doses was easier if at least one of the variables (using fulvestrant) was held constant. Now that it better understands how zovegalisib and atirmociclib behave in combination, it can more quickly evaluate other agents in future triplets.

Relay Therapeutics intends to proceed with 150 mg of zovegalisib and 300 mg of atirmociclib, each taken twice-daily with food, for its first planned pivotal study in a CDKi-naïve patient population. The initial triplet will not use fulvestrant…

Optimizing endocrine therapy

I haven't spilled much ink dissecting the 1L commercial opportunity because there weren't any data. That made it easier to just mention fulvestrant in the zovegalisib doublets for 2L+ populations and keep moving, but that won't work anymore.

Remember that in HR+/HER2- breast cancer, the "HR+" means "hormone receptor positive". Breast cancer primarily impacts women, which means the hormone receptor is for estrogen. Estrogen receptors sit on the surface of cells and capture estrogen floating around in the blood, like a lock and key. When breast tumors are driven by the hormone estrogen, doctors attempt to disrupt their growth with endocrine therapy (ET).

There are two primary types of ET for this tumor type:

• Selective estrogen receptor degraders (SERD) such as fulvestrant chew up the estrogen receptors on the surface of cells, but don't impact estrogen production.
• Aromatase inhibitors (AI) such as anastrozole or letrozole stop the production of estrogen, but leave estrogen receptors intact.

More advanced HR+/HER2- breast cancer tumors tend to be treated with SERDs like fulvestrant, whereas less advanced tumors tend to be treated with aromatase inhibitors. The dividing line actually occurs within the 1L patient population.

• Roughly 60% of 1L patients are considered endocrine sensitive, which means their tumors progressed more than 12 months since receiving endocrine therapy. Their tumors are considered less advanced and they generally have a better prognosis. These individuals typically receive an aromatase inhibitor.
• Roughly 40% of 1L patients are considered endocrine resistant, which means their tumors progressed less than 12 months since receiving endocrine therapy. Their tumors are considered more advanced and they generally have a slightly worse prognosis. These individuals typically receive a SERD.

That means roughly 40% of 1L patients and all 2L+ patients receive a SERD like fulvestrant as part of their treatment plan. The initial development plan focused on the more advanced patient population, which is why data readouts to date have included zovegalisib doublets with fulvestrant.

That leaves roughly 60% of 1L patients who are endocrine sensitive and receive an aromatase inhibitor.

Relay Therapeutics has decided to initially focus on the endocrine sensitive patient population for its first zovegalisib triplet. That means the triplet will include zovegalisib, atirmociclib, and an aromatase inhibitor. Remember, there aren't any data for such a triplet yet, although investors can expect a future data readout from the phase 1/2 ReDiscover study (the "sandbox study") for a cohort of patients receiving the recommended phase 3 dose (RP3D). It's enrolling now, but won't include many 1L patients.

Importantly, Roche's Itovebi is currently approved in the endocrine resistant 1L setting.

The Zovegalisib Triplet Data Readout, Explained

Keep in mind this is a preliminary data readout. It includes a low number of patients, treated for a short period of time, and multiple dosing combinations of each zovegalisib and atirmociclib. The next data readout for this zovegalisib triplet will include fixed doses of all three components, including an aromatase inhibitor.

Demographics

Relay Therapeutics has done a great job matching enrollment in the phase 1/2 ReDiscover study to the real-world patient population, which increases confidence in how well the data will translate to future pivotal studies. This is one of those small, nerdy details that increases conviction in the investment thesis, but is often lost on analysts or investors.

Most precommercial drug developers let enrollment happen. Relay Therapeutics makes it happen by setting strict inclusion criteria and randomization procedures.

The April 2026 data readout included 62 patients. The PI3K-alpha mutation hotspot, prediabetic population, and ESR1 mutation status almost exactly matched the real-world prevalence of HR+/HER2- breast cancer tumors.

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Tolerability profile

Relay Therapeutics continues to execute on its vision of using protein motion to develop more selective molecules capable of fully realizing established commercial opportunities. The HR+/HER2- breast cancer landscape is well characterized and well developed. Yet, despite clear evidence and clinical data demonstrating PI3K-alpha inhibitors could change the treatment paradigm, past development attempts have been stunted by poor tolerability.

This triplet is the first to include two next-gen molecules – and it appears to be a homerun.

Zovegalisib has demonstrated lower rates of hyperglycemia and off-target side effects compared to prior-generation PI3K pathway inhibitors, while the CDK4-selective atirmociclib has demonstrated lower rates of blood toxicities and diarrhea compared to CDK4/6 inhibitors.

Importantly, atirmociclib increases the exposure of zovegalisib, which allows a lower dose of zovegalisib to get the same results, which resulted in a significantly improved tolerability profile relative to the molecule's known side effects.

• Hyperglycemia (+): Only 23% of patients experienced any grade of hyperglycemia. There were zero cases of Grade 3+ hyperglycemia. By comparison, the zovegalisib doublet with fulvestrant triggered hyperglycemia in 43% of patients, including 8% Grade 3 cases.
• Diarrhea (+): Taking zovegalisib with food significantly increased the rate of diarrhea compared to a fasted state. That could've sunk combinations with CDK inhibitors, which also trigger high rates of diarrhea. However, a lower-dose of zovegalisib and the selectivity of atirmociclib led to a manageable profile in combination – a great development.
• Rash (-): The one blemish for the combination of zovegalisib and atirmociclib is a relatively higher rate of skin rashes. These are known side effects from inhibiting the PI3K (although it's an off-target toxicity for alpha) and CDK pathways.
• CDKi-specific: Investors will notice some new side effects with the introduction of atirmociclib, namely mucking up white blood cells and hair loss.

At least at this preliminary checkpoint, this zovegalisib triplet had a lower rate of toxicity-related discontinuations (3%) compared to the zovegalisib doublet with fulvestrant (7%). Both lead the competitive landscape.

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The CDK inhibitor class has relatively high rates of Grade 3+ toxicities, especially disruptions to white blood cells and diarrhea. The former are measured through neutropenia, the reduction of neutrophils (a type of white blood cell), and the general reduction in total white blood cell count.

These three side effects have been the primary limitation of using CDK4/6 inhibitors at any stage of treatment for HR+/HER2- breast cancer. Add a less selective PI3K pathway inhibitor to the mix and the tolerability profile quickly becomes unworkable.

Relay Therapeutics appears to have proven that a selective pan-mutant PI3K-alpha inhibitor combined with a selective CDK4 inhibitor is a viable path forward.

Roche explored triplets using its PI3K-alpha inhibitor Itovebi (inavolasib) and fulvestrant in the 2L+ population, allowing doctors to choose any of the three leading CDK4/6 inhibitors. The rate of Grade 3+ adverse events was 68% with Novartis' Kisqali and 92% with Eli Lilly's Verzenio. The recent zovegalisib triplet was just 40% at the preliminary checkpoint.

That's also lower than approved 1L doublets from Novartis and Eli Lilly, as well as Roche's Itovebi triplet in the 1L endocrine resistant population.

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Efficacy

Relay Therapeutics is executing a relatively simple development strategy across its pipeline: More selective molecules lead to improved tolerability leads to improved efficacy.

The April 2026 data readout included 34 evaluable patients. At this preliminary checkpoint, the zovegalisib triplet demonstrated an objective response rate (ORR) of 44%. The ORR was identical in kinase mutants (44%, 8/18) and helical mutants (44%, 7/16).

That's already better than Roche's exploratory triplets with Itovebi and CDK4/6 inhibitors. It's also on par with approved 1L regimens from Novartis (doublet), Eli Lilly (doublet), and Itovebi (triplet).

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Early signals also support the homerun potential of zovegalisib plus atirmociclib.

• Complete responses: There was one unconfirmed complete response (CR), meaning the patient's tumors were undetectable at a recent follow up. That's incredible for a 3L+ patient. This specific patient had also previously been treated with a PI3K pathway inhibitor. A second patient also had tumor reductions of 100%, but was classified as a partial response (PR) at the data cutoff. This patient may be upgraded to a CR at the next data readout.
• How does CRR compare?: In Roche's pivotal study evaluating the Itovebi triplet in 1L endocrine resistant patients, 4.3% (7/161) patients experienced a CR. None of these patients had previously received a CDKi, let alone multiple other treatments beyond an aromatase inhibitor. The super early CR rate (CRR) for the initial zovegalisib triplet might be 5.9% (2/34) in a much more heavily-treated population with one-third of the median follow up (7.3 months vs. 21.3 months).
• ORR potential: The ORR from this initial set of patients is likely to increase. At the data cutoff, 8 patients remained on treatment who had tumor reductions that didn't qualify as a PR. That means the ORR could be as high as 68% (23/34) in these 3L patients. Obviously, not all will respond. This is the ceiling. But the ORR in the 1L setting with an optimized RP3D and longer duration of treatment could exceed 70%.
• How does ORR compare?: When Roche let its pivotal study persist to collect overall survival (OS) data, the ORR for the Itovebi triplet increased from 58% to 63%.

The April 2026 data readout had a median follow up of just 7.4 months. This is an important detail.

The earlier the treatment setting (adjuvant > 1L > 2L > 3L+) the longer the duration of treatment (DoT). In other words, 7.4 months is further from the expected median DoT in the 1L setting than the 2L+ setting. There's some statistical fog for these specific data in 3L patients, but we can expect very long DoT in earlier treatment lines. That means longer mPFS and OS compared to later treatment lines.

It also means pivotal studies in the 1L setting will take at least 18 additional months to generate data compared to, say, the pivotal ReDiscover-2 study in the 2L+ patient population. Circle your calendars for 2031.

What Happens Next?

These preliminary data provide important signals for the evolving standard of care, competitive landscape, and commercial strategies.

Planned pivotal study

Relay Therapeutics will announce future data readouts from zovegalisib triplets at the RP3D generated from the phase 1/2 ReDiscover study. That includes triplets that include an aromatase inhibitor or fulvestrant. Investors can expect a more mature data profile, although reporting data from an aromatase inhibitor in 2L+ patients may backfire as tumors may already be resistant.

The drug developer intends to conduct a pivotal study in the 1L endocrine sensitive patient population, meaning tumors that have only been exposed to adjuvant treatment at most.

• The triplet of zovegalisib, atirmociclib, and an aromatase inhibitor will be compared to a doublet of a CDK4/6 inhibitor (doctor's choice) and an aromatase inhibitor. These doublets are the current standard of care in the 1L endocrine sensitive setting.
• The proposed primary endpoint is mPFS. The proposed key secondary endpoint is OS.
• Patients will be randomized one-to-one (1:1) in either arm.
• The pivotal study could enroll patients as soon as early 2027.

Regulators get a say in the proposed study design.

Adjuvant setting in an evolving treatment landscape

Although the April 2026 data readout is part of the company's development plans in the 1L setting, there's an even earlier setting called adjuvant treatment. These are patients who have successfully had surgery or responded to chemotherapy, but receive maintenance (adjuvant) therapy to reduce the risk of recurrence.

If a patient's tumor progresses on or after adjuvant treatment, then they advance to a 1L treatment.

Relay Therapeutics' strategic decision to initially focus on the endocrine sensitive 1L setting moves it closer to one day evaluating zovegalisib as a potential adjuvant therapy. This is an important detail for the long-term investment thesis.

• AI ready: Adjuvant treatment typically includes an aromatase inhibitor. By including an aromatase inhibitor in the initial zovegalisib triplet, Relay Therapeutics will have more data to optimize a future pivotal study in the adjuvant setting.
• Largest patient population: The adjuvant commercial opportunity is by far the largest, representing more total patients than the 1L and 2L patient populations combined.
• Longest duration of treatment: Adjuvant treatment has a much longer duration, on average, than the 1L or 2L setting. That means adjuvant treatments can generate significantly more revenue per patient.
• Evolving landscape: Adjuvant treatment increasingly includes a CDK4/6 inhibitor. That means the term "CDKi-naïve" isn't exactly the same thing as "1L treatment setting", and will become outdated or sloppy over time. However, the company's development strategy – including the April 2026 data readout in median 3L patients for zovegalisib triplets – means it has a deeper understanding of how patients previously treated with a CDK inhibitor will respond to its next-generation triplets. That's very valuable.

Relay Therapeutics estimated the U.S. total addressable market (TAM) opportunity for the 1L setting is at least $7 billion and the 2L setting is at least $2 billion. That suggests the U.S. TAM for the adjuvant setting is well over $10 billion alone. (Vascular anomalies is at least $6 billion on the same basis.)

There's a very long way to go, but zovegalisib has the potential to be one of the bestselling drugs on the planet and perhaps of all-time. You don't get many opportunities to own one of those at a valuation of less than $3 billion.

Multiple triplets are in development

Relay Therapeutics is being smart and managing its limited resources. Although it's initially focusing on the 1L endocrine sensitive patient population, that's not where development ends.

A separate triplet is being optimized that includes fulvestrant as the endocrine therapy, which could be evaluated in a third pivotal study (or added to the second pivotal study) in the 1L endocrine resistant patient population. Investors can likely expect triplets to be explored in 2L+ treatment settings, too. The latter might eventually replace the zovegalisib doublet with fulvestrant now being evaluated in the pivotal ReDiscover-2 study.

Arms race cometh

The market may not realize it yet, but Relay Therapeutics just triggered another arms race.

It was the first scientific team to solve the full-length structure of the wild-type PI3K-alpha protein and its mutants, which kicked off the first arms race for pan-mutant PI3K-alpha inhibitors aimed at a novel allosteric binding pocket. That has led to at least two $2 billion acquisitions of molecules (not companies).

The next arms race will be for next-generation CDK inhibitors, beginning with CDK4 and likely eventually progressing to CDK2 inhibitors.

• The value of a CDK4 inhibitor is an improved tolerability profile compared to prior-gen CDK4/6 inhibitors.
• The value of a CDK2 inhibitor is the potential to reverse resistance mechanisms tumors develop after prolonged treatment with CDK4/6 and likely CDK4 inhibitors. These might become increasingly important if CDK4 inhibitors become embedded in the adjuvant and 1L treatment settings.

Relay Therapeutics advanced an internal CDK2 inhibitor, RLY-2139, which was ready to begin clinical trials. The asset is not currently listed in pipeline graphics or mentioned in recent SEC filings, but it could be resurrected depending on learnings from optimization cohorts and the evolving competitive landscape.

It may also just decide to cozy up to Pfizer, which wields a robust stack of breast cancer drug candidates – except a PI3K-alpha inhibitor.

Deepening relationship with Pfizer

The initial zovegalisib triplet data readout likely increases pressure on Pfizer to make a deeper commitment to Relay Therapeutics.

The large pharma owns drug candidates spanning the CDK4 inhibitor atirmociclib, the CDK2 inhibitor tegtociclib, the KAT6 inhibitor prifetrastat, and the next-gen KAT6/7 inhibitor PF-08032560; as well as the approved HER2+ inhibitor Tukysa. All assets have potential in breast cancers. There are other CDK4 and CDK2 inhibitors in development across the industry. The protein motion pioneer might find big bags of cash from Pfizer as a great option to remain independent and retain exclusive rights to zovegalisib, or might spread its bets across external assets.

News Flow & Modeling Insights

I need more time to add the 1L endocrine sensitive opportunity to the current model, but didn't want to delay this research note any longer.

Margin of Safety & Conviction

(No change.)

Relay Therapeutics is considered a Future Compounder position with the following Conviction rating.

• 1 = High
• 2 = Above Average
• 3 = Average
• 4 = Below Average

The estimated fair valuation based on my current model is below:

• Market close May 1: $12.72 per share
• Modeled Fair Valuation: $17.68 per share

Relay Therapeutics reported 178.725 million shares outstanding as of February 20, 2026. The modeled fair valuation above assumes 237.5 million shares outstanding, which prices in full dilution through the initial launch of zovegalisib in 2L+ treatment settings.

Further Reading

• March 2026 press release analyzing the data readout for the RP3D of the zovegalisib doublet with fulvestrant
• February 2026 regulatory filing (10-K) detailing Q4 2026 operating results